Evidence for a Graves' disease susceptibility locus at chromosome Xp11 in a United Kingdom population.
Graves' disease (GD), which has a strong female preponderance (female/male ratio, >5:1), is inherited as a complex genetic trait. Loci for GD have started to be defined using genome-wide approaches for genetic linkage. To date, 3 loci have been confirmed in at least 2 cohorts of GD patients, the strongest effect being at the cytotoxic T lymphocyte antigen-4 (CTLA-4) locus on chromosome 2q33 in our population. Two other loci for GD have recently been proposed, but not confirmed, on chromosomes Xq21 (GD3) and 14q31 (GD1). We studied a cohort of 75 sibling pairs with GD from the United Kingdom for linkage to 12 markers over a 83-cM region of the X chromosome and for 8 markers over a 36-cM region of 14q31-q33. A peak multipoint nonparametric linkage score of 2.21 (P = 0.014) was found at marker DXS8083 on Xp11, which increased to a nonparametric linkage score of 3.18 (P = 0.001) in data that had been conditioned for allele sharing at the CTLA-4 locus under an epistatic model. There was no evidence to support linkage of GD to Xq21.33-q22 (GD3) or at the 14q31-q33 (GD1) region in our population. A locus with a moderate contribution to GD susceptibility (lambda(s) = 1.4) is likely to exist in the Xp11 region, but we are unable to confirm that the GD1 or the GD3 regions contain major susceptibility loci in our United Kingdom GD population.
Imrie
H
H
Endocrine Group, Department of Medicine, University of Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom NE2 4HH.
Vaidya
B
B
Perros
P
P
Kelly
W F
WF
Toft
A D
AD
Young
E T
ET
Kendall-Taylor
P
P
Pearce
S H
SH
D000069594:Abatacept; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics; D060908:CTLA-4 Antigen; D002874:Chromosome Mapping; D002883:Chromosomes, Human, Pair 14; D002889:Chromosomes, Human, Pair 2; D008040:Genetic Linkage; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006111:Graves Disease / Q000235:genetics*; D006801:Humans; D018796:Immunoconjugates; D008285:Major Histocompatibility Complex; D018895:Microsatellite Repeats / Q000235:genetics; D009679:Nuclear Family; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D011989:Receptors, Thyrotropin / Q000235:genetics; D018709:Statistics, Nonparametric; D013967:Thyroiditis, Autoimmune / Q000235:genetics*; D006113:United Kingdom; D014960:X Chromosome
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D005819:Genetic Markers; D018796:Immunoconjugates; D011989:Receptors, Thyrotropin; D000069594:Abatacept