Genotypic variability based association identifies novel non-additive loci DHCR7 and IRF4 in sero-negative rheumatoid arthritis

Sci Rep. 2017 Jul 13;7(1):5261. doi: 10.1038/s41598-017-05447-1.

Abstract

Sero-negative rheumatoid arthritis (RA) is a highly heterogeneous disorder with only a few additive loci identified to date. We report a genotypic variability-based genome-wide association study (vGWAS) of six cohorts of sero-negative RA recruited in Europe and the US that were genotyped with the Immunochip. A two-stage approach was used: (1) a mixed model to partition dichotomous phenotypes into an additive component and non-additive residuals on the liability scale and (2) the Levene's test to assess equality of the residual variances across genotype groups. The vGWAS identified rs2852853 (P = 1.3e-08, DHCR7) and rs62389423 (P = 1.8e-05, near IRF4) in addition to two previously identified loci (HLA-DQB1 and ANKRD55), which were all statistically validated using cross validation. DHCR7 encodes an enzyme important in cutaneous synthesis of vitamin D and DHCR7 mutations are believed to be important for early humans to adapt to Northern Europe where residents have reduced ultraviolet-B exposure and tend to have light skin color. IRF4 is a key locus responsible for skin color, with a vitamin D receptor-binding interval. These vGWAS results together suggest that vitamin D deficiency is potentially causal of sero-negative RA and provide new insights into the pathogenesis of the disorder.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Arthritis, Rheumatoid / blood*
  • Arthritis, Rheumatoid / genetics*
  • Case-Control Studies
  • Cohort Studies
  • Epistasis, Genetic
  • Female
  • Genetic Predisposition to Disease*
  • Genome-Wide Association Study
  • Genotype
  • Humans
  • Interferon Regulatory Factors / genetics*
  • Male
  • Oxidoreductases Acting on CH-CH Group Donors / genetics*
  • Phenotype
  • Polymorphism, Single Nucleotide*

Substances

  • Interferon Regulatory Factors
  • interferon regulatory factor-4
  • Oxidoreductases Acting on CH-CH Group Donors
  • 7-dehydrocholesterol reductase