Association of HLA-DRB1 with Sarcoidosis Susceptibility and Progression in African Americans

Abstract

HLA-DRB1 is a sarcoidosis risk gene, and the *03:01 allele is strongly associated with disease resolution in European sarcoidosis cases. Whereas the HLA-DRB1 variation is associated with sarcoidosis susceptibility in African Americans, DRB1 risk alleles are not as well defined, and associations with disease resolution have not been studied. Associations between genotyped and imputed HLA-DRB1 alleles and disease susceptibility/resolution were evaluated in a sample of 1,277 African-American patients with sarcoidosis and 1,467 control subjects. In silico binding assays were performed to assess the functional significance of the associated alleles. Increased disease susceptibility was associated with the HLA-DRB1 alleles *12:01 (odds ratio [OR], 2.11; 95% confidence interval [CI], 1.65-2.69; P = 3.2 3 10 29 ) and *11:01 (OR, 1.69; 95% CI, 1.42-2.01; P = 3.0 3 10 29 ). The strongest protective association was found with *03:01 (OR, 0.56; 95% CI, 0.44-0.73; P = 1.0 3 10 25 ). The African-derived allele *03:02 was associated with decreased risk of persistent radiographic disease (OR, 0.52; 95% CI, 0.37-0.72; P = 1.3 3 10 24 ), a finding consistent across the three component studies comprising the analytic sample. The DRB1*03:01 association with disease persistence was dependent upon local ancestry, with carriers of at least one European allele at DRB1 at a decreased risk of persistent disease (OR, 0.36; 95% CI, 0.14-0.94; P = 0.037). Results of in silico binding analyses showed that DRB1*03:01 consistently demonstrated the highest binding affinities for six bacterial peptides previously found in sarcoidosis granulomas, whereas *12:01 displayed the lowest binding affinities. This study has identified DRB1*03:01 and *03:02 as novel alleles associated with disease susceptibility and course in African Americans. Further investigation of DRB1*03 alleles may uncover immunologic factors that favor sarcoidosis protection and resolution among African Americans.

Association of HLA antigens with the clinical course of sarcoidosis and familial disease

“…Sarcoidosis often shows an unpredictable disease course. Clinical manifestations also vary with the organs involved [5][6][7]. In our study, deteriorating FVC and DLCO values were also more frequent in HLA-DRB1*014 and HLA-DRB1*15 positive patients.…”

“…The cause of sarcoidosis and its wide phenotopic differences are not yet fully understood [4]. Prevalence in different ethnic groups, familial occurrence, and its high incidence among monozygotic twins suggests genetic predisposition and several studies indicate that HLA antigens are more frequent in patients with sarcoidosis and genetic factors may play an important role in modifying the risk for the disease, its phenotype, and outcome [1,[5][6][7][8][9][10].…”

Personalized medicine in interstitial lung diseases

“…Levin et al [58] genotyped a large population of African American patients (n ¼ 1277) and matched controls (n ¼ 1467), and found that, consistent with previous findings among individuals of European descent [57], carriage of the HLA-DRB1…”

Granuloma genes in sarcoidosis

“…Levin et al further showed carriage of DRB1*0301 decreased risk for extra-pulmonary manifestations of sarcoidosis in non-thoracic lymph nodes, eyes, skin and liver 12 . Alternatively, carriage of DRB1*0302 increased risk for skin involvement in African American sarcoidosis patients.…”

“…Levin et al examine DRB1 variation in the context of disease phenotype in 1,277 African Americans patients and 1,468 controls 12 . They found that the DRB1*03:02 allele conferred a similar likelihood of resolving disease in African American sarcoidosis patients as *03:01 -positivity does in Europeans 14 .…”