Sirtuin 1 genetic variation, energy balance and colorectal cancer risk by sex and subsite in the Netherlands Cohort Study

C C J M Simons,R W Godschalk,P A Van Den Brandt,L J Schouten,F J Van Schooten,M P Weijenberg

doi:10.1038/s41598-018-34728-6

Abstract

Sirtuin 1 (SIRT1) is an energy-sensing protein, which may affect tumorigenesis. We used SIRT1 variants as time-independent indicators of SIRT1 involvement in carcinogenesis and we studied two tagging SIRT1 variants in relation to colorectal cancer (CRC) risk. We also evaluated known energy balance-related CRC risk factors within SIRT1 genotype strata. The Netherlands Cohort Study includes 120,852 individuals and has 20.3 years follow-up (case-cohort: nsubcohort = 5000; nCRC cases = 4667). At baseline, participants self-reported weight, weight at age 20, height, trouser/skirt size reflecting waist circumference, physical activity, and early life energy restriction. SIRT1 rs12778366 and rs10997870 were genotyped in toenail DNA available for ~75% of the cohort. Sex- and subsite-specific Cox hazard ratios (HRs) showed that the rs12778366 CC versus TT genotype decreased CRC and colon cancer risks in women (HRCRC = 0.53, 95% confidence interval: 0.30–0.94) but not men. Multiplicative interactions were observed between SIRT1 variants and energy balance-related factors in relation to CRC endpoints, but the direction of associations was not always conform expectation nor specific to one genotype stratum. In conclusion, these results support SIRT1 involvement in colon cancer development in women. No conclusions could be made regarding a modifying effect of SIRT1 variants on associations between energy balance-related factors and CRC risk.

Highlights

Colorectal cancer (CRC) is one of the most common cancers in men and women constituting close to 10% of the 14.1 million incident cancer cases worldwide in 20121
We expect colorectal cancer (CRC) risk factor-associations, to be consistent with previous Netherlands Cohort Study (NLCS) findings showing that a higher BMI and larger trouser/skirt size in men and tallness in women were associated with an increased CRC risk, distal colon cancer risk; showing that a higher level of physical activity was associated with a decreased CRC risk, distal colon cancer risk; and showing that early life energy restriction in women was associated with a decreased CRC risk, proximal colon and rectal cancer risk[3,4,5]
Sirtuin 1 (SIRT1) rs10997870 was not associated with any of the CRC endpoints considered in men and women in both co-dominant and additive models

Summary

Introduction

Colorectal cancer (CRC) is one of the most common cancers in men and women constituting close to 10% of the 14.1 million incident cancer cases worldwide in 20121. Associated with adiposity measures[14,15], high glucose, insulin, insulin-like growth factor 1, and diabetes[6] This suggests SIRT1 expression can be modified along the energy balance spectrum and concomitant diseases, with potential for CRC prevention when changing lifestyles that influence energy balance and CRC risk. We used two SIRT1 single nucleotide polymorphisms (SNPs) (rs10997870 and rs12778366) as time-independent indicators of SIRT1 involvement in carcinogenesis[17] We investigated these SIRT1 variants in relation to CRC risk by sex and subsite using data from 20.3 years follow-up from the Netherlands Cohort Study (NLCS). We hypothesized that associations between energy balance-relatd factors and CRC risk differ (in strength) between strata of SIRT1 genetic variants (effect modification), given SIRT1’s role in carcinogenesis and its role as an energy-sensing molecule. We expect CRC risk factor-associations, to be consistent with previous NLCS findings showing that a higher BMI and larger trouser/skirt size in men and tallness in women were associated with an increased CRC risk, distal colon cancer risk; showing that a higher level of physical activity (occupational physical activity in men and non-occupational physical activity in women) was associated with a decreased CRC risk, distal colon cancer risk; and showing that early life energy restriction in women was associated with a decreased CRC risk, proximal colon and rectal cancer risk[3,4,5]

Methods

Results

Conclusion