Journal Article

Conditional linkage disequilibrium analysis of a complex disease superlocus, <i>IDDM1</i> in the HLA region, reveals the presence of independent modifying gene effects influencing the type 1 diabetes risk encoded by the major <i>HLA-DQB1</i>, <i>-DRB1</i> disease loci

Patrizia Zavattari, Rosanna Lampis, Costantino Motzo, Miriam Loddo, Annapaola Mulargia, Michael Whalen, Mario Maioli, Efisio Angius, John A. Todd and Francesco Cucca

in Human Molecular Genetics

Volume 10, issue 8, pages 881-889
Published in print April 2001 | ISSN: 0964-6906
Published online April 2001 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/10.8.881
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

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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 ∼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.

Journal Article.  5452 words.  Illustrated.

Subjects: Genetics and Genomics

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