@article{pmid12089448b,

title = {Correction of AĐA-SCIĐ by stem cell gene therapy combined with nonmyeloablative conditioning},

year  = {2002},

date = {2002-06-01},

journal = {Science},

volume = {296},

number = {5577},

pages = {2410--2413},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid12089448c,

title = {Correction of AĐA-SCIĐ by stem cell gene therapy combined with nonmyeloablative conditioning},

year  = {2002},

date = {2002-06-01},

journal = {Science},

volume = {296},

number = {5577},

pages = {2410--2413},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid12077301,

title = {Đome formation in cell cultures as expression of an early stage of lactogenic differentiation of the mammary gland},

author = {I Zucchi and L Bini and D Albani and R Valaperta and S Liberatori and R Raggiaschi and C Montagna and L Susani and O Barbieri and V Pallini and P Vezzoni and R Dulbecco},

year  = {2002},

date = {2002-06-01},

journal = {Proc Natl Acad Sci U S A},

volume = {99},

number = {13},

pages = {8660--8665},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid12011466,

title = {Ŧhe gamma-secretase-generated intracellular domain of beta-amyloid precursor protein binds Numb and inhibits Notch signaling},

author = {R Roncarati and N Sestan and M H Scheinfeld and B E Berechid and P A Lopez and O Meucci and J C McGlade and P Rakic and L DÁdamio},

year  = {2002},

date = {2002-05-01},

journal = {Proc Natl Acad Sci U S A},

volume = {99},

number = {10},

pages = {7102--7107},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{dahlman_parameters_2002,

title = {Parameters for reliable results in genetic association studies in common disease.},

author = {Dahlman, Ingrid and Eaves, Iain A. and Kosoy, Roman and Morrison, V. Anne and Heward, Joanne and Gough, Stephen C. L. and Allahabadia, Amit and Franklyn, Jayne A. and Tuomilehto, Jaakko and Tuomilehto-Wolf, Eva and Cucca, Francesco and Guja, Cristian and Ionescu-Tirgoviste, Constantin and Stevens, Helen and Carr, Philippa and Nutland, Sarah and McKinney, Patricia and Shield, Julian P. and Wang, William and Cordell, Heather J. and Walker, Neil and Todd, John A. and Concannon, Patrick},

doi = {10.1038/ng825},

issn = {1061-4036 1061-4036},

year  = {2002},

date = {2002-02-01},

journal = {Nat Genet},

volume = {30},

number = {2},

pages = {149--150},

abstract = {It is increasingly apparent that the identification of true genetic associations in common multifactorial disease will require studies comprising thousands rather than the hundreds of individuals employed to date. Using 2,873 families, we were unable to confirm a recently published association of the interleukin 12B gene in 422 type I diabetic families. These results emphasize the need for large datasets, small P values and independent replication if results are to be reliable.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid11724784,

title = {Jun NĦ2-terminal kinase (JNK) interacting protein 1 (JIP1) binds the cytoplasmic domain of the Alzheimer's beta-amyloid precursor protein (APP)},

author = {M H Scheinfeld and R Roncarati and P Vito and P A Lopez and M Abdallah and L DÁdamio},

year  = {2002},

date = {2002-02-01},

journal = {J Biol Chem},

volume = {277},

number = {5},

pages = {3767--3775},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid12490281,

title = {Cloning MafF by recognition site screening with the NFE2 tandem repeat of ĦS2: analysis of its role in globin and GCSl genes regulation},

author = { M. G. Marini and I. Asunis and K. Chan and J. Y. Chan and Y. W. Kan and L. Porcu and A. Cao and P. Moi},

year  = {2002},

date = {2002-01-01},

journal = {Blood Cells Mol Dis},

volume = {29},

number = {2},

pages = {145--158},

abstract = {The erythroid-specific enhancer within hypersensitivity site 2 (HS2) of the human beta-globin locus control region is required for high level globin gene expression. We used an oligonucleotide of the NF-E2 tandem repeat, within HS2, as recognition site probe to screen a K562 cDNA library for interacting transcription factors. A 2.3 kb full length cDNA encoding the b-zip transcription factor MafF was isolated. MafF can form both homodimers and high affinity heterodimers with Nrf1, Nrf2 and Nf-E2, three members of the CNC-bZip family. Despite obvious structural similarities with the other small Maf proteins, MafF differs in its tissue distribution and its inability to repress transcription when overexpressed as homodimer. In fact, in different cell lines and on different promoters (gamma-globin, beta-globin and glutamylcysteine synthetase genes) the MafF homodimers do not appreciably affect transcription of target promoters, whereas MafF/CNC member heterodimers act as weak transcriptional activators. Even though MafF was cloned using probes derived from the globin LCR, it is in the context of the GCSl promoter and in combination with Jun that MafF shows a rather distinct and specific regulatory role. These observations suggest that a complex network of small Maf and CNC-AP1 protein interactions might be involved in regulating transcription in diverse tissues or developmental stages.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Marrosu2001,

title = {Dissection of the HLA association with multiple sclerosis in the founder isolated population of Sardinia.},

author = {Marrosu, M G and Murru, R and Murru, M R and Costa, G and Zavattari, P and Whalen, M and Cocco, E and Mancosu, C and Schirru, L and Solla, E and Fadda, E and Melis, C and Porru, I and Rolesu, M and Cucca, F},

url = {http://www.ncbi.nlm.nih.gov/pubmed/11741834},

issn = {0964-6906},

year  = {2001},

date = {2001-12-01},

journal = {Human molecular genetics},

volume = {10},

number = {25},

pages = {2907--16},

abstract = {Several studies have indicated that multiple sclerosis (MS) is associated and linked to the major histocompatibility complex (MHC)/human leukocyte antigen (HLA) region of chromosome 6p21.3, but the exact location and nature of the primarily associated locus within the HLA complex is still controversial and largely presumptive. By linkage disequilibrium mapping, we have systematically investigated this chromosome region in the founder population of Sardinia to determine the relative associations of the various loci with MS. An overall 11.4 Mb region, which encompasses the whole HLA complex, was scanned with 19 microsatellite markers and with single nucleotide polymorphisms within 12 functional candidate genes and assessed for MS association using the extended transmission disequilibrium test (ETDT). A peak of association represented by the three adjacent DRB1, -DQA1 and -DQB1 loci was detected in the class II region. Two additional less significant areas of association were detected, respectively, in the centromeric side of the class II region at the DPB1 locus and, telomeric of the classically defined class I loci, at the D6S1683 microsatellite. Conditional ETDT analysis indicated that these regions of association could be independent of each other. Within the main peak of association, DRB1 and DQB1 contribute to the disease association independently of each other whereas DQA1 had no detectable primary genetic effects. We evaluated the haplotype distribution at the region showing the strongest association and found five DQB1-DRB1 haplotypes positively associated with MS in Sardinia. These consistently included all the haplotypes previously found associated with MS in the various human populations, thus supporting a primary effect of the products of these loci in MS. Overall these results are consistent with a multilocus model of the MHC encoded susceptibility to MS.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{catassi_distribution_2001,

title = {The distribution of DQ genes in the Saharawi population provides only a partial explanation for the high celiac disease prevalence.},

author = {Catassi, C. and Doloretta Macis, M. and Ratsch, I. M. and De Virgiliis, S. and Cucca, F.},

issn = {0001-2815 0001-2815},

year  = {2001},

date = {2001-12-01},

journal = {Tissue Antigens},

volume = {58},

number = {6},

pages = {402--406},

abstract = {Celiac disease (CD) is a multifactorial disorder of the small intestine caused by a permanent dietary intolerance to gluten. The combined presence of the HLA class II DQA1*0501 and DQB1*0201 alleles represents the major genetic component for disease predisposition. It has been shown that the Saharawi refugees living in northern Africa have a very high frequency of CD. In the present study we analysed this population to evaluate the degree of association with CD of the haplotypes and genotypes at the main HLA-DQB1 and DQA1 disease loci. We found a strong association of the DR3, DQB1*0201-DQA1*0501-positive haplotypes and genotypes. A very high frequency of DR3, DQB1*0201-DQA1*0501 was also observed in the general Saharawi population. These results indicate that there is a good correlation between disease prevalence and frequency of the main predisposing haplotype in the background population. However, the correlation is incomplete because similar frequencies of DR3 are also observed in populations such as the Sardinians showing a much lower prevalence of CD. We can conclude that the distribution of DQ genes in the Saharawi population only provides a partial explanation for the high prevalence of CD. Other factors, such as rapidly changing dietary habits and/or non-DQ genes, may also play some role.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Cucca2001a,

title = {A correlation between the relative predisposition of MHC class II alleles to type 1 diabetes and the structure of their proteins.},

author = {Cucca, F and Lampis, R and Congia, M and Angius, E and Nutland, S and Bain, S C and Barnett, A H and Todd, J A},

url = {http://www.ncbi.nlm.nih.gov/pubmed/11590120},

issn = {0964-6906},

year  = {2001},

date = {2001-09-01},

journal = {Human molecular genetics},

volume = {10},

number = {19},

pages = {2025--37},

abstract = {In human type 1 diabetes (T1D) and in its murine model, the major histocompatibility complex (MHC) class II molecules, human leukocyte antigens (HLA)-DQ and -DR and their murine orthologues, IA and IE, are the major genetic determinants. In this report, we have ranked HLA class II molecule-associated T1D risk in a two-sided gradient from very high to very low. Very low risk corresponded to dominant protection from T1D. We predicted the protein structure of DQ by using the published crystal structures of different allotypes of the murine orthologue of DQ, IA. We discovered marked similarities both within, and cross species between T1D protective class II molecules. Likewise, the T1D predisposing molecules showed conserved similarities that contrasted with the shared patterns observed between the protective molecules. We also found striking inter-isotypic conservation between protective DQ, IA allotypes and protective DR4 subtypes. The data provide evidence for a joint action of the class II peptide-binding pockets P1, P4 and P9 in disease susceptibility and resistance with a main role for P9 in DQ/IA and for P1 and P4 in DR/IE. Overall, these results suggest shared epitope(s) in the target autoantigen(s), and common pathways in human and murine T1D.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pociot_no_2001,

title = {No evidence for SEL1L as a candidate gene for IDDM11-conferred susceptibility.},

author = {Pociot, F. and Larsen, Z. M. and Zavattari, P. and Deidda, E. and Nerup, J. and Cattaneo, M. and Chiaramonte, R. and Comi, P. and Sabbadini, M. and Zollo, M. and Biunno, I. and Cucca, F.},

issn = {1520-7552 1520-7552},

year  = {2001},

date = {2001-08-01},

journal = {Diabetes Metab Res Rev},

volume = {17},

number = {4},

pages = {292--295},

abstract = {BACKGROUND: The SEL1L gene is located on human chromosome 14q24.3-31 close to D14S67 which has been previously proposed to be a type 1 diabetes mellitus locus (IDDM11). Sel-1 is a negative regulator of the Notch signalling pathway and SEL1L is selectively expressed in adult pancreas and islets of Langerhans. This suggests that SEL1L may be a candidate gene for IDDM11. METHODS: We have analysed two newly identified CA-repeat polymorphisms within the genomic sequence of the SEL1L locus for association with type 1 diabetes mellitus (T1DM) in 152 Danish},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Cucca2001,

title = {The HLA-DPB1--associated component of the IDDM1 and its relationship to the major loci HLA-DQB1, -DQA1, and -DRB1.},

author = {Cucca, F and Dudbridge, F and Loddo, M and Mulargia, A P and Lampis, R and Angius, E and {De Virgiliis}, S and Koeleman, B P and Bain, S C and Barnett, A H and Gilchrist, F and Cordell, H and Welsh, K and Todd, J A},

url = {http://www.ncbi.nlm.nih.gov/pubmed/11334427},

issn = {0012-1797},

year  = {2001},

date = {2001-05-01},

journal = {Diabetes},

volume = {50},

number = {5},

pages = {1200--5},

abstract = {The major histocompatibility complex (MHC) HLA region on chromosome 6p21 contains the major locus of type 1 diabetes (IDDM1). Common allelic variants at the class II HLA-DRB1, -DQA1, and -DQB1 loci account for the major part of IDDM1. Previous studies suggested that other MHC loci are likely to contribute to IDDM1, but determination of their relative contributions and identities is difficult because of strong linkage disequilibrium between MHC loci. One prime candidate is the polymorphic HLA-DPB1 locus, which (with the DPA1 locus) encodes the third class II antigen-presenting molecule. However, the results obtained in previous studies appear to be contradictory. Therefore, we have analyzed 408 white European families (200 from Sardinia and 208 from the U.K.) using a combination of association tests designed to directly compare the effect of DPB1 variation on the relative predisposition of DR-DQ haplotypes, taking into account linkage disequilibrium between DPB1 and the DRB1, DQA1, and DQB1 loci. In these populations, the overall contribution of DPB1 to IDDM1 is small. The main component of the DPB1 contribution to IDDM1 in these populations appears to be the protection associated with DPB1*0402 on DR4-negative haplotypes. We suggest that the HLA-DP molecule itself contributes to IDDM1.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid11331746,

title = {Proteomic dissection of dome formation in a mammary cell line: role of tropomyosin-5b and maspin},

author = {I Zucchi and L Bini and R Valaperta and A Ginestra and D Albani and L Susani and J C Sanchez and S Liberatori and B Magi and R Raggiaschi and D F Hochstrasser and V Pallini and P Vezzoni and R Dulbecco},

year  = {2001},

date = {2001-05-01},

journal = {Proc Natl Acad Sci U S A},

volume = {98},

number = {10},

pages = {5608--5613},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Zavattari2001,

title = {Conditional linkage disequilibrium analysis of a complex disease superlocus, IDDM1 in the HLA region, reveals the presence of independent modifying gene effects influencing the type 1 diabetes risk encoded by the major HLA-DQB1, -DRB1 disease loci.},

author = {Zavattari, P and Lampis, R and Motzo, C and Loddo, M and Mulargia, A and Whalen, M and Maioli, M and Angius, E and Todd, J A and Cucca, F},

url = {http://www.ncbi.nlm.nih.gov/pubmed/11285254},

issn = {0964-6906},

year  = {2001},

date = {2001-04-01},

journal = {Human molecular genetics},

volume = {10},

number = {8},

pages = {881--9},

abstract = {Type 1 diabetes mellitus is a common disease with a complex mode of inheritance. Its aetiology is underpinned by a major locus, insulin-dependent diabetes mellitus 1 (IDDM1) in the human leukocyte antigen (HLA) region of chromosome 6p21, and an unknown number of loci of lesser individual effect. In linkage analyses IDDM1 is a single peak, but it is evident that the linkage is caused by allelic variation of three adjacent genes in a 75 kb region, namely the class II genes, HLA-DRB1, -DQA1 and -DQB1. However, even these three genes may not explain all of the HLA association. We investigated, in the founder population of Sardinia, whether non-DQ/DR polymorphic markers within a 9.452 Mb region encompassing the whole HLA complex further influence the disease risk, after taking into account linkage disequilibrium with the disease loci HLA-DQB1, -DQA1 and -DRB1. We generalized the conditional association test, the haplotype method, to detect marker associations that are independent of the main DR/DQ disease associations. Three regions were identified as risk modifiers. These associations were not only independent of the polymorphic exon 2 sequences of HLA-DQB1, -DQA1 and -DRB1, but also independent of each other. The individual contributions of these risk modifiers were relatively modest but their combined impact was highly significant. Together, alleles of single nucleotide polymorphisms at the DMB and DOB genes, and the microsatellite locus TNFc, identified approximately 40% of Sardinian DR3 haplotypes as non-predisposing. This conditional analysis approach can be applied to any chromosome region involved in the predisposition to complex traits.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid11175783,

title = {The putative forkhead transcription factor FOXL2 is mutated in blepharophimosis/ptosis/epicanthus inversus syndrome},

author = {Crisponi, L. and Deiana, M. and Loi, A. and Chiappe, F. and Uda, M. and Amati, P. and Bisceglia, L. and Zelante, L. and Nagaraja, R. and Porcu, S. and Ristaldi, M. S. and Marzella, R. and Rocchi, M. and Nicolino, M. and Lienhardt-Roussie, A. and Nivelon, A. and Verloes, A. and Schlessinger, D. and Gasparini, P. and Bonneau, D. and Cao, A. and Pilia, G.},

year  = {2001},

date = {2001-02-01},

journal = {Nat Genet},

volume = {27},

number = {2},

pages = {159--166},

abstract = {In type I blepharophimosis/ptosis/epicanthus inversus syndrome (BPES), eyelid abnormalities are associated with ovarian failure. Type II BPES shows only the eyelid defects, but both types map to chromosome 3q23. We have positionally cloned a novel, putative winged helix/forkhead transcription factor gene, FOXL2, that is mutated to produce truncated proteins in type I families and larger proteins in type II. Consistent with an involvement in those tissues, FOXL2 is selectively expressed in the mesenchyme of developing mouse eyelids and in adult ovarian follicles; in adult humans, it appears predominantly in the ovary. FOXL2 represents a candidate gene for the polled/intersex syndrome XX sex-reversal goat.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{cucca_correlation_2001,

title = {A correlation between the relative predisposition of MHC class II alleles to type 1 diabetes and the structure of their proteins.},

author = {Cucca, F. and Lampis, R. and Congia, M. and Angius, E. and Nutland, S. and Bain, S. C. and Barnett, A. H. and Todd, J. A.},

issn = {0964-6906 0964-6906},

year  = {2001},

date = {2001-01-01},

journal = {Hum Mol Genet},

volume = {10},

number = {19},

pages = {2025--2037},

abstract = {In human type 1 diabetes (T1D) and in its murine model, the major histocompatibility complex (MHC) class II molecules, human leukocyte antigens (HLA)-DQ and -DR and their murine orthologues, IA and IE, are the major genetic determinants. In this report, we have ranked HLA class II molecule-associated T1D risk in a two-sided gradient from very high to very low. Very low risk corresponded to dominant protection from T1D. We predicted the protein structure of DQ by using the published crystal structures of different allotypes of the murine orthologue of DQ, IA. We discovered marked similarities both within, and cross species between T1D protective class II molecules. Likewise, the T1D predisposing molecules showed conserved similarities that contrasted with the shared patterns observed between the protective molecules. We also found striking inter-isotypic conservation between protective DQ, IA allotypes and protective DR4 subtypes. The data provide evidence for a joint action of the class II peptide-binding pockets P1, P4 and P9 in disease susceptibility and resistance with a main role for P9 in DQ/IA and for P1 and P4 in DR/IE. Overall, these results suggest shared epitope(s) in the target autoantigen(s), and common pathways in human and murine T1D.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{merriman_suggestive_2001,

title = {Suggestive evidence for association of human chromosome 18q12-q21 and its orthologue on rat and mouse chromosome 18 with several autoimmune diseases.},

author = {Merriman, T. R. and Cordell, H. J. and Eaves, I. A. and Danoy, P. A. and Coraddu, F. and Barber, R. and Cucca, F. and Broadley, S. and Sawcer, S. and Compston, A. and Wordsworth, P. and Shatford, J. and Laval, S. and Jirholt, J. and Holmdahl, R. and Theofilopoulos, A. N. and Kono, D. H. and Tuomilehto, J. and Tuomilehto-Wolf, E. and Buzzetti, R. and Marrosu, M. G. and Undlien, D. E. and Ronningen, K. S. and Ionesco-Tirgoviste, C. and Shield, J. P. and Pociot, F. and Nerup, J. and Jacob, C. O. and Polychronakos, C. and Bain, S. C. and Todd, J. A.},

issn = {0012-1797 0012-1797},

year  = {2001},

date = {2001-01-01},

journal = {Diabetes},

volume = {50},

number = {1},

pages = {184--194},

abstract = {Some immune system disorders, such as type 1 diabetes, multiple sclerosis (MS), and rheumatoid arthritis (RA), share common features: the presence of autoantibodies and self-reactive T-cells, and a genetic association with the major histocompatibility complex. We have previously published evidence, from 1,708 families, for linkage and association of a haplotype of three markers in the D18S487 region of chromosome 18q21 with type 1 diabetes. Here, the three markers were typed in an independent set of 627 families and, although there was evidence for linkage (maximum logarithm of odds score [MLS] = 1.2; P = 0.02), no association was detected. Further linkage analysis revealed suggestive evidence for linkage of chromosome 18q21 to type 1 diabetes in 882 multiplex families (MLS = 2.2; lambdas = 1.2; P = 0.001), and by meta-analysis the orthologous region (also on chromosome 18) is linked to diabetes in rodents (P = 9 x 10(-4)). By meta-analysis, both human chromosome 18q12-q21 and the rodent orthologous region show positive evidence for linkage to an autoimmune phenotype (P = 0.004 and 2 x 10(-8), respectively, empirical P = 0.01 and 2 x 10(-4), respectively). In the diabetes-linked region of chromosome 18q12-q21, a candidate gene, deleted in colorectal carcinoma (DCC), was tested for association with human autoimmunity in 3,380 families with type 1 diabetes, MS, and RA. A haplotype ("2-10") of two newly characterized microsatellite markers within DCC showed evidence for association with autoimmunity (P = 5 x 10(-6)). Collectively, these data suggest that a locus (or loci) exists on human chromosome 18q12-q21 that influences multiple autoimmune diseases and that this association might be conserved between species.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid11511926,

title = {Archival, demographic and genetic studies define a Sardinian sub-isolate as a suitable model for mapping complex traits},

year  = {2001},

date = {2001-01-01},

journal = {Hum Genet},

volume = {109},

number = {2},

pages = {198--209},

abstract = {Genetic isolates represent exceptional resources for the mapping of complex traits but not all isolates are similar. We have selected a genetic and cultural isolate, the village of Talana from an isolated area of Sardinia, and propose that this population is suitable for the mapping of complex traits. A wealth of historical and archive data allowed the reconstruction of the demographic and genealogical history of the village. Key features of the population, which has grown slowly with no significant immigration, were defined by using a combination of historical, demographic and genetic studies. The genealogy of each Talana inhabitant was reconstructed and the main maternal and paternal lineages of the village were defined. Haplotype and phylogenetic analyses of the Y chromosome and characterisation of mitochondrial DNA haplogroups were used to determine the number of ancestral village founders. The extent of linkage disequilibrium (LD) was evaluated by the analysis of several microsatellites in chromosomal region Xq13.3, which was previously used to asses the extension of LD. Genealogical reconstructions were confirmed and reinforced by the genetic analyses, since some lineages were found to have merged prior to the beginning of the archival records, suggesting an even smaller number of founders than initially predicted. About 80% of the present-day population appears to derive from eight paternal and eleven maternal ancestral lineages. LD was found to span, on average, a 5-Mb region in Xq13.3. This suggests the possibility of identifying identical-by-descent regions associated with complex traits in a genome-wide search by using a low-density marker map. The present study emphasises the importance of combining genetic studies with genealogical and historical information.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid11493678,

title = {Ħeart-targeted overexpression of caspase3 in mice increases infarct size and depresses cardiac function},

author = {G Condorelli and R Roncarati and J Ross and A Pisani and G Stassi and M Todaro and S Trocha and A Drusco and Y Gu and M A Russo and G Frati and S P Jones and D J Lefer and C Napoli and C M Croce},

year  = {2001},

date = {2001-01-01},

journal = {Proc Natl Acad Sci U S A},

volume = {98},

number = {17},

pages = {9977--9982},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Zavattari2000,

title = {Confirmation of the DRB1-DQB1 loci as the major component of IDDM1 in the isolated founder population of Sardinia.},

author = {Zavattari, P and Lampis, R and Mulargia, A and Loddo, M and Angius, E and Todd, J A and Cucca, F},

url = {http://www.ncbi.nlm.nih.gov/pubmed/11115840},

issn = {0964-6906},

year  = {2000},

date = {2000-12-01},

journal = {Human molecular genetics},

volume = {9},

number = {20},

pages = {2967--72},

abstract = {There is considerable uncertainty and debate concerning the application of linkage disequilibrium (LD) mapping in common multifactorial diseases, including the choice of population and the density of the marker map. Previously, it has been shown that, in the large cosmopolitan population of the UK, the established type 1 diabetes IDDM1 locus in the HLA region could be mapped with high resolution by LD. The LD curve peaked at marker D6S2444, 85 kb from the HLA class II gene DQB1, which is known to be a major determinant of IDDM1. However, given the many unknown parameters underlying LD, a validation of the approach in a genetically distinct population is necessary. In the present report we have achieved this by the LD mapping of IDDM1 in the isolated founder population of Sardinia. Using a dense map of microsatellite markers, we determined the peak of LD to be located at marker D6S2447, which is only 6.5 kb from DQB1. Next, we typed a large number of SNPs defining allelic variation at functional candidate genes within the critical region. The association curve, with both classes of marker, peaked at the loci DRB1-DQB1. These results, while representing conclusive evidence that the class II loci DRB1-DQB1 dominate the association of the HLA region to type 1 diabetes, provide empirical support for LD mapping.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Lampis2000,

title = {The inter-regional distribution of HLA class II haplotypes indicates the suitability of the Sardinian population for case-control association studies in complex diseases.},

author = {Lampis, R and Morelli, L and Congia, M and Macis, M D and Mulargia, A and Loddo, M and {De Virgiliis}, S and Marrosu, M G and Todd, J A and Cucca, F},

url = {http://www.ncbi.nlm.nih.gov/pubmed/11115839},

issn = {0964-6906},

year  = {2000},

date = {2000-12-01},

journal = {Human molecular genetics},

volume = {9},

number = {20},

pages = {2959--65},

abstract = {We have analysed HLA class II gene-based substructure of the Sardinian population in order to evaluate the possible influence of this parameter in the mapping of common disease loci using association methods. We first examined the distribution of the HLA-DRB1-DQA1-DQB1 haplotypes in 631 newborns from seven different regions of the island, and found that the most frequent haplotypes were uniformly distributed in all regions, but at frequencies unique to Sardinia. Other haplotypes, common in other white European populations, are consistently rare or absent across the whole island. Analysis of molecular variance (AMOVA) showed a very low degree of genetic differentiation between the coastal regions, which have suffered repeated invasions over many years, and the most internal and isolated part of the island. This suggests that there has been little genetic flow from the various populations that have invaded the island during the last 3000 years and that Sardinia is a relatively homogeneous population. The validity of these unrelated control HLA haplotype frequencies and our claim of homogeneity were established by demonstrating the near identity of the affected family-based control (AFBAC) HLA haplotype frequencies in 243 type 1 diabetes and 495 multiple sclerosis families from Sardinia and those of the unrelated controls. These results indicate that robust case-control studies can be carried out in Sardinia offering cost efficiency over certain family-based designs.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Zavattari2000a,

title = {Major factors influencing linkage disequilibrium by analysis of different chromosome regions in distinct populations: demography, chromosome recombination frequency and selection.},

author = {Zavattari, P and Deidda, E and Whalen, M and Lampis, R and Mulargia, A and Loddo, M and Eaves, I and Mastio, G and Todd, J A and Cucca, F},

url = {http://www.ncbi.nlm.nih.gov/pubmed/11115838},

issn = {0964-6906},

year  = {2000},

date = {2000-12-01},

journal = {Human molecular genetics},

volume = {9},

number = {20},

pages = {2947--57},

abstract = {Linkage disequilibrium (LD) mapping of disease genes is complicated by population- and chromosome-region-specific factors. We have analysed demographic factors by contrasting intermarker LD results obtained in a large cosmopolitan population (UK), a large genetic isolate (Sardinia) and a subisolate (village of Gavoi) for two regions of the X chromosome. A dramatic increase of LD was found in the subisolate. Demographic history of populations therefore influences LD. Chromosome-region-specific effects, namely the pattern and frequency of homologous recombination, were next delineated by the analysis of chromosome 6p21, including the HLA region. Patterns of global LD in this region were very similar in the UK and Sardinian populations despite their entirely distinct demographies, and correlate well with the pattern of recombinations. Nevertheless, haplotypes extend across recombination hot spots indicative of selection of certain haplotypes. Subisolate aside, chromosome-region-specific differences in LD patterns appear to be more important than the differences in intermarker LD between distinct populations.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{lampis_distribution_2000,

title = {The distribution of HLA class II haplotypes reveals that the Sardinian population is genetically differentiated from the other Caucasian populations.},

author = {Lampis, R. and Morelli, L. and De Virgiliis, S. and Congia, M. and Cucca, F.},

issn = {0001-2815 0001-2815},

year  = {2000},

date = {2000-12-01},

journal = {Tissue Antigens},

volume = {56},

number = {6},

pages = {515--521},

abstract = {In this study we have established the frequencies of the DRB1-DQA1-DQB1 haplotypes in a large cohort of Sardinian new-borns and found that the most frequent haplotypes were detected at frequencies unique to the Sardinians. Other haplotypes, common in other Caucasian populations, are rare or absent across the island. Next, the DRB1-DQA1-DQB1 haplotype frequencies obtained in Sardinians and those reported in other human populations were used to compute genetic distances and construct phylogenetic trees. A clear-cut pattern appeared with a split between the three major human groups: Caucasians, Asians and Blacks. Among the Caucasians there were three major clusters: a group representing the North-Africans, a group including most of the European-derived populations and a group encompassing Bulgaria, Greece and Sardinia. When we increased the resolution of the tree using the genetic distances calculated from both},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{lampis_inter-regional_2000,

title = {The inter-regional distribution of HLA class II haplotypes indicates the suitability of the Sardinian population for case-control association studies in complex diseases.},

author = {Lampis, R. and Morelli, L. and Congia, M. and Macis, M. D. and Mulargia, A. and Loddo, M. and De Virgiliis, S. and Marrosu, M. G. and Todd, J. A. and Cucca, F.},

issn = {0964-6906 0964-6906},

year  = {2000},

date = {2000-12-01},

journal = {Hum Mol Genet},

volume = {9},

number = {20},

pages = {2959--2965},

abstract = {We have analysed HLA class II gene-based substructure of the Sardinian population in order to evaluate the possible influence of this parameter in the mapping of common disease loci using association methods. We first examined the distribution of the HLA-DRB1-DQA1-DQB1 haplotypes in 631 newborns from seven different regions of the island, and found that the most frequent haplotypes were uniformly distributed in all regions, but at frequencies unique to Sardinia. Other haplotypes, common in other white European populations, are consistently rare or absent across the whole island. Analysis of molecular variance (AMOVA) showed a very low degree of genetic differentiation between the coastal regions, which have suffered repeated invasions over many years, and the most internal and isolated part of the island. This suggests that there has been little genetic flow from the various populations that have invaded the island during the last 3000 years and that Sardinia is a relatively homogeneous population. The validity of these unrelated control HLA haplotype frequencies and our claim of homogeneity were established by demonstrating the near identity of the affected family-based control (AFBAC) HLA haplotype frequencies in 243 type 1 diabetes and 495 multiple sclerosis families from Sardinia and those of the unrelated controls. These results indicate that robust case-control studies can be carried out in Sardinia offering cost efficiency over certain family-based designs.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{marrosu_icam-1_2000,

title = {ICAM-1 gene is not associated with multiple sclerosis in sardinian patients.},

author = {Marrosu, M. G. and Schirru, L. and Fadda, E. and Mancosu, C. and Lai, M. and Cocco, E. and Cucca, F.},

issn = {0340-5354 0340-5354},

year  = {2000},

date = {2000-09-01},

journal = {J Neurol},

volume = {247},

number = {9},

pages = {677--680},

abstract = {An increased amount of the intercellular adhesion molecule (ICAM) 1 molecule has been found in the blood of actively relapsing multiple sclerosis (MS) patients, but is unclear whether this enhanced expression is partially causative of the MS process, or whether it is merely an epiphenomenon of the inflammatory-immunological reaction. Using the transmission disequilibrium test (TDT), we studied exon 4 and exon 6 polymorphism of the ICAM-1 gene from 157 families with both parents, one affected and one healthy sib coming from Sardinia, an Italian island having a high incidence and prevalence of MS. TDT did not show variation in the expected 50:50 frequency in transmission in either healthy or affected sibs, using phenotypic or genotypic analysis. Moreover, independence from the predisposing HLA-DRB1-DQA1-DQB1 haplotype was confirmed by TDT analysis performed on patients stratified according to the presence or absence of the HLA-DRB1, DQA1, DQB1 Sardinian predisposing haplotypes. Our data suggest that the increased expression of the ICAM-1 molecule observed in both blood and periplaque microvessels may be considered a consequence of the inflammatory process rather than the result of a genetic variation.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Todd2000,

title = {The genetically isolated populations of Finland and sardinia may not be a panacea for linkage disequilibrium mapping of common disease genes.},

author = {Todd, John A. and Eaves, Iain A. and Merriman, Tony R. and Barber, Rachael A. and Nutland, Sarah and Tuomilehto-Wolf, Eva and Tuomilehto, Jaakko and Cucca, Francesco},

url = {http://www.ncbi.nlm.nih.gov/pubmed/10888882 http://www.nature.com/doifinder/10.1038/77091},

doi = {10.1038/77091},

issn = {10614036},

year  = {2000},

date = {2000-07-01},

journal = {Nature Genetics},

volume = {25},

number = {3},

pages = {320--323},

abstract = {The choice of which population to study in the mapping of common disease genes may be critical. Isolated founder populations, such as that found in Finland, have already proved extremely useful for mapping the genes for specific rare monogenic disorders and are being used in attempts to map the genes underlying common, complex diseases. But simulation results suggest that, under the common disease-common variant hypothesis, most isolated populations will prove no more useful for linkage disequilibrium (LD) mapping of common disease genes than large outbred populations. There is very little empirical data to either support or refute this conclusion at present. Therefore, we evaluated LD between 21 common microsatellite polymorphisms on chromosome 18q21 in 2 genetic isolates (Finland and Sardinia) and compared the results with those observed in two mixed populations (United Kingdom and United States of America). Mean levels of LD were similar across all four populations. Our results provide empirical support for the expectation that genetic isolates like Finland and Sardinia will not prove significantly more valuable than general populations for LD mapping of common variants underlying complex disease.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{eaves_genetically_2000,

title = {The genetically isolated populations of Finland and sardinia may not be a panacea for linkage disequilibrium mapping of common disease genes.},

author = {Eaves, I. A. and Merriman, T. R. and Barber, R. A. and Nutland, S. and Tuomilehto-Wolf, E. and Tuomilehto, J. and Cucca, F. and Todd, J. A.},

doi = {10.1038/77091},

issn = {1061-4036 1061-4036},

year  = {2000},

date = {2000-07-01},

journal = {Nat Genet},

volume = {25},

number = {3},

pages = {320--323},

abstract = {The choice of which population to study in the mapping of common disease genes may be critical. Isolated founder populations, such as that found in Finland, have already proved extremely useful for mapping the genes for specific rare monogenic disorders and are being used in attempts to map the genes underlying common, complex diseases. But simulation results suggest that, under the common disease-common variant hypothesis, most isolated populations will prove no more useful for linkage disequilibrium (LD) mapping of common disease genes than large outbred populations. There is very little empirical data to either support or refute this conclusion at present. Therefore, we evaluated LD between 21 common microsatellite polymorphisms on chromosome 18q21 in 2 genetic isolates (Finland and Sardinia) and compared the results with those observed in two mixed populations (United Kingdom and United States of America). Mean levels of LD were similar across all four populations. Our results provide empirical support for the expectation that genetic isolates like Finland and Sardinia will not prove significantly more valuable than general populations for LD mapping of common variants underlying complex disease.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid10888887,

title = {Đefects in ŦCIRG1 subunit of the vacuolar proton pump are responsible for a subset of human autosomal recessive osteopetrosis},

author = {A Frattini and P J Orchard and C Sobacchi and S Giliani and M Abinun and J P Mattsson and D J Keeling and A K Andersson and P Wallbrandt and L Zecca and L D Notarangelo and P Vezzoni and A Villa},

year  = {2000},

date = {2000-07-01},

journal = {Nat Genet},

volume = {25},

number = {3},

pages = {343--346},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{muntoni_nutritional_2000,

title = {Nutritional factors and worldwide incidence of childhood type 1 diabetes.},

author = {Muntoni, S. and Cocco, P. and Aru, G. and Cucca, F.},

issn = {0002-9165 0002-9165},

year  = {2000},

date = {2000-06-01},

journal = {Am J Clin Nutr},

volume = {71},

number = {6},

pages = {1525--1529},

abstract = {BACKGROUND: Some dietary factors have been associated with the risk of type 1 diabetes in childhood. OBJECTIVE: We investigated relations between dietary energy from major food groups and incidence of childhood type 1 diabetes by using an ecologic study design. DESIGN: We conducted univariate and multivariate regression analysis with incidence rates of type 1 diabetes in the late 1980s and early 1990s among children aged textless15 y in 40 countries as the dependent variable and average per capita daily intake of major food items and other socioeconomic, demographic, and geographic risk factors as the independent variables. RESULTS: In the univariate regression model, per capita total energy intake was nonsignificantly associated with type 1 diabetes incidence (r = 0.31, NS), whereas energy from animal sources was associated (r = 0.61, P textless 0.01) and energy from vegetal sources was inversely associated (r = -0.35, P textless 0.05) with diabetes incidence. Among dietary items of animal origin, meat (r = 0.55, P textless 0.001) and dairy products (r = 0. 80, P textless 0.0001) were predictors of elevated incidence rates, whereas among dietary items of vegetal origin, cereals (r = -0.64, P textless 0. 001) were inverse predictors. In the multivariate analysis, the inverse relation of diabetes incidence with energy from vegetables and the direct correlation with energy from animal sources explained the positive associations of type 1 diabetes incidence with geographic and socioeconomic covariates. CONCLUSION: The incidence of type 1 diabetes varied worldwide according to dietary patterns. In-depth exploration of dietary risk factors during pregnancy and early neonatal life is warranted to confirm whether and to what extent diet cooperates with genetic susceptibility in the early onset of type 1 diabetes.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{koeleman_conditional_2000,

title = {Conditional ETDT analysis of the human leukocyte antigen region in type 1 diabetes.},

author = {Koeleman, B. P. and Herr, M. H. and Zavattari, P. and Dudbridge, F. and March, R. and Campbell, D. and Barnett, A. H. and Bain, S. C. and Mulargia, A. P. and Loddo, M. and Amos, W. and Cucca, F. and Todd, J. A.},

doi = {doi:10.1017/S0003480000008101},

issn = {0003-4800 0003-4800},

year  = {2000},

date = {2000-05-01},

journal = {Ann Hum Genet},

volume = {64},

number = {Pt 3},

pages = {215--221},

abstract = {Several studies have indicated that additional genes in the major histocompatibility complex (MHC) region, other than the class II genes HLA-DQB1 and -DRB1 (the IDDM1 locus), may contribute to susceptibility and resistance to type 1 diabetes. The relative magnitude of these non- DR/DQ effects is uncertain and their map location is unknown owing to the extraordinary linkage disequilibrium that extends over the 3.5 Mb of the MHC. The homozygous parent test has been proposed as a method for detection of additional risk factors conditional on HLA-DQB1 and -DRB1. However, this method is inefficient since it uses only parents homozygous for the primary disease locus, the DQB1-DRB1 haplotype. To overcome this limitation, Conditional ETDT was used in the present report to test for association conditional on the DQB1-DRB1 haplotype, thereby allowing all parents to be included in the analysis. First, we confirm in UK and Sardinian type 1 diabetic families that allelic variation at HLA-DRB1 has a very significant effect on the association of DQB1 and vice versa. The Conditional ETDT was then applied to the HLA TNF (tumour necrosis factor) region and microsatellite marker D6S273 region, both of which have been reported to contribute to IDDM1 independent of the HLA-DQB1-DRB1 genes. We found no evidence for a major role for either of these two regions in IDDM1.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{herr_evaluation_2000,

title = {Evaluation of fine mapping strategies for a multifactorial disease locus: systematic linkage and association analysis of IDDM1 in the HLA region on chromosome 6p21.},

author = {Herr, M. and Dudbridge, F. and Zavattari, P. and Cucca, F. and Guja, C. and March, R. and Campbell, R. D. and Barnett, A. H. and Bain, S. C. and Todd, J. A. and Koeleman, B. P.},

issn = {0964-6906 0964-6906},

year  = {2000},

date = {2000-05-01},

journal = {Hum Mol Genet},

volume = {9},

number = {9},

pages = {1291--1301},

abstract = {The positional cloning of multifactorial disease genes is a major challenge in human genetics. We have therefore empirically tested the utility of the available polymorphic microsatellite map to locate the already identified type 1 diabetes locus IDDM1 (sibling risk/population prevalence ratio lambda(s)= 2.7) within a 14 Mb region of chromosome 6p21 linked to disease. In a two-stage approach to fine mapping, linkage was evaluated in 385 affected sib-pair families using 13 evenly spaced polymorphic microsatellite markers. The whole 14 Mb showed strong linkage. Then, each marker was analysed for evidence of allelic association, revealing evidence of disease association at one marker located within the 95% confidence interval of 1.7 cM obtained by linkage. Analysis of an additional 12 markers flanking this marker revealed a highly specific region of 570 kb associated with disease ( P = 7.5 x 10(-35)), which included the HLA class II genes, known to be the primary determinants of IDDM1. The peak of association was as close as 85 kb centromeric of the disease-predisposing class II gene HLA-DQB1. We investigated the importance of the underlying inter-marker linkage disequilibrium, marker informativity and recombination for fine mapping and demonstrate that the majority of disease association in the region can be explained by linkage disequilibrium with the class II susceptibility genes. Recombination within the major histocompatibility complex was rare and nearly absent in the class III region. We demonstrate that fine mapping of a multifactorial disease gene is possible with high accuracy even in a region with extraordinary linkage disequilibrium across distances of several Mb. The results will be applicable to association studies of disease loci with lambda(s)values textless2.7 except that much larger data sets will be required.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{zavattari_transmission-ratio_2000,

title = {Transmission-ratio distortion at Xp11.4-p21.1 in type 1 diabetes.},

author = {Zavattari, P. and Esposito, L. and Nutland, S. and Todd, J. A. and Cucca, F.},

doi = {10.1086/302701},

issn = {0002-9297 0002-9297},

year  = {2000},

date = {2000-01-01},

journal = {Am J Hum Genet},

volume = {66},

number = {1},

pages = {330--332},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid10570147,

title = {Genetic dissection of dome formation in a mammary cell line: identification of two genes with opposing action},

author = {I Zucchi and C Montagna and L Susani and R Montesano and M Affer and S Zanotti and E Redolfi and P Vezzoni and R Dulbecco},

year  = {1999},

date = {1999-11-01},

journal = {Proc Natl Acad Sci U S A},

volume = {96},

number = {24},

pages = {13766--13770},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{dalfonso_linkage_1999,

title = {Linkage analysis of multiple sclerosis with candidate region markers in Sardinian and Continental Italian families.},

author = {D'Alfonso, S. and Nistico, L. and Zavattari, P. and Marrosu, M. G. and Murru, R. and Lai, M. and Massacesi, L. and Ballerini, C. and Gestri, D. and Salvetti, M. and Ristori, G. and Bomprezzi, R. and Trojano, M. and Liguori, M. and Gambi, D. and Quattrone, A. and Fruci, D. and Cucca, F. and Richiardi, P. M. and Tosi, R.},

doi = {10.1038/sj.ejhg.5200301},

issn = {1018-4813 1018-4813},

year  = {1999},

date = {1999-04-01},

journal = {Eur J Hum Genet},

volume = {7},

number = {3},

pages = {377--385},

abstract = {Previous genome screens in multiple sclerosis have shown some evidence of linkage in scattered chromosomal regions. Although in no case the evidence of each single study was compelling and although in general the linkage 'peaks' of the different studies did not coincide, some regions can be considered likely candidates for the presence of MS risk genes because of the clustering of MLS scores and homology with eae loci. We performed a linkage analysis of markers in these regions and of intragenic markers of some individual candidate genes (HLA-DRB1,},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{esposito_genetic_1998,

title = {Genetic analysis of chromosome 2 in type 1 diabetes: analysis of putative loci IDDM7, IDDM12, and IDDM13 and candidate genes NRAMP1 and IA-2 and the interleukin-1 gene cluster. IMDIAB Group.},

author = {Esposito, L. and Hill, N. J. and Pritchard, L. E. and Cucca, F. and Muxworthy, C. and Merriman, M. E. and Wilson, A. and Julier, C. and Delepine, M. and Tuomilehto, J. and Tuomilehto-Wolf, E. and Ionesco-Tirgoviste, C. and Nistico', L. and Buzzetti, R. and Pozzilli, P. and Ferrari, M. and Bosi, E. and Pociot, F. and Nerup, J. and Bain, S. C. and Todd, J. A.},

issn = {0012-1797 0012-1797},

year  = {1998},

date = {1998-11-01},

journal = {Diabetes},

volume = {47},

number = {11},

pages = {1797--1799},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Cucca1998a,

title = {Investigation of linkage of chromosome 8 to type 1 diabetes: multipoint analysis and exclusion mapping of human chromosome 8 in 593 affected sib-pair families from the U.K. and U.S.},

author = {Cucca, F and Esposito, L and Goy, J V and Merriman, M E and Wilson, A J and Reed, P W and Bain, S C and Todd, J A},

url = {http://www.ncbi.nlm.nih.gov/pubmed/9726245},

issn = {0012-1797},

year  = {1998},

date = {1998-09-01},

journal = {Diabetes},

volume = {47},

number = {9},

pages = {1525--7},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Marrosu1998,

title = {DRB1-DQA1-DQB1 loci and multiple sclerosis predisposition in the Sardinian population.},

author = {Marrosu, M G and Murru, M R and Costa, G and Murru, R and Muntoni, F and Cucca, F},

url = {http://www.ncbi.nlm.nih.gov/pubmed/9668164},

issn = {0964-6906},

year  = {1998},

date = {1998-08-01},

journal = {Human molecular genetics},

volume = {7},

number = {8},

pages = {1235--7},

abstract = {Multiple sclerosis (MS) is a common neurological disease caused by genetic and environmental factors. Previous genetic analyses have suggested that theMHC/HLA region on chromosome 6p21 contains an MS-predisposing component. Which of the many genes present in this region is primarily responsible for disease susceptibility is still an open issue. In this study, we evaluated, in a large cohort of MS families from the Mediterranean island of Sardinia, the role of allelic variation at the HLA-DRB1, DQA1 and DQB1 candidate loci in MS predisposition. Using the transmission disequilibrium test (TDT), we found significant evidence of association with MS in both the Sardinian-specific DRB1*0405(DR4)- DQA1*0501-DQB1*0301 haplotype and the DRB1* 0301(DR3)-DQA1*0501-DQB1*0201 haplotype. Detailed comparative analysis of the DRB1-DQA1- DQB1 haplotypes present in this data set did not identify an individual locus that could explain MS susceptibility. The predisposing effect is haplotype specific, in that it is confined to specific combinations of alleles at the DRB1, DQA1 and DQB1 loci. Cross-ethnic comparison between the two HLA haplotypes associated with MS in Sardinians and the DRB1*1501 (DR2)-DQA1*0102-DQB1* 0602 haplotype, associated with MS in other Caucasian populations, failed to identify any shared epitopes in the DR and DQ molecules that segregated with disease susceptibility. These results suggest that another MHC gene(s), in linkage disequilibrium with specific HLA-DRB1, DQA1, DQB1 haploypes, might be primarily responsible for genetic susceptibility to MS. Alternatively, the presence of complex interactions between different HLA haplotypes, other non-HLA predisposing genes and environmental factors may explain different associations in different populations.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{nakagawa_fine_1998,

title = {Fine mapping of the diabetes-susceptibility locus, IDDM4, on chromosome 11q13.},

author = {Nakagawa, Y. and Kawaguchi, Y. and Twells, R. C. and Muxworthy, C. and Hunter, K. M. and Wilson, A. and Merriman, M. E. and Cox, R. D. and Merriman, T. and Cucca, F. and McKinney, P. A. and Shield, J. P. and Tuomilehto, J. and Tuomilehto-Wolf, E. and Ionesco-Tirgoviste, C. and Nistico, L. and Buzzetti, R. and Pozzilli, P. and Joner, G. and Thorsby, E. and Undlien, D. E. and Pociot, F. and Nerup, J. and Ronningen, K. S. and Bain, S. C. and Todd, J. A.},

issn = {0002-9297 0002-9297},

year  = {1998},

date = {1998-08-01},

journal = {Am J Hum Genet},

volume = {63},

number = {2},

pages = {547--556},

abstract = {Genomewide linkage studies of type 1 diabetes (or insulin-dependent diabetes mellitus [IDDM]) indicate that several unlinked susceptibility loci can explain the clustering of the disease in families. One such locus has been mapped to chromosome 11q13 (IDDM4). In the present report we have analyzed 707 affected sib pairs, obtaining a peak multipoint maximum LOD score (MLS) of 2.7 (lambda(s)=1.09) with linkage (MLStextgreater=0.7) extending over a 15-cM region. The problem is, therefore, to fine map the locus to permit structural analysis of positional candidate genes. In a two-stage approach, we first scanned the 15-cM linked region for increased or decreased transmission, from heterozygous parents to affected siblings in 340 families, of the three most common alleles of each of 12 microsatellite loci. One of the 36 alleles showed decreased transmission (50% expected, 45.1% observed [P=.02, corrected P=.72]) at marker D11S1917. Analysis of an additional 1,702 families provided further support for negative transmission (48%) of D11S1917 allele 3 to affected offspring and positive transmission (55%) to unaffected siblings (test of heterogeneity P=3x10-4, corrected P=. 01]). A second polymorphic marker, H0570polyA, was isolated from a cosmid clone containing D11S1917, and genotyping of 2,042 families revealed strong linkage disequilibrium between the two markers (15 kb apart), with a specific haplotype, D11S1917*03-H0570polyA*02, showing decreased transmission (46.4%) to affected offspring and increased transmission (56.6%) to unaffected siblings (test of heterogeneity P=1.5x10-6, corrected P=4.3x10-4). These results not only provide sufficient justification for analysis of the gene content of the D11S1917 region for positional candidates but also show that, in the mapping of genes for common multifactorial diseases, analysis of both affected and unaffected siblings is of value and that both predisposing and nonpredisposing alleles should be anticipated.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Cucca1998,

title = {A male-female bias in type 1 diabetes and linkage to chromosome Xp in MHC HLA-DR3-positive patients.},

author = {Cucca, F and Goy, J V and Kawaguchi, Y and Esposito, L and Merriman, M E and Wilson, A J and Cordell, H J and Bain, S C and Todd, J A},

url = {http://www.nature.com/doifinder/10.1038/995 http://www.ncbi.nlm.nih.gov/pubmed/9662410},

doi = {10.1038/995},

issn = {1061-4036},

year  = {1998},

date = {1998-07-01},

journal = {Nature genetics},

volume = {19},

number = {3},

pages = {301--2},

abstract = {It is generally assumed that the male:female (M:F) ratio in patients with type 1 (insulin-dependent) diabetes mellitus (IDDM) is 1. A recent survey, however, revealed that high incidence countries (mainly European) have a high M:F ratio and low incidence ones (Asian and African) have a low M:F ratio. We have now analysed the M:F ratio according to genotype at the major locus, the major histocompatibility complex (MHC; IDDM1). There are two main IDDM1 susceptibility haplotypes, HLA-DR3 and -DR4, which are present in 95% of Caucasian cases. We report here that in medium/high incidence Caucasian populations from the United States of America, United Kingdom and Sardinia (1307 cases), the bias in male incidence is largely restricted to the DR3/X category of patients (X not = DR4) with a M:F ratio of 1.7 (P=9.3x10(-7)), compared with a ratio of 1.0 in the DR4/Y category (Y;DR3). This is additional evidence for significant heterogeneity between the aetiology of 'DR4-associated' and 'DR3-associated' diabetes. We analysed linkage of type 1 diabetes to chromosome X, and as expected, most of the linkage to Xp13-p11 was in the DR3/X affected sibpair families (n=97; peak multipoint MLS at DXS1068=3.5},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{mein_search_1998,

title = {A search for type 1 diabetes susceptibility genes in families from the United Kingdom.},

author = {Mein, C. A. and Esposito, L. and Dunn, M. G. and Johnson, G. C. and Timms, A. E. and Goy, J. V. and Smith, A. N. and Sebag-Montefiore, L. and Merriman, M. E. and Wilson, A. J. and Pritchard, L. E. and Cucca, F. and Barnett, A. H. and Bain, S. C. and Todd, J. A.},

doi = {10.1038/991},

issn = {1061-4036 1061-4036},

year  = {1998},

date = {1998-07-01},

journal = {Nat Genet},

volume = {19},

number = {3},

pages = {297--300},

abstract = {Genetic analysis of a mouse model of major histocompatability complex (MHC)-associated autoimmune type 1 (insulin-dependent) diabetes mellitus (IDDM) has shown that the disease is caused by a combination of a major effect at the MHC and at least ten other susceptibility loci elsewhere in the genome. A genome-wide scan of 93 affected sibpair families (ASP) from the UK (UK93) indicated a similar genetic basis for human type 1 diabetes, with the major genetic component at the MHC locus (IDDM1) explaining 34% of the familial clustering of the disease (lambda(s)=2.5; refs 3,4). In the present report, we have analysed a further 263 multiplex families from the same population (UK263) to provide a total UK data set of 356 ASP families (UK356). Only four regions of the genome outside IDDM1/MHC, which was still the only major locus detected, were not excluded at lambda(s)=3 and lod=-2, of which two showed evidence of linkage: chromosome 10p13-p11 (maximum lod score (MLS)=4.7},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{villa_partial_1998,

title = {Partial V(D)J recombination activity leads to Omenn syndrome.},

author = {A Villa and S Santagata and F Bozzi and S Giliani and A Frattini and L Imberti and L B Gatta and H D Ochs and K Schwarz and L D Notarangelo and P Vezzoni and E Spanopoulou},

url = {http://www.ncbi.nlm.nih.gov/pubmed/9630231},

issn = {0092-8674},

year  = {1998},

date = {1998-05-01},

journal = {Cell},

volume = {93},

number = {5},

pages = {885--96},

abstract = {Genomic rearrangement of the antigen receptor loci is initiated by the two lymphoid-specific proteins Rag-1 and Rag-2. Null mutations in either of the two proteins abrogate initiation of V(D)J recombination and cause severe combined immunodeficiency with complete absence of mature B and T lymphocytes. We report here that patients with Omenn syndrome, a severe immunodeficiency characterized by the presence of activated, anergic, oligoclonal T cells, hypereosinophilia, and high IgE levels, bear missense mutations in either the Rag-1 or Rag-2 genes that result in partial activity of the two proteins. Two of the amino acid substitutions map within the Rag-1 homeodomain and decrease DNA binding activity, while three others lower the efficiency of Rag-1/Rag-2 interaction. These findings provide evidence to indicate that the immunodeficiency manifested in patients with Omenn syndrome arises from mutations that decrease the efficiency of V(D)J recombination.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{merriman_transmission_1998,

title = {Transmission of haplotypes of microsatellite markers rather than single marker alleles in the mapping of a putative type 1 diabetes susceptibility gene (IDDM6).},

author = {Merriman, T. R. and Eaves, I. A. and Twells, R. C. and Merriman, M. E. and Danoy, P. A. and Muxworthy, C. E. and Hunter, K. M. and Cox, R. D. and Cucca, F. and McKinney, P. A. and Shield, J. P. and Baum, J. D. and Tuomilehto, J. and Tuomilehto-Wolf, E. and Ionesco-Tirgoviste, C. and Joner, G. and Thorsby, E. and Undlien, D. E. and Pociot, F. and Nerup, J. and Ronningen, K. S. and Bain, S. C. and Todd, J. A.},

issn = {0964-6906 0964-6906},

year  = {1998},

date = {1998-03-01},

journal = {Hum Mol Genet},

volume = {7},

number = {3},

pages = {517--524},

abstract = {Allelic association methods based on increased transmission of marker alleles will have to be employed for the mapping of complex disease susceptibility genes. However, because the extent of association of single marker alleles with disease is a function of the relative frequency of the allele on disease-associated chromosomes versus non disease-predisposing chromosomes, the most associated marker allele in a region will not necessarily be closest to the disease locus. To overcome this problem we describe a haplotype-based approach developed for mapping of the putative type 1 diabetes susceptibility gene IDDM6. Ten microsatellite markers spanning a 550 kb segment of chromosome 18q21 in the putative IDDM6 region were genotyped in 1708 type 1 diabetic Caucasian families from seven countries. The most likely ancestral diabetogenic chromosome was reconstructed in a stepwise fashion by analysing linkage disequilibrium between a previously defined haplotype of three adjacent markers and the next marker along the chromosome. A plot of transmission from heterozygous parents to affected offspring of single marker alleles present on the ancestral chromosome versus the physical distance between them, was compared with a plot of transmission of haplotypes of groups of three adjacent markers. Analysing transmission of haplotypes largely negated apparent decreases in transmission of single marker alleles. Peak support for association of the D18S487 region with IDDM6 is P = 0.0002 (corrected P = 0.01). The results also demonstrate the utility of polymorphic microsatellite markers to trace and delineate extended and presumably ancient haplotypes in the analysis of common disease and in the search for identical-by-descent chromosome regions that carry an aetiological variant.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid9448288,

title = {Ŧhe rat gene homologous to the human gene 9-27 is involved in the development of the mammary gland},

author = {I Zucchi and C Montagna and L Susani and P Vezzoni and R Dulbecco},

year  = {1998},

date = {1998-02-01},

journal = {Proc Natl Acad Sci U S A},

volume = {95},

number = {3},

pages = {1079--1084},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{cucca_male-female_1998,

title = {A male-female bias in type 1 diabetes and linkage to chromosome Xp in MHC},

author = {Cucca, F. and Goy, J. V. and Kawaguchi, Y. and Esposito, L. and Merriman, M. E. and Wilson, A. J. and Cordell, H. J. and Bain, S. C. and Todd, J. A.},

doi = {10.1038/995},

issn = {1061-4036 1061-4036},

year  = {1998},

date = {1998-01-01},

journal = {Nat Genet},

volume = {19},

number = {3},

pages = {301--302},

abstract = {It is generally assumed that the male:female (M:F) ratio in patients with type 1 (insulin-dependent) diabetes mellitus (IDDM) is 1. A recent survey, however, revealed that high incidence countries (mainly European) have a high M:F ratio and low incidence ones (Asian and African) have a low M:F ratio. We have now analysed the M:F ratio according to genotype at the major locus, the major histocompatibility complex (MHC; IDDM1). There are two main IDDM1 susceptibility haplotypes, HLA-DR3 and -DR4, which are present in 95% of Caucasian cases. We report here that in medium/high incidence Caucasian populations from the United States of America, United Kingdom and Sardinia (1307 cases), the bias in male incidence is largely restricted to the DR3/X category of patients (X not = DR4) with a M:F ratio of 1.7 (P=9.3x10(-7)), compared with a ratio of 1.0 in the DR4/Y category (Y;DR3). This is additional evidence for significant heterogeneity between the aetiology of 'DR4-associated' and 'DR3-associated' diabetes. We analysed linkage of type 1 diabetes to chromosome X, and as expected, most of the linkage to Xp13-p11 was in the DR3/X affected sibpair families (n=97; peak multipoint MLS at DXS1068=3.5},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{cucca_evaluation_1998,

title = {Evaluation of IgA deficiency in Sardinians indicates a susceptibility gene is encoded within the HLA class III region.},

author = {Cucca, F. and Zhu, Z. B. and Khanna, A. and Cossu, F. and Congia, M. and Badiali, M. and Lampis, R. and Frau, F. and De Virgiliis, S. and Cao, A. and Arnone, M. and Piras, P. and Campbell, R. D. and Cooper, M. D. and Volanakis, J. E. and Powis, S. H.},

issn = {0009-9104 0009-9104},

year  = {1998},

date = {1998-01-01},

journal = {Clin Exp Immunol},

volume = {111},

number = {1},

pages = {76--80},

abstract = {IgA deficiency (IgA-D) has been associated with the HLA region, in particular with the North European haplotype HLA-A1, -B8, -DR3, but the exact location of the susceptibility gene(s) is unknown. Some reports suggest that a susceptibility gene is encoded in the class II region, while others implicate the class III region. We exploited differences between the common Sardinian and North European},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{marrosu_multiple_1997,

title = {Multiple sclerosis in Sardinia is associated and in linkage disequilibrium with},

author = {Marrosu, M. G. and Murru, M. R. and Costa, G. and Cucca, F. and Sotgiu, S. and Rosati, G. and Muntoni, F.},

doi = {10.1016/S0002-9297(07)64074-9},

issn = {0002-9297 0002-9297},

year  = {1997},

date = {1997-08-01},

journal = {Am J Hum Genet},

volume = {61},

number = {2},

pages = {454--457},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{merriman_evidence_1997,

title = {Evidence by allelic association-dependent methods for a type 1 diabetes polygene (IDDM6) on chromosome 18q21.},

author = {Merriman, T. and Twells, R. and Merriman, M. and Eaves, I. and Cox, R. and Cucca, F. and McKinney, P. and Shield, J. and Baum, D. and Bosi, E. and Pozzilli, P. and Nistico, L. and Buzzetti, R. and Joner, G. and Ronningen, K. S. and Thorsby, E. and Undlien, D. and Pociot, F. and Nerup, J. and Bain, S. and Barnett, A. and Todd, J.},

issn = {0964-6906 0964-6906},

year  = {1997},

date = {1997-07-01},

journal = {Hum Mol Genet},

volume = {6},

number = {7},

pages = {1003--1010},

abstract = {Type 1 diabetes is a common polygenic disease. Fine mapping of polygenes by affected sibpair linkage analysis is not practical and allelic association or linkage disequilibrium mapping will have to be employed to attempt to detect founder chromosomes. Given prior evidence of linkage of the Jk-D18S64 region of chromosome 18q12-q21 to type 1 diabetes, we evaluated the 12 informative microsatellite markers in the region for linkage with disease by the transmission disequilibrium test (TDT) in a UK data set of type 1 diabetic families (n = 195). Increased transmission of allele 4 of marker D18S487 to affected children was detected (P = 0.02). Support for this was extended in a total of 1067 families from four different countries by isolating, and evaluating by the TDT, two novel microsatellites within 70 kb of D18S487. Evidence for linkage and association was P = 5 x 10(-5) and 3 x 10(-4), respectively. There was no evidence for increased transmission of associated alleles to nonaffected siblings. Analysis of an additional 390 families by the TDT did not extend the evidence further, and reduced support in the total 1457 families to P = 0.001 for linkage and P = 0.003 for association. However, evidence for linkage by affected sibpair allele sharing was strong (P = 3.2 x 10(-5)) in the second data set. Heterogeneity in TDT results between data sets was, in part, accounted for by the presence of more than one common disease-associated haplotype (allelic heterogeneity) which confounds the analysis of individual alleles by the TDT. Guidelines for strategies for the mapping of polygenes are suggested with the emphasis on collections of large numbers of families from multiple populations that should be as genetically homogeneous as possible.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{reed_evidence_1997,

title = {Evidence for a type 1 diabetes susceptibility locus (IDDM10) on human chromosome 10p11-q11.},

author = {Reed, P. and Cucca, F. and Jenkins, S. and Merriman, M. and Wilson, A. and McKinney, P. and Bosi, E. and Joner, G. and Ronningen, K. S. and Thorsby, E. and Undlien, D. and Merriman, T. and Barnett, A. and Bain, S. and Todd, J.},

issn = {0964-6906 0964-6906},

year  = {1997},

date = {1997-07-01},

journal = {Hum Mol Genet},

volume = {6},

number = {7},

pages = {1011--1016},

abstract = {A region of linkage to type 1 diabetes has been defined on human chromosome 10p11-q11 (IDDM10; P = 0.0007) using 236 UK and 76 US affected sibpairs and a 1 cM resolution microsatellite marker map. Analysis by the transmission disequilibrium test (TDT) in 1159 families with at least one diabetic child, from the UK, the US, Norway, Sardinia and Italy provided additional support for linkage at D10S193 (P = 0.006},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid9195958,

title = {hMAF, a small human transcription factor that heterodimerizes specifically with Nrf1 and Nrf2},

author = { M. G. Marini and K. Chan and L. Casula and Y. W. Kan and A. Cao and P. Moi},

year  = {1997},

date = {1997-06-01},

journal = {J Biol Chem},

volume = {272},

number = {26},

pages = {16490--16497},

abstract = {A 1.6-kilobase pair full-length cDNA encoding a transcription factor homologous to the Maf family of proteins was isolated by screening a K562 cDNA library with the NFE2 tandem repeat probe derived from the globin locus control region. The protein, which was designated hMAF, contains a basic DNA binding domain and an extended leucine zipper but lacks any recognizable activation domain. Expressed in vitro, the hMAF protein is able to homodimerize in solution and band-shift the NFE2 tandem repeat probe. In addition to homodimers, hMAF can also form high affinity heterodimers with two members of the NFE2/CNC-bZip family (Nrf1 and Nrf2) but not with a third family member, p45-NFE2. Although hMAF/hMAF homodimers and hMAF/Nrf1 and hMAF/Nrf2 heterodimers bind to the same NFE2 site, they exert functionally opposite effects on the activity of a linked gamma-globin gene. In fact, whereas all hMAF/CNC-bZip heterodimers stimulate the activity of a gamma-promoter reporter construct in K562 cells, the association into homodimers that is induced by overexpressing hMAF inhibits the activity of the same construct. Thus variations in the expression of hMAF may account for the modulation in the activity of the genes that bear NFE2 recognition sites.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Marrosu1997,

title = {Parenteral inheritance of susceptible and protective hla-dr, dq haplotypes in sardinian multiple sclerosis},

author = {Marrosu, M.G., Cucca, F., Murru, R., Costa, G., Murru, M.R., Muntoni, F. },

issn = {03920461},

year  = {1997},

date = {1997-04-01},

journal = {Italian Journal of Neurological Sciences},

volume = {18},

number = {4},

pages = {27},

abstract = {The preponderance of genetic factors in accounting for susceptibility to multiple sclerosis (MS) has recently been demonstrated. Regarding parenteral inheritance, data on MS susceptibility are discordant. Using the transmission-disequilibrium test, we examined maternal and paternal segregation of susceptible and protective HLA-DR,DQ haplotype from 109 MS Sardinian pedigrees. The susceptible DRB1*0405,DQA1*0501,DQB1*0301 haplo-type, found in linkage-disequilium with MS (chi-square=0.001), was inherited by mothers (chi-square=0.001). The protective DRB1*1502,DQA1*0103, DQB1*0603 haplotype, found increased in healthy siblings (chi-square=0.01), was inherited by mothers (chi-square =0.02). These data may suggest an imprinting mechanism in inheritance of HLA alleles involved in MS.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}