Journal Article

The Cytotoxic T Lymphocyte Antigen-4 is a Major Graves' Disease Locus

Bijayeswar Vaidya, Helen Imrie, Petros Perros, Eric T. Young, William F. Kelly, David Carr, David M. Large, Anthony D. Toft, Mark I. McCarthy, Pat Kendall-Taylor and Simon H. S. Pearce

in Human Molecular Genetics

Volume 8, issue 7, pages 1195-1199
Published in print July 1999 | ISSN: 0964-6906
Published online July 1999 | e-ISSN: 1460-2083 | DOI:
The Cytotoxic T Lymphocyte Antigen-4 is a Major Graves' Disease Locus

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Graves' disease (GD) is an autoimmune thyroid disorder that is inherited as a complex trait. We have genotyped 77 affected sib-pairs with autoimmune thyroid disease for eight polymorphic markers spanning the cytotoxic T lymphocyte antigen-4 (CTLA-4) region of chromosome 2q31–q33, and for five markers spanning the major histocompatibility complex (MHC) region of chromosome 6p21. Non-parametric analysis showed linkage of GD to the CTLA-4 region with a peak non-parametric linkage (NPL) score of 3.43 (P = 0.0004) at the marker D2S117. The proportion of affected full-sibs sharing zero alleles (z0) reached a minimum of 0.113 close to D2S117, giving a locus-specific λs for this region of 2.2. Families with brother-sister sib-pairs showed a peak NPL of 3.46 (P = 0.0003, λs >10) at D2S117, compared with 2.00 (P = 0.02, λs = 1.9) in the families with only affected females, suggesting a stronger influence in families with affected males. Association between GD and the G allele of the Thr17Ala polymorphism within the CTLA-4 gene (CTLA4A/G) was observed using unaffected sib controls (P = 0.005). Lesser evidence for linkage was found at the MHC locus, with a peak NPL score of 1.95 (P = 0.026), between the markers D6S273 and TNFα. We demonstrate that the CTLA-4 locus (λs = 2.2)and the MHC locus (λs = 1.6) together confer ∼50% of the inherited susceptibility to GD disease in our population.

Journal Article.  3955 words.  Illustrated.

Subjects: Genetics and Genomics

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