Human Molecular Genetics

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Human Molecular Genetics, 1999, Vol. 8, No. 7 1195-1199
© 1999 Oxford University Press

The cytotoxic T lymphocyte antigen-4 is a major Graves’ disease locus

Bijayeswar Vaidya^a, Helen Imrie^a, Petros Perros¹, Eric T. Young², William F. Kelly³, David Carr⁴, David M. Large⁵, Anthony D. Toft⁶, Mark I. McCarthy⁷, Pat Kendall-Taylor and Simon H. S. Pearce^b

Endocrine Group, Department of Medicine, 4th Floor Leech Building, The Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne NE2 4HH, UK, ¹Department of Medicine, Freeman Hospital, Newcastle upon Tyne NE7 7DN, UK, ²Department of Medicine, Wansbeck General Hospital, Ashington, Northumbria NE63 9JJ, UK, ³Diabetes Care Centre, Middlesbrough General Hospital, Middlesbrough TS5 5AZ, UK, ⁴Department of Medicine, North Tees General Hospital, Stockton on Tees TS19 8PE, UK, ⁵Department of Medicine, Cumberland Infirmary, Carlisle CA2 7HY, UK, ⁶Endocrine Unit, Royal Infirmary of Edinburgh, Edinburgh EH3 9YW, UK and ⁷Section of Endocrinology, Division of Medicine, Imperial College School of Medicine at St Mary’s, London W2 1PG, UK

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 _s for this region of 2.2. Families with brother–sister sib-pairs showed a peak NPL of 3.46 (P = 0.0003, _s > 10) at D2S117, compared with 2.00 (P = 0.02, _s = 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 TNF. We demonstrate that the CTLA-4 locus (_s = 2.2) and the MHC locus (_s = 1.6) together confer ~50% of the inherited susceptibility to GD disease in our population.

^a These authors contributed equally to this work

^b To whom correspondence should be addressed. Tel: +44 191 222 8026; Fax. +44 191 222 0723; Email: spearce{at}hgmp.mrc.ac.uk

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