Abstract
Background
Obesity is a convincing risk factor for colorectal cancer. Genetic variants in or near FTO and MC4R are consistently associated with body mass index and other body size measures, but whether they are also associated with colorectal cancer risk is unclear.
Methods
In the discovery stage, we tested associations of 677 FTO and 323 MC4R single nucleotide polymorphisms (SNPs) 100kb upstream and 300kb downstream from each respective locus with risk of colorectal cancer in data from the Colon Cancer Family Registry (CCFR: 1,960 cases; 1,777 controls). Next, all SNPs that were nominally statistically signif icant (p<0.05) in the discovery stage were included in replication analyses in data from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO: 9,716 cases; 9,844 controls).
Results
In the discovery stage, 43 FTO variants and 18 MC4R variants were associated with colorectal cancer risk (p<0.05). No SNPs remained statistically significant in the replication analysis after accounting for multiple comparisons.
Conclusion
We found no evidence that individual variants in or near the obesity-related genes FTO and MC4R are associated with risk of colorectal cancer.
Keywords: obesity, genetic variants, colorectal cancer, case-control study
Introduction
Obesity is a convincing risk factor for colorectal cancer [1]. Determinants of body mass index (BMI: kg/m2) are multifactorial, but invariably relate to energy balance; individual differences in the capacity to gain or lose body weight have a strong genetic basis. Genome-wide association studies (GWAS) have identified two loci, for which the genes fat mass and obesity-associated (FTO) and melanocortin-4 receptor (MC4R) were hypothesized, among other variants, that are consistently associated with body mass index (BMI) and other body size measures [2]. To date, GWAS have not identified any FTO or MC4R variants associated with colorectal cancer risk. Only three case-control studies have assessed the associations of variants in or near FTO and MC4R with colorectal cancer risk, and all reported null results [3–5]. However, these studies only included a limited number of SNPs in/near these two genes. Also, since the association of a specific SNP with the risk of cancer, if any, is typically relatively weak, insufficient statistical power is a major potential source of false negative findings in studies with smaller sample sizes.
Herein, we aimed to conduct a candidate gene study of FTO and MC4R, and to be exhaustive in that endeavor for those two genes. Specifically, we evaluated the associations of 1,000 single nucleotide polymorphisms (SNPs) in or near FTO and MC4R with colorectal cancer risk and whether the associations were mediated by BMI, using a two-stage design in data from the Colon Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO).
Materials and Methods
The initial discovery stage included two case-control series of non-Hispanic white participants from the CCFR. The first case-control series included 1,173 microsatellite-stable/microsatellite instability-low colorectal cancer cases and 984 population-based controls; the second case-control series included 787 cases and 793 of their unaffected siblings as controls. The replication stage comprised an independent series of 9,716 cases and 9,844 controls from GECCO. Details on data collection, selection criteria, and recruitment procedures in the CCFR and GECCO have been described previously [1, 6, 7]. Characteristics of CCFR and studies included in GECCO are demonstrated in Supplementary Table 1. All participants provided written informed consent, and studies were approved by their Institutional Review Boards.
Genotyping, quality control, and imputation procedures for the CCFR and GECCO were previously described [8], and further information can be found in the Supplementary Material. FTO and MC4R SNPs with >5% missing information or minor allele frequencies (MAF) <5% were excluded from analyses. We examined 677 FTO SNPs and 323 MC4R SNPs (including SNPs that were 100kb upstream and 300kb downstream from each respective locus) in the discovery stage. The odds ratio (OR) and 95% confidence intervals (CI) for each SNP (in log-additive models) with colorectal cancer was estimated using unconditional or conditional logistic regression, as appropriate depending upon study design, while adjusting for age, sex, and principal components of genetic ancestry (PCAs) to account for potential population substructure (all analyses were restricted to those of European descent). We analyzed models with and without adjustment for BMI to assess if the risk imposed by a given SNP operates through its effects on body size. Results from both CCFR case-control series were combined using random-effects meta-analysis. SNPs that were nominally associated with colorectal cancer risk (p < 0.05) in the combined discovery stage (with or without adjustment for BMI) were assessed in GECCO using unconditional logistic regression and adjusted for age, sex, and the top three PCAs. Bonferroni correction was applied to the replication results (Bonferroni-corrected alpha 0.001 for FTO SNPs and 0.003 for MC4R SNPs, calculated based on the number of SNPs that entered the replication stage for each gene). Statistical analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC). Power was estimated using PS Power and Sample Size software [9].
Results
Meta-analyses of the discovery stage data identified 43 FTO and 18 MC4R SNPs that were nominally associated with colorectal cancer risk (p < 0.05) after adjustment for age, sex, and PCAs, with or without further adjustment for BMI (Table 1). In the replication stage, 29 of the FTO SNPs and 1 of the MC4R SNPs were statistically significantly associated with BMI (Supplementary Table 2). None of the initially-identified SNPs from the discovery stage were associated with colorectal cancer risk with adjustment for age, sex, and PCAs; after additionally adjusting for BMI, two FTO SNPs (rs8046502 and rs4784329) had p-values < 0.05; the ORs were 1.04 (95% CI: 1.00 - 1.09; p = 0.048) and 0.96 (95% CI: 0.92 - 1.00; p = 0.048) for these two SNPs, respectively (Table 1). Associations of these two SNPs with colorectal cancer risk were not statistically significant after applying a Bonferroni-corrected α of 0.001. The results remained unchanged when we additionally adjusted the models for physical activity level and total energy intake.
Table 1.
Associations between FTO and MC4R SNPs and colorectal cancer risk in CCFR and GECCO
| SNP | Discovery phase |
Replication phase |
||||
|---|---|---|---|---|---|---|
| OR (95% CI) | P value | Model 1 |
Model 2 |
|||
| OR (95% CI) | P value | OR (95% CI) | P value | |||
| FTO | ||||||
| rs12149832 | 1.18 (1.06, 1.32) | 0.004 | 0.99 (0.95, 1.03) | 0.543 | 1.00 (0.95, 1.04) | 0.810 |
| rs4784336* | 1.30 (1.08, 1.57) | 0.005 | 0.99 (0.92, 1.06) | 0.801 | 1.00 (0.93, 1.07) | 0.916 |
| rs11075990 | 1.17 (1.05, 1.30) | 0.006 | 0.99 (0.95, 1.03) | 0.640 | 1.00 (0.96, 1.04) | 0.958 |
| rs9922619 | 1.17 (1.05, 1.30) | 0.006 | 0.99 (0.95, 1.03) | 0.519 | 0.99 (0.95, 1.04) | 0.749 |
| rs11075989 | 1.17 (1.04, 1.31) | 0.006 | 0.99 (0.95, 1.03) | 0.639 | 1.00 (0.96, 1.04) | 0.958 |
| rs9930506 | 1.16 (1.04, 1.30) | 0.007 | 0.99 (0.95, 1.03) | 0.552 | 0.99 (0.95, 1.04) | 0.790 |
| rs9936385 | 1.16 (1.04, 1.30) | 0.007 | 0.99 (0.95, 1.03) | 0.661 | 1.00 (0.96, 1.04) | 0.981 |
| rs9939609 | 1.16 (1.04, 1.30) | 0.007 | 0.99 (0.95, 1.03) | 0.639 | 1.00 (0.96, 1.04) | 0.957 |
| rs9922708 | 1.16 (1.04, 1.29) | 0.007 | 0.99 (0.95, 1.03) | 0.542 | 0.99 (0.95, 1.04) | 0.767 |
| rs9930501 | 1.16 (1.04, 1.29) | 0.007 | 0.99 (0.95, 1.03) | 0.553 | 0.99 (0.95, 1.04) | 0.791 |
| rs8050136 | 1.16 (1.04, 1.30) | 0.007 | 0.99 (0.95, 1.03) | 0.735 | 1.00 (0.96, 1.04) | 0.958 |
| rs8043757 | 1.16 (1.04, 1.29) | 0.008 | 0.99 (0.95, 1.03) | 0.731 | 1.00 (0.96, 1.04) | 0.956 |
| rs17817449 | 1.16 (1.04, 1.29) | 0.008 | 0.99 (0.95, 1.03) | 0.708 | 1.00 (0.96, 1.04) | 0.981 |
| rs9932754 | 1.16 (1.04, 1.29) | 0.008 | 0.99 (0.95, 1.03) | 0.552 | 0.99 (0.95, 1.04) | 0.789 |
| rs7193144 | 1.16 (1.04, 1.30) | 0.008 | 0.99 (0.95, 1.03) | 0.701 | 1.00 (0.96, 1.04) | 0.991 |
| rs8051591 | 1.16 (1.04, 1.29) | 0.008 | 0.99 (0.95, 1.03) | 0.723 | 1.00 (0.96, 1.04) | 0.970 |
| rs9935401 | 1.16 (1.04, 1.29) | 0.008 | 0.99 (0.95, 1.03) | 0.725 | 1.00 (0.96, 1.04) | 0.969 |
| rs1420571* | 1.26 (1.06, 1.51) | 0.009 | 0.99 (0.92, 1.06) | 0.747 | 0.99 (0.93, 1.06) | 0.827 |
| rs7202116 | 1.16 (1.04, 1.29) | 0.009 | 0.99 (0.95, 1.03) | 0.637 | 1.00 (0.96, 1.04) | 0.955 |
| rs3751812 | 1.16 (1.04, 1.29) | 0.009 | 0.99 (0.95, 1.03) | 0.733 | 1.00 (0.96, 1.04) | 0.964 |
| rs9923233 | 1.16 (1.04, 1.29) | 0.010 | 0.99 (0.95, 1.03) | 0.661 | 1.00 (0.96, 1.04) | 0.981 |
| rs7185735 | 1.15 (1.03, 1.29) | 0.011 | 0.99 (0.95, 1.03) | 0.627 | 1.00 (0.96, 1.04) | 0.940 |
| rs17817964 | 1.15 (1.03, 1.29) | 0.011 | 0.99 (0.95, 1.03) | 0.680 | 1.00 (0.96, 1.04) | 0.977 |
| rs4784337* | 1.26 (1.05, 1.51) | 0.013 | 0.99 (0.93, 1.06) | 0.790 | 1.00 (0.93, 1.07) | 0.889 |
| rs7201850 | 1.14 (1.03, 1.28) | 0.015 | 0.99 (0.95, 1.03) | 0.579 | 1.00 (0.96, 1.04) | 0.833 |
| rs4784346* | 1.16 (1.03, 1.31) | 0.017 | 1.00 (0.95, 1.04) | 0.891 | 1.00 (0.95, 1.04) | 0.870 |
| rs8044769 | 0.88 (0.79, 0.98) | 0.018 | 1.01 (0.97, 1.05) | 0.582 | 1.01 (0.97, 1.05) | 0.782 |
| rs7186220* | 1.19 (1.03, 1.37) | 0.018 | 1.00 (0.94, 1.05) | 0.844 | 0.99 (0.94, 1.05) | 0.772 |
| rs9941349 | 1.14 (1.02, 1.27) | 0.019 | 0.99 (0.95, 1.03) | 0.620 | 1.00 (0.96, 1.04) | 0.856 |
| rs9931494 | 1.14 (1.02, 1.27) | 0.019 | 0.99 (0.95, 1.03) | 0.635 | 1.00 (0.96, 1.04) | 0.866 |
| rs1107355* | 1.16 (1.02, 1.31) | 0.020 | 1.00 (0.95, 1.05) | 0.914 | 1.00 (0.95, 1.05) | 0.900 |
| rs7194243* | 1.15 (1.02, 1.30) | 0.022 | 1.00 (0.95, 1.04) | 0.859 | 1.00 (0.95, 1.04) | 0.850 |
| rs9933805* | 0.88 (0.79, 0.98) | 0.024 | 0.99 (0.95, 1.03) | 0.531 | 0.99 (0.95, 1.03) | 0.570 |
| rs1421085 | 1.13 (1.01, 1.26) | 0.026 | 1.00 (0.96, 1.04) | 0.928 | 1.01 (0.96, 1.05) | 0.805 |
| rs1558902 | 1.13 (1.01, 1.26) | 0.032 | 1.00 (0.96, 1.04) | 0.937 | 1.01 (0.97, 1.05) | 0.795 |
| rs2024471* | 1.12 (1.01, 1.25) | 0.036 | 1.04 (1.00, 1.08) | 0.069 | 1.04 (1.00, 1.09) | 0.052 |
| rs12596210* | 1.20 (1.01, 1.43) | 0.038 | 0.99 (0.93, 1.06) | 0.761 | 0.99 (0.93, 1.06) | 0.824 |
| rs12918363 | 1.12 (1.00, 1.24) | 0.041 | 0.97 (0.93, 1.01) | 0.182 | 0.97 (0.93, 1.01) | 0.127 |
| rs1121980 | 1.12 (1.00, 1.25) | 0.041 | 1.00 (0.96, 1.04) | 0.840 | 1.00 (0.96, 1.04) | 0.947 |
| rs11075987 | 1.12 (1.00, 1.24) | 0.044 | 1.01 (0.97, 1.05) | 0.787 | 1.00 (0.96, 1.04) | 0.968 |
| rs8046502* | 1.12 (1.00, 1.24) | 0.045 | 1.04 (1.00, 1.08) | 0.066 | 1.04 (1.00, 1.09) | 0.048 |
| rs16952770* | 1.20 (1.00, 1.42) | 0.047 | 0.99 (0.93, 1.06) | 0.791 | 0.99 (0.93, 1.06) | 0.811 |
| rs4784329* | 1.12 (1.00, 1.24) | 0.049 | 0.96 (0.92, 1.00) | 0.057 | 0.96 (0.92, 1.00) | 0.048 |
| MC4R | ||||||
| rs689353 | 1.18 (1.06, 1.32) | 0.003 | 1.01 (0.97, 1.05) | 0.803 | 1.01 (0.97, 1.05) | 0.798 |
| rs598214 | 1.18 (1.05, 1.31) | 0.004 | 1.01 (0.97, 1.05) | 0.792 | 1.01 (0.97, 1.05) | 0.789 |
| rs596340 | 1.18 (1.05, 1.31) | 0.004 | 1.01 (0.97, 1.05) | 0.817 | 1.01 (0.96, 1.05) | 0.811 |
| rs545195 | 1.17 (1.05, 1.31) | 0.005 | 1.01 (0.97, 1.05) | 0.802 | 1.01 (0.97, 1.05) | 0.797 |
| rs596365 | 1.17 (1.05, 1.30) | 0.006 | 1.01 (0.97, 1.05) | 0.806 | 1.01 (0.97, 1.05) | 0.801 |
| rs1943235 | 0.86 (0.77, 0.96) | 0.009 | 1.03 (0.99, 1.07) | 0.228 | 1.02 (0.98, 1.06) | 0.307 |
| rs579054 | 1.16 (1.04, 1.30) | 0.010 | 1.01 (0.96, 1.05) | 0.824 | 1.01 (0.96, 1.05) | 0.805 |
| rs1943227* | 0.81 (0.69, 0.96) | 0.012 | 0.94 (0.87, 1.02) | 0.148 | 0.95 (0.87, 1.03) | 0.218 |
| rs12962636 | 0.75 (0.60, 0.96) | 0.020 | 0.98 (0.88, 1.08) | 0.638 | 0.98 (0.88, 1.09) | 0.756 |
| rs499219* | 1.22 (1.02, 1.47) | 0.026 | 1.02 (0.96, 1.09) | 0.549 | 1.02 (0.96, 1.09) | 0.523 |
| rs560248* | 1.14 (1.01, 1.28) | 0.032 | 1.02 (0.98, 1.07) | 0.359 | 1.02 (0.98, 1.07) | 0.323 |
| rs12966035 | 0.89 (0.80, 0.99) | 0.035 | 1.01 (0.97, 1.05) | 0.692 | 1.01 (0.97, 1.05) | 0.791 |
| rs12953429 | 1.12 (1.01, 1.25) | 0.037 | 0.99 (0.95, 1.03) | 0.683 | 0.99 (0.95, 1.03) | 0.523 |
| rs489310* | 1.20 (1.01, 1.43) | 0.038 | 1.02 (0.96, 1.09) | 0.511 | 1.02 (0.96, 1.09) | 0.499 |
| rs547363 | 0.89 (0.80, 0.99) | 0.040 | 1.00 (0.96, 1.04) | 0.905 | 1.00 (0.96, 1.04) | 0.983 |
| rs2156335* | 0.89 (0.80, 1.00) | 0.041 | 1.02 (0.98, 1.06) | 0.412 | 1.01 (0.97, 1.06) | 0.496 |
| rs4378703* | 1.15 (1.00, 1.32) | 0.047 | 1.01 (0.96, 1.07) | 0.612 | 1.01 (0.96, 1.07) | 0.729 |
| rs612238* | 1.20 (1.00, 1.43) | 0.048 | 1.03 (0.96, 1.09) | 0.457 | 1.03 (0.96, 1.10) | 0.440 |
Abbreviations:
CCFR, Colon Cancer Family Registry; CI, confidence interval; FTO, fat-mass and obesity-associated; GECCO, Genetics and Epidemiology of Colorectal Cancer Consortium; MC4R, melanocortin-4 receptor; OR, odds ratio; SNP, single nucleotide polymorphism.
Note:
Model 1: adjusted for age, sex, and the top three principal components of ancestry
Model 2: adjusted for age, sex, body mass index, and the top three principal components of ancestry Odd ratio, 95% CI and P values in the discovery phase obtained from model 1 (SNPs with no *) or model 2 (SNPs with *), whichever generates the smaller p value, from the meta-analyses.
Discussion
In this study, we found that individual variants in the obesity-related genes FTO and MC4R were not associated with colorectal cancer risk. Although obesity is an established risk factor for colorectal cancer, our results do not support the hypothesis that obesity and colorectal carcinogenesis share a common genetic predisposition through individual SNPs in or near FTO or MC4R.
A number of studies have reported associations between FTO or MC4R variants and risk of various types of cancer [10, 11]; some of the associations were independent of obesity, but the mechanisms were unclear [11]. Our results are consistent with the few previous studies that reported null associations of FTO and MC4R with risk of colorectal cancer [3–5]. Tenesa et al. conducted a two-phase case-control study among 1,765 colorectal cancer cases and 2,077 controls, and observed no association between four MC4R SNPs with the risk of colorectal cancer, although these SNPs were associated with intermediate phenotype such as BMI and waist circumference [4]. Similarly, Tarabra et al. reported no association between one FTO SNP and colorectal cancer or adenoma risk among 726 patients and 311 controls [3]. Additionally, among 2,033 cases and 9,640 controls in the Multiethnic Cohort and PAGE studies, Lim et al. examined 24 SNPs in 15 obesity-related genes, including eight in FTO and one near MC4R; although the only MC4R SNP examined (rs17782313) was associated with colorectal cancer risk (OR 1.12, 95% CI 1.02–1.22; p = 0.02), it was no longer statistically significant after adjustment for multiple comparisons [5]. However, the Lim et al. study, being the largest of the three previous studies, was only powered to detect ORs of 1.5 or higher. Our study is the most comprehensive, large-scale evaluation of FTO and MC4R SNPs in relation to colorectal cancer risk so far. Our null results suggest that although these two genes are associated with body size, they are indeed unlikely to influence the risk of colorectal cancer substantially.
The strengths of our study include its large sample size, centralized data harmonization, and comprehensive evaluation of FTO and MC4R SNPs. Our study was sufficiently powered to detect a modest association of these SNPs with colorectal cancer risk: for SNPs with a MAF of 0.3, we had >80% power to detect an OR as low as 1.22 in the discovery stage and 1.09 in the replication stage. Limitations of this study include the derivation of BMI from self-reported height and weight, and use of Bonferroni correction for multiple comparisons which may be overly conservative, but these results would still be null even with less conservative multiple testing adjustment. Finally, compared to the more conventional candidate gene approach, Mendelian randomization studies, which use information from multiple genetic variants associated with body size to create a weighted genetic risk score for obesity, may be superior to examine genetically influenced BMI and colorectal cancer risk [12], as we have shown in GECCO and the CCFR more recently.
In summary, we did not observe associations between individual variants in the obesity-related genes FTO and MC4R with colorectal cancer risk. This study does not support the hypothesis that obesity and colorectal carcinogenesis share a common genetic predisposition through individual SNPs in or near FTO or MC4R.
Supplementary Material
Highlights.
We found no evidence that individual variants in or near the obesity-related genes FTO and MC4R are associated with risk of colorectal cancer.
This paper is the largest and most comprehensive evaluation of obesity-related genes FTO and MC4R in relation to colorectal cancer risk.
Abbreviations
- BMI
body mass index
- CCFR
Colon Cancer Family Registry
- CI
confidence interval
- FTO
fat-mass and obesity-associated
- GECCO
Genetics and Epidemiology of Colorectal Cancer Consortium
- GWAS
genome-wide association study
- MAF
minor allele frequency
- MC4R
melanocortin-4 receptor
- OR
odds ratio
- PCA
principal component of genetic ancestry
- SNP
single nucleotide polymorphism
Footnotes
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Authorship Contributions
Conception and design: Baiyu Yang, Aaron P. Thrift, Peter T. Campbell
Financial and administrative support: Peter T. Campbell, Mark A. Jenkins, Sonja I. Berndt, Hermann Brenner, Andrew T. Chan, Jenny Chang-Claude, Michael Hoffmeister, Loïc Le Marchand, Polly A. Newcomb, Martha L. Slattery, Emily White, Ulrike Peters, Graham Casey
Provision of study materials or patients: Peter T. Campbell, Jane C. Figueiredo, Mark A. Jenkins, Fredrick R. Schumacher, David V. Conti, Aung Ko Win, Paul J. Limburg, Sonja I. Berndt, Hermann Brenner, Andrew T. Chan, Jenny Chang-Claude, Michael Hoffmeister, Thomas J. Hudson, Loïc Le Marchand, Polly A. Newcomb, Martha L. Slattery, Emily White, Ulrike Peters, Graham Casey
Collection and assembly of data: All authors
Data analysis and interpretation: Baiyu Yang, Aaron P. Thrift, Peter T. Campbell
Manuscript writing: All authors
Final approval of manuscript: All authors
Conflict of Interest
None
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