Genetic characterization and fine mapping of susceptibility loci for sarcoidosis in African Americans on chromosome 5

Abstract

Sarcoidosis, a systemic granulomatous disease, likely results from both environmental agents and genetic susceptibility. Sarcoidosis is more prevalent in women and, in the United States, African Americans are both more commonly and more severely affected than Caucasians. We report a follow up of the first genome scan for sarcoidosis susceptibility genes in African Americans. Both the genome scan and the present study comprise 229 African American nuclear families ascertained through two or more sibs with sarcoidosis. Regions studied included those which reached a significance in the genome scan of 0.01 (2p25, 5q11, 5q35, 9q34, 11p15 and 20q13), 0.05 (3p25 and 5p15-13) or which replicated previous findings (3p14-11). We performed genotyping with additional markers in the same families used in the genome scan. We examined multi-locus models for epistasis and performed model-based linkage analysis on subsets of the most linked families to characterize the underlying genetic model. The strongest signal was at marker D5S407 (P=0.005) on 5q11.2, using both full and half sibling pairs. Our results support, in an African American population, a sarcoidosis susceptibility gene on chromosome 5q11.2, and a gene protective for sarcoidosis on 5p15.2. These fine mapping results further prioritize the importance of candidate regions on chromosomes 2p25, 3p25, 5q35, 9q34, 11p15 and 20q13 for African Americans. Additionally, our results suggest joint action of the effects of putative genes on chromosome 3p14-11 and 5p15.2. We conclude that multiple susceptibility loci for sarcoidosis exist in African Americans and that some may have interdependent effects on disease pathogenesis.

Recent advances in the genetics of sarcoidosis

“…In addition, there was only modest agreement for linkage between the scans performed in the German and African American populations. In a follow-up study on the same patient population using additional microsatellite markers to refine regions with significant linkage, sarcoidosis susceptibility alleles were identified on chromosome 5p15.2 and protective alleles on chromosome 5q11.2 46. A further linkage analysis of the SAGA sample stratified by genetically determined ancestry (in order to reduce ethnic confounding) confirmed the peaks on chromosome 5 and revealed additional-associated loci 47…”

Sarcoidosis: the links between epidemiology and aetiology

“…In a follow-up to this, microsatellite markers positioned this susceptibility allele on chromosome 5 at 5p15.2, with a protective allele at position 5q11.2 46. More recently, several studies have identified multiple gene loci associated with the risk of sarcoidosis, on chromosomes 1, 2, 5, 6, 9, 11, 12, and 20 33–36.…”

Genetic Predisposition to Respiratory Diseases: Infiltrative Lung Diseases

“…Replication of the susceptibility allele in BTNL2, rs2076530, was performed in an African-American family-based population, and in African-American and Caucasian case-control populations. In all 3 study populations there was a haplotype associated with sarcoidosis, but the association was much stronger in Caucasians (p = 0.0006) compared with the African-American family population (p = 0.03) or case-control population (p = 0.02) [69, 70, 73]. These authors suggested that while in Caucasians the effects of BTNL2 are independent of HLA class II genes, there may be an antagonistic interaction between these loci in African-Americans.…”