Human Leukocyte Antigen Shared Epitope and Inflammation, Cardiovascular Disease, Cancer, and Mortality Among Postmenopausal Women in the Women's Health Initiative Rheumatoid Arthritis Study

Abstract

Specific alleles of the human leukocyte antigen (HLA)-DRB1 gene (HLA-DRB1) encode a "shared epitope" (SE) associated with rheumatoid arthritis (RA), especially more severe cyclic-citrullinated peptide antibody-positive (anti-CCP+) RA. We evaluated associations of number of SE alleles (0, 1, or 2) with total and cardiovascular disease (CVD) mortality and incident coronary heart disease (CHD), CVD, and cancer over a mean 8.9 (standard deviation, 3.5) years of follow-up, stratifying by baseline anti-CCP status (positive (+) vs. negative (-)). A longitudinal study, the Women's Health Initiative RA Study (1993-2010), sampled postmenopausal women who reported RA at baseline (1993-1998) or follow-up in the Women's Health Initiative, classified as anti-CCP+ RA (n = 556) or anti-CCP- non-RA (n = 1,070). Among anti-CCP+ RA women, SE alleles were not related to age-adjusted risks of CHD, CVD, or cancer or to total or CVD mortality. Among anti-CCP- non-RA women, age-adjusted hazard ratios for 1 and 2 SE alleles versus 0 SE alleles were 0.41 (95% confidence interval (CI): 0.34, 0.50) and 0.44 (95% CI: 0.27, 0.72), respectively, for CVD; 0.43 (95% CI: 0.37, 0.53) and 0.30 (95% CI: 0.16, 0.64), respectively, for CHD; and 0.62 (95% CI: 0.53, 0.73) and 0.52 (95% CI: 0.33, 0.83), respectively, for cancer. Associations persisted after adjustment for CVD risk factors, joint pain, rheumatoid factor positivity, and inflammatory markers (white blood cell count or cytokine level). In future studies, investigators should evaluate SE associations among anti-CCP- adults without RA and potential mechanisms.

Keywords: HLA-DRB1 gene; cancer; cardiovascular disease; human leukocyte antigen; mortality; rheumatoid arthritis; shared epitope.

Figure 1.

Median cytokine concentrations (pg/mL) according to the presence of antibodies to cyclic citrullinated peptides (anti-CCP) and number of human leukocyte antigen (HLA)-DRB1 gene (HLA-DRB1) shared epitope (SE) alleles among participants reporting rheumatoid arthritis (RA), Women's Health Initiative Rheumatoid Arthritis Study, 1993–2010. Women reporting RA at a follow-up visit only were excluded. Black columns, 0 SE alleles; striped columns, 1 SE allele; white columns, 2 SE alleles. P values presented below are from Kruskal-Wallis tests of the difference in median cytokine levels by number of SE alleles. A) Interleukin 2 (anti-CCP-positive (anti-CCP+) RA participants: P = 0.02; anti-CCP-negative (anti-CCP−) non-RA participants: P = 0.16); B) interleukin 6 (anti-CCP+ RA: P = 0.001; anti-CCP− non-RA: P = 0.24); C) interleukin 1β (anti-CCP+ RA: P = 0.04; anti-CCP− non-RA: P = 0.31); D) tumor necrosis factor α (TNF-α) (anti-CCP+ RA: P = 0.03; anti-CCP− non-RA: P = 0.22); E) interferon γ (anti-CCP+ RA: P = 0.01; anti-CCP− non-RA: P = 0.13); F) interleukin 10 (anti-CCP+ RA: P = 0.07; anti-CCP− non-RA: P = 0.003); G) interleukin 12 (anti-CCP+ RA: P = 0.19; anti-CCP− non-RA: P = 0.03); H) granulocyte colony-stimulating factor (G-CSF) (anti-CCP+ RA: P = 0.85; anti-CCP− non-RA: P = 0.04).