Single‐nucleotide polymorphisms in tumor necrosis factor receptor genes: Definition of novel haplotypes and racial/ethnic differences

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Abstract
Objective To characterize allele frequencies of known single‐nucleotide polymorphisms (SNPs) in tumor necrosis factor receptor (TNFR) genes in African Americans with rheumatoid arthritis (RA), healthy African Americans, and healthy Caucasians. Methods One TNFRSF1B SNP (196 G/T) that influences susceptibility to familial RA in Caucasians and 3 SNPs in the 5′ flanking region of the TNFRSF1A gene (‐609G/T, ‐580A/G, and ‐383A/C) were genotyped in 108 African Americans with RA, 62 healthy African Americans, and 59 healthy Caucasians. Results There were no differences in TNFRSF1A allele frequencies between African Americans with RA and healthy African Americans. Allele frequencies were strikingly different, however, between healthy African Americans and healthy Caucasians: 0.13 versus 0.42 for ‐609T, 0.49 versus 0 for ‐580G, and 0.14 versus 0 for ‐383C. We identified 4 novel haplotypes defined by the 3 TNFRSF1A SNPs, the distribution of which was markedly different in healthy Caucasians and healthy African Americans (P = 0.000001 by chi‐square test‐. The frequencies of the TNFRSF1B 196 genotypes were similar in African Americans with RA and healthy African Americans but differed between healthy African Americans and healthy Caucasians (P = 0.05). Conclusion Although we observed no associations between known TNFR SNPs or haplotypes and RA, significant racial differences were observed at both loci. Comparison of these data with other published frequencies of TNFRSF1A and TNFRSF1B genotypes according to race suggests that the distribution in African American, Caucasian, and Asian populations differs significantly. These striking racial/ethnic differences in TNFR SNP frequencies may influence the likelihood of familial RA, severe disease, or response to TNF inhibitors and may have important evolutionary implications.