Effects of vitamin A and D receptor gene polymorphisms/haplotypes on immune responses to measles vaccine.

摘要

OBJECTIVE: Vitamins A and D, and their receptors, are important regulators of the immune system, including vaccine immune response. We assessed the association between polymorphisms in the vitamin A receptors [retinoic acid receptor alpha, retinoic acid receptor beta (RARB), and retinoic acid receptor gamma] and vitamin D receptor (VDR)/retinoid X receptor alpha (RXRA) genes and interindividual variations in immune responses after two doses of measles vaccine in 745 children. METHODS: Using a tag single nucleotide polymorphism (SNP) approach, we genotyped 745 healthy children for the 391 polymorphisms in vitamin A receptor and VDR genes. RESULTS: The RARB haplotype (rs6800566/rs6550976/rs9834818) was significantly associated with variations in both measles antibody (global, P=0.013) and cytokine secretion levels, such as interleukin (IL)-10 (global, P=0.006), interferon (IFN)-alpha (global, P=0.008), and tumor necrosis factor-alpha (global, P=0.039) in the Caucasian subgroup. Specifically, the RARB haplotype, AAC, was associated with higher (t-statistic: 3.27, P=0.001) measles antibody levels. At the other end of the spectrum, haplotype GG for rs6550978/rs6777544 was associated with lower antibody levels (t-statistic: -2.32, P=0.020) in the Caucasian subgroup. In a sensitivity analysis, the RARB haplotype, CTGGGCAA, remained marginally significant (P<0.02) when the single SNP rs12630816 was included in the model for IL-10 secretion levels. A significant association was found between lower measles-specific IFN-gamma Enzyme-linked immunosorbent spot responses and haplotypes rs11102986/rs11103473/rs11103482/rs10776909/rs12004589/rs35780541/rs2266677/rs875 444 (global, P=0.004) and rs6537944/rs3118571 (global, P<0.001) in the RXRA gene for Caucasians. We also found associations between multiple RARB, VDR, and RXRA SNPs/haplotypes and measles-specific IL-2, IL-6, IL-10, IFN-alpha, IFN-gamma, IFNlambda-1, and TNF-alpha cytokine secretions. CONCLUSION: Our results suggest that specific allelic variations and haplotypes in the vitamin A receptor and VDR genes may influence adaptive immune responses to measles vaccine.