Sarcoidosis Susceptibility and Resistance HLA-DQB1 Alleles in African Americans

Abstract

Sarcoidosis, in the United States, more commonly and severely affects African Americans. HLA associations with sarcoidosis have been reported, but most studies used case-control designs, which may produce biased results because of population stratification. We examined transmission of HLA-DQB1 alleles in 225 African American families with at least one offspring with sarcoidosis. Of five low-resolution HLA-DQB1 alleles, *02 and *06 showed significant deviation in transmission patterns to affected offspring. High-resolution typing of these allelic subsets revealed that HLA-DQB1*0201 was transmitted to affected offspring half as often as expected (p = 0.001), whereas DQB1*0602 was transmitted to affected offspring about 20% more often than expected (p = 0.029). Examining interactions between *0201 and *0602 alleles and environmental exposures showed that *0602 varied little with respect to exposure, but sarcoidosis risk associated with *0201 often depended on exposure status. Alternatively, the *0602 allele in affected probands was associated with radiographic disease progression, but the *0201 allele showed no significant correlation with phenotype. Major differences in the amino acid sequences encoded by *0201 and *0602 alleles exist, which may explain the differential effects these alleles have on sarcoidosis susceptibility and progression in African Americans.

Genome-wide search for sarcoidosis susceptibility genes in African Americans

“…We thought this dense marker coverage of the MHC was warranted given the strong linkage to sarcoidosis found in German Caucasians and the multitude of reported HLA associations with sarcoidosis including an association we previously reported between HLA-DQB1 and sarcoidosis susceptibility in a separate African-American sample. 16 We found no evidence for linkage of sarcoidosis susceptibility to the MHC region of chromosome 6p in our SAGA study population. The SAGA study did have potential agreements with the previously reported scan by Schurmann et al 14 on chromosomes 1p and 9q.…”

“…On the basis of 225 microsatellite markers tested in 63 German families (Caucasians) with affected sib pairs, linkage at the major histocompatibility complex (MHC) on chromosome 6p was found with additional suggested linkage to markers on chromosome 1, 3, 9 and X. 14 Several candidate genes from the MHC region have been investigated [15][16][17] with the DRB1 gene most consistently identified as a risk factor for sarcoidosis. [18][19][20] Replicating linkage findings in additional samples is key to unraveling the genetics of complex diseases, such as sarcoidosis.…”

Gene-environment interactions in sarcoidosis: challenge and opportunity

“…Much genetic research to date has focused on the roles of genes governing the molecules necessary for antigen-specific T-cell stimulation. In this regard, numerous investigators have described disease associations with HLA polymorphisms, especially those coding for Class II molecules [3,4]. Predictably, analysis of T-cell receptor variants has also revealed patterns associated with disease susceptibility or phenotype [46].…”

“…The first study to systematically examine gene-environment interactions employed familybased association analysis to identify HLA-DQB1 susceptibility alleles in 704 individuals from 225 African-American families [3]. Unclear consanguity, suspected by finding non-Mendelian segregation for a panel of unlinked genomic markers, resulted in exclusion of 8% of the families.…”

“…There are accumulating parallel data suggesting important roles for both genetic susceptibility (reviewed by DuBois) and specific transmissible environmental agents (reviewed by Crouser) ( Table 1). A variety of investigators have reported important susceptibility and protective roles for genes mediating immune responses, especially for the human leukocyte antigen (HLA) genes located on Chromosome 6p [2][3][4]. The HLA genes govern the expression of the Type II major histocompatibility complex (MHC) on antigen presenting cells, which mediates antigenspecific responses to exogenous agents by presenting the relevant antigen to a cognate T-cell antigen receptor that is expressed on the surface of T-cells.…”