Early life sun exposure, vitamin D-related gene variants, and risk of non-Hodgkin lymphoma

Purpose: It has been hypothesized that vitamin D mediates the inverse relationship between sun exposure and non-Hodgkin lymphoma (NHL) risk reported in several recent studies. We evaluated the association of self-reported sun exposure at ages <13, 13-21, 22-40, and 41+ years and 19 single nucleotide polymorphisms (SNPs) from 4 candidate genes relevant to vitamin D metabolism (RXR, VDR , CYP24A1, CYP27B1) with NHL risk. Methods: This analysis included 1,009 newly diagnosed NHL cases and 1,233 frequency-matched controls from an ongoing clinic-based study. Odds ratios (OR), 95 % confidence intervals (CI), and tests for trend were estimated using unconditional logistic regression. Results: There was a significant decrease in NHL risk with increased sun exposure at ages 13-21 years (OR _{≥15 vs.≤3 h/week} = 0.68; 95 % CI, 0.43-1.08; p _trend = 0.0025), which attenuated for older ages at exposure. We observed significant main effect associations for 3 SNPs in VDR and 1 SNP in CYP24A1: rs886441 (OR _per-allele = 0.82; 95 % CI, 0.70-0.96; p = 0.016), rs3819545 (OR _per-allele = 1.24; 95 % CI, 1.10-1.40; p = 0.00043), and rs2239186 (OR _per-allele = 1.22; 95 % CI, 1.05-1.41; p = 0.0095) for VDR and rs2762939 (OR _per-allele = 0.85; 95 % CI, 0.75-0.98; p = 0.023) for CYP24A1. Moreover, the effect of sun exposure at age 13-21 years on overall NHL risk appears to be modified by germline variation in VDR (rs4516035; p _interaction = 0.0066). Exploratory analysis indicated potential heterogeneity of these associations by NHL subtype. Conclusion: These results suggest that germline genetic variation in VDR, and therefore the vitamin D pathway, may mediate an association between early life sun exposure and NHL risk.