In the United States, incidence and mortality from sarcoidosis, a chronic, granulomatous disease, are increased in black women. In data from the Black Women's Health Study, a follow-up of US black women, we assessed two SNPs (rs2076530 and rs9268480) previously identified in the BTNL2 gene (chromosome 6p21), of which rs4424066 and rs3817963 are perfect proxies, to determine if they represent independent signals of disease risk. We also assessed whether local ancestry in four genomic regions previously identified through admixture mapping was associated with sarcoidosis. Finally, we assessed the relation of global percent African ancestry to risk. We conducted a nested case–control study of 486 sarcoidosis cases and 943 age- and geography-matched controls. Both BTNL2 SNPs were associated with risk of sarcoidosis in separate models, but in a combined analysis the increased risk was due to the A-allele of the rs3817963 SNP; each copy of the A-allele was associated with a 40 % increase in risk of sarcoidosis (p = 0.02) and was confirmed by our haplotypic analysis. Local African ancestry around the rs30533 ancestry informative marker at chromosome 5q31 was associated with a 29 % risk reduction (p = 0.01). Therefore, we adjusted our analysis of global African ancestry for number of copies of African alleles in rs30533. Subjects in the highest quintile of percent African ancestry had a 54 % increased risk of sarcoidosis. The present results from a population of African-American women support the role of the BTNL2 gene and the 5q31 locus in the etiology of sarcoidosis, and also demonstrate that percent African ancestry is associated with disease risk.
