title: The cytotoxic T lymphocyte antigen-4 is a major Graves' disease locus.
abstract: 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 lambdas for this region of 2.2. Families with brother-sister sib-pairs showed a peak NPL of 3.46 ( P = 0.0003, lambdas > 10) at D2S117, compared with 2.00 ( P = 0.02, lambdas = 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 TNFalpha. We demonstrate that the CTLA-4 locus (lambdas = 2.2) and the MHC locus (lambdas = 1.6) together confer approximately 50% of the inherited susceptibility to GD disease in our population.
authors.affiliation: Endocrine Group, Department of Medicine, The Medical School, University of Newcastle upon Tyne, UK.
authors.forename: B
authors.initials: B
authors.lastname: Vaidya
authors.forename: H
authors.initials: H
authors.lastname: Imrie
authors.forename: P
authors.initials: P
authors.lastname: Perros
authors.forename: E T
authors.initials: ET
authors.lastname: Young
authors.forename: W F
authors.initials: WF
authors.lastname: Kelly
authors.forename: D
authors.initials: D
authors.lastname: Carr
authors.forename: D M
authors.initials: DM
authors.lastname: Large
authors.forename: A D
authors.initials: AD
authors.lastname: Toft
authors.forename: M I
authors.initials: MI
authors.lastname: McCarthy
authors.forename: P
authors.initials: P
authors.lastname: Kendall-Taylor
authors.forename: S H
authors.initials: SH
authors.lastname: Pearce
mesh_terms: D000069594:Abatacept; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics*; D001327:Autoimmune Diseases / Q000235:genetics; D060908:CTLA-4 Antigen; D002889:Chromosomes, Human, Pair 2; D002896:Chromosomes, Human, Pair 6; D005260:Female; D008040:Genetic Linkage; D006111:Graves Disease / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D018796:Immunoconjugates; D008285:Major Histocompatibility Complex / Q000235:genetics; D008297:Male
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D018796:Immunoconjugates; D000069594:Abatacept