期刊
SCIENTIFIC REPORTS
卷 7, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41598-017-05447-1
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资金
- Higher Education Funding Council for England (HEFCE)
- Cure Kids NZ
- University of Otago
- Arthritis Research UK [17552]
- Manchester Biomedical Research Centre
- Arthritis Foundation
- US National Institutes Health [K08AR055688, 1R01AR062886-01]
- Wellcome Trust [076113/C/04/Z, 068545/Z/02]
- US National Institutes for Health [RP-PG-0310-1002]
- UK Medical Research Council [G0000934]
- US National Institutes of Health [RO1-AR-4-4422, NO1-AR-2-2263, NO1-AR1-2256, RO1 AI068759, RC2AR059092-01]
- Eileen Ludwig Greenland Center for Rheumatoid Arthritis
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.
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