Genetic association of htSNPs across the major histocompatibility complex with rheumatoid arthritis in an African-American population

Abstract

Notwithstanding the well-established association of HLA-DRB1 shared epitope alleles, interest remains in identifying additional major histocompatibility complex (MHC) region variants associated with rheumatoid arthritis (RA). We used a panel of 1201 haplotype-tagging single nucleotide polymorphisms (SNPs) designed for African Americans to find genetic variants associated with RA in a 3.8-Mb region encompassing the MHC. Conditioning on seven covariates, including HLA-DRB1 risk alleles and population structure, we identified an SNP in HLA-DOA (rs9276977) significantly associated with RA; minor allele frequency (MAF) 0.27 in cases versus 0.21 in controls, odds ratio (+/-95% confidence interval)=2.86 (1.61, 5.31). Genotyping of rs9276977 in an independent sample of African-American RA patients and controls did not replicate the association (MAF 0.28 in cases versus 0.27 in controls). This study points to the potential association of a SNP in the HLA-DOA gene with RA in African Americans, but also underscores the importance of replication of findings in larger patient cohorts.

Figure 1

−log P values of additive htSNP effect on case (+RA) - control status plotted by map position. Generalized linear models (binomial link function) were used to model case (N = 276)/control (N = 94) status with seven predictors for each of the 1,201 SNP markers using the statistical software package [R]. The patients and controls studied and the procedures for genotyping were fully described in Hughes et al. and Kelley et al. The predictors included the seven covariates, HLA-DRB1 risk alleles (0, 1, 2), gender, age, current smoking status (Yes/No), admixture (proportion of European ancestry), anti-CCP antibody status (Pos/Neg), and IgG serum RF factor (Pos/Neg), and the SNP with minor alleles coded 0, 1, or 2. The horizontal line is the adjusted type 1 error rate based on 702 effectively independent markers. The vertical line is the map position of the HLA-DRB1 locus. A permutation test based procedure (N = 100,000 permutations) was used to calculate an empirical p-value for rs9276977 of 6 × 10⁻⁵. The genotypic scores but not the responses were permuted in order to preserve the linkage among the potentially correlated covariates and disease status for each individual in the study. This permutation procedure has equivalent statistical properties as permuting the residuals of the regression of the response on the covariates.