Vitamin D (VitD) has immunomodulatory activity relevant to rheumatoid arthritis (RA) and acts by binding nuclear receptors that regulate gene transcription. VitD receptor polymorphisms have been variably associated with RA. Because North American Native (NAN) populations have a high prevalence of RA with a strong genetic contribution, we studied potential associations of the rs2228570 (Fok1) VitD receptor polymorphism in a Canadian NAN population.
The single-nucleotide polymorphism (SNP) Fok1 was tested by sequencing NAN patients with RA (n=448) and unrelated NAN controls (n=704). Associations were tested using genotypic, dominant, and recessive models.
The minor allele frequency (F/C) in the NAN control population was 0.44 and lower than reported in white subjects of the same geographical area. The Fok1 VitD receptor SNP was significantly associated with RA. Comparing patients with RA to unaffected NAN controls, the Fok1 SNP was associated with RA using both genotypic [FF vs Ff vs ff: RA 20%, 54%, 26% vs control 22%, 44%, 34% (chi-square 13.35, p=0.003)] and dominant models [FF/Ff vs ff: RA 74% vs 26% control 66% vs 34% (OR 1.5, 95% CI 1.16-1.96, p=0.003)]. This association was strongest in shared-epitope-positive RA.
VitD receptor polymorphisms may contribute to the high prevalence of RA in NAN populations.