Abstract

Context: Despite much investigation, a substantial amount of the genetic susceptibility to autoimmune diseases remains unaccounted for. Recently, a single-nucleotide polymorphism (SNP) in the programmed death ligand 1 (PD-L1) gene has been associated with Graves’ disease (GD) in a Japanese patient cohort. Our aim was to determine whether variants in PD-L1 are also associated with autoimmune Addison’s disease (AAD) and to replicate the previous association in patients with GD from the United Kingdom. DesignandPatients:WeanalyzedeightSNPswithinPD-L1inaUnitedKingdomcohortof315AAD subjectsand316healthycontrols.Wethenreplicatedourexperimentinacohortof342Norwegian AAD cases and 379 controls and in 496 United Kingdom GD subjects. Results: Three of the eight SNPs studied, part of a haplotype block in the PD-L1 gene, showed modestassociationwithbothAADandGDintheUnitedKingdomcohort,withmaximumevidence at the marker RS1411262 [United Kingdom AAD odds ratio 1.33 (5–95% confidence interval 1.02– 1.73), P(genotype) 0.028; GD odds ratio 1.36 (5–95% confidence interval 1.07–1.72), P(genotype) 0.033]. Association with genotypes at the same three markers was confirmed in the Norwegian AAD cohort [P(genotype) 0.011–0.020]. A recessive effect at the most associated alleles was observed in both the AAD and GD cohorts. Conclusions: We confirm the role of PD-L1 variants in GD susceptibility and extend these findings to demonstrate association in two Northern European patient cohorts with AAD. PD-L1 joins the growing number of known susceptibility loci exerting modest effects in these autoimmune disorders. (J Clin Endocrinol Metab 94: 5139–5145, 2009)

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