Abstract 2859: Genetic polymorphisms in thePTHandPTHR1genes and colorectal adenoma risk

Background: A number of cohort studies and randomized trials suggest that high calcium consumption may confer a reduced risk of colorectal cancer. Results, however, have been inconsistent. It is possible that the calcium effect may differ by polymorphisms in the genes involved in calcium regulation. Parathyroid hormone (PTH) is a critical hormone in the regulation of calcium concentration in extracellular fluid. The PTH and its receptors (PTHR) play an essential role in calcium homeostasis. Thus far, no study has been conducted to investigate the association of genetic variations in the PTH pathway and risk of colorectal adenoma or cancer. In the present study, we examined single nucleotide polymorphisms (SNPs) in the PTH and PTHR genes and their interaction with calcium intake in relation to risk of colorectal adenoma using data from the Tennessee Colorectal Polyp Study. Methods: Included in the study were participants of the Tennessee Colorectal Polyp study, an ongoing colonoscopy-based case control study conducted in Nashville, TN. Genotyping was performed at Vanderbilt Microarray Shared resource using the Affymetrix Human Mapping 500K array set. Three SNPs in the PTH gene and two SNPs in the PTHR1 were genotyped for 738 colorectal adenoma cases and 776 controls. Hardy-Weinberg equilibrium was assessed for each SNP among controls. The associations of each genotype with colorectal adenoma risk were evaluated under dominant, recessive and additive models, respectively. Multivariate unconditional logistic regression models were used to estimate the odds ratio and 95% confidence intervals for each SNP. Multiplicative interactions were evaluated for gene-diet interactions using likelihood ratio tests. Results: There were no significant differences in selected demographic characteristics and potential confounding factors between the colorectal adenoma case and control groups. All the genotype frequencies for PTH and PTHR1 were in Hardy-Weinberg equilibrium. There were no associations between the PTH genotypes and the risk for colorectal adenoma under dominant, recessive or additive models. One SNP (rs 7652849) in the PTHR1 gene was significantly associated with the risk of colorectal adenoma in both unadjusted model (OR: 1.32; 95%CI: 1.02, 1.71; p = 0.034) and adjusted model (OR: 1.32; 95%CI: 1.00, 1.73; p = 0.047). Furthermore, we found the SNP (rs 936173) in the PTHR1 gene significantly interacted with calcium intake in relation to risk of colorectal cancer (p = 0.046). No significant interactions with calcium intake were observed for the PTH gene. Conclusions: Our results suggest polymorphisms in PTHR1 may contribute to or interact with calcium intake in relation to risk of colorectal adenoma. Although further investigations of the PTHR1 gene polymorphisms on colorectal adenoma risk are required, our findings might provide some new insights into the mechanisms through which calcium reduces colorectal cancer risk. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2859.