rs2305160

This association study examined nine functional SNPs in circadian positive feedback loop genes (CLOCK, BMAL1, NPAS2) in 704 Chinese gastric cancer patients. Three SNPs showed significant associations with overall survival and recurrence-free survival: rs11133399 in CLOCK (HR 1.27-1.29, p=0.007-0.020), rs2279284 in BMAL1 (HR 1.12-1.18, p=0.024-0.048), and rs1044432 in BMAL1 (HR 0.82-0.84, p=0.042-0.047). Functional assays confirmed that the G allele of rs11133399 enhanced CLOCK promoter activity and gene expression.

This prospective cohort study of 609 breast cancer cases and 1,216 matched controls from the Nurses' Health Study II found no main effect of 178 common variants in circadian and melatonin metabolism genes on breast cancer risk. However, it identified a significant gene-environment interaction between NPAS2 Ala394Thr (rs2305160) and rotating shift-work exposure: among women with ≥2 years of night shift work, the Thr/Thr genotype was associated with a 2.83-fold increased breast cancer risk (OR=2.83, 95% CI: 1.47-5.56) compared to the Thr/Thr genotype with minimal shift exposure.

This case-control study of 455 NHL cases and 527 controls examined the Ala394Thr polymorphism (rs2305160) in the circadian gene NPAS2. The variant Thr genotypes were associated with significantly reduced NHL risk (OR = 0.66, 95% CI: 0.51-0.85, p = 0.001), particularly for B-cell lymphoma (OR = 0.61, 95% CI: 0.47-0.80, p ≤ 0.0001). This study provides the first molecular epidemiologic evidence that genetic variation in circadian genes may modify susceptibility to lymphoma.