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 × 10(-9)) and *11:01 (OR, 1.69; 95% CI, 1.42-2.01; P = 3.0 × 10(-9)). The strongest protective association was found with *03:01 (OR, 0.56; 95% CI, 0.44-0.73; P = 1.0 × 10(-5)). 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 × 10(-4)), 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.

Keywords: HLA-DRB1 chains; SNPs; association studies; genetic; molecular docking simulation; pulmonary sarcoidosis.

Figure 1.

Half-maximal inhibitory concentration (IC₅₀) values for class II HLA-DRB1*03:01, *03:02, *11:01, and *12:01 allelic epitopes for selected proteins previously shown to be associated with sarcoidosis. IC₅₀ values are plotted for all possible 15-mer peptides across the amino acid sequences of ESAT6 (Mycobacterium tuberculosis) (A), T KatG (M. tuberculosis) (B), HSP70 (M. tuberculosis) (C), soda (M. tuberculosis) (D), trigger factor (Propionibacterium acnes) (E), and MAP2694 (Mycobacterium avium ssp. paratuberculosis K-10) (F). The dashed line on each graph represents an IC₅₀ binding threshold of 50 nM, which is considered strong binding.

Figure 2.

The binding motifs of the HLA-DRB1*03:01 and 03:02 alleles visualized using a logo-plot. The Kullback–Leibler (KL) sequence logo representation of the binding motifs of the HLA-DRB1*03:01 and *03:02 alleles is taken from the MHC Motif Viewer website (http://www.cbs.dtu.dk/biotools/MHCMotifViewer/Home.html). The KL information content is plotted along the nine-amino-acid binding core. Amino acids with greater binding preference are plotted on the positive y axis, whereas amino acids with a negative influence on binding are plotted on the negative y axis. The height of each amino acid represents its relative binding specificity. Color-coding of amino acids represent the physicochemical properties of acidic (red), basic (blue), hydrophobic (black), and neutral (green). Of the primary anchor positions (P1, P4, P6, and P9), positions 1 and 4 show the most dramatic differences in amino acid preferences between the two HLA molecules. At P1, *03:01 prefers hydrophobic amino acids, whereas *03:02 prefers hydrophobic but will also bind neutral tyrosine. The allele *03:01 has a preference for basic amino acids at P6, whereas *03:02 is more promiscuous, preferentially binding with hydrophobic or neutral amino acids at the P6 anchor.