Programmed Death Ligand 1 (PD-L1) Gene Variants Contribute to Autoimmune Addison's Disease and Graves' Disease Susceptibility

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. Design and Patients: We analyzed eight SNPs within PD-L1 in a United Kingdom cohort of 315 AAD subjects and 316 healthy controls. We then replicated our experiment in a cohort of 342 Norwegian 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 modest association with both AAD and GD in the United Kingdom cohort, with maximum evidence 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)