Programmed death ligand 1 (PD-L1) gene variants contribute to autoimmune Addison's disease and Graves' disease susceptibility.
BACKGROUND
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.


METHODS
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.
Institute of Human Genetics, Newcastle University, Newcastle upon Tyne NE1 3BZ, United Kingdom.
Anna L
AL
Mitchell
Heather J
HJ
Cordell
Rachel
R
Soemedi
Kate
K
Owen
Beate
B
Skinningsrud
Anette Bøe
AB
Wolff
Martina
M
Ericksen
Dag
D
Undlien
Eystein
E
Husebye
Simon H S
SH
Pearce
D000224:Addison Disease / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D015703:Antigens, CD / Q000235:genetics*; D001327:Autoimmune Diseases / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D060890:B7-H1 Antigen; D015331:Cohort Studies; D005260:Female; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006111:Graves Disease / Q000235:genetics* / Q000473:pathology; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D009664:Norway / Q000453:epidemiology; D020641:Polymorphism, Single Nucleotide; D006113:United Kingdom / Q000453:epidemiology; D055815:Young Adult
D015703:Antigens, CD; D060890:B7-H1 Antigen; C423236:CD274 protein, human; D005819:Genetic Markers