Abstract 32: PER3 gene in association with plasma melatonin in Caucasian men.

Circadian rhythm disruption is classified as a possible human carcinogen, and has been associated with incidence, survival and prognosis of multiple cancers. Melatonin is the central circadian rhythm biomarker and identifying its genetic determinants will shed light on the mechanisms of the circadian rhythm-cancer relationship. We have conducted what we believe is the first genome wide association scan (GWAS) of morning circulating melatonin levels in humans. We used data from 1250 Caucasian men from the screening arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO). Serum used for melatonin measurements were prospectively collected and prediagnostic of cancer; all serum were collected in the morning (7:00-11:00 am). We evaluated ∼ 2.5 million single nucleotide polymorphisms (SNP), and gave priority to 1298 SNPs in 20 candidate genes related to melatonin and circadian rhythm (20 kb upstream-10 kb downstream). Single SNP analyses were performed using linear models for log transformed melatonin concentrations, coding SNPs additively, and adjusting for age (≤59, 60-64, 65-69, ≥70 years) time of blood draw (6-7, 8, 9, 10, 11 am), study center, prostate cancer status, and eigenvectors that captured population stratification. Gene based P-values (Pgene) were computed using the minP method and 10,000 permutations. For the most significant SNPs, we also performed sensitivity analyses by restricting the analysis to men who were not subsequently diagnosed with prostate cancer. We did not detect a signal at the genome-wide significance level (10-8). However, we observed that PER3 , one of the 9 core circadian rhythm regulating genes, was significantly associated with serum melatonin after Bonferroni correction for the 20 a priori candidate genes (Pgene=9×10−4). The top SNP (SNP1-7763877 G>T) achieved significance after Bonferroni correction that takes into account the total number of SNPs (1298) in the 20 candidate genes selected (P=1.24×10−5). For this SNP, serum melatonin decreased by 28% (14.8-40%) per T allele. Our study suggests that PER3 gene polymorphisms might be associated with melatonin production, the velocity of diurnal decrease, or its diurnal pattern. This results warrant replication in independent samples, in females, and in urine for metabolites of melatonin. Citation Format: Fangyi Gu, Lisa W. Chu, Kai Yu, Zhaoming Wang, Stephen Chanock, Ann Hsing, Neil E. Caporaso. PER3 gene in association with plasma melatonin in Caucasian men. [abstract]. In: Proceedings of the AACR Special Conference on Post-GWAS Horizons in Molecular Epidemiology: Digging Deeper into the Environment; 2012 Nov 11-14; Hollywood, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(11 Suppl):Abstract nr 32.