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Mendelian randomisation analysis strongly implicates adiposity with risk of developing colorectal cancer.

ABSTRACT: BACKGROUND:Observational studies have associated adiposity with an increased risk of colorectal cancer (CRC). However, such studies do not establish a causal relationship. To minimise bias from confounding we performed a Mendelian randomisation (MR) analysis to examine the relationship between adiposity and CRC. METHODS:We used SNPs associated with adult body mass index (BMI), waist-hip ratio (WHR), childhood obesity and birth weight as instrumental variables in a MR analysis of 9254 CRC cases and 18?386 controls. RESULTS:In the MR analysis, the odds ratios (ORs) of CRC risk per unit increase in BMI, WHR and childhood obesity were 1.23 (95% CI: 1.02-1.49, P=0.033), 1.59 (95% CI: 1.08-2.34, P=0.019) and 1.07 (95% CI: 1.03-1.13, P=0.018), respectively. There was no evidence for association between birth weight and CRC (OR=1.22, 95% CI: 0.89-1.67, P=0.22). Combining these data with a concurrent MR-based analysis for BMI and WHR with CRC risk (totalling to 18?190 cases, 27?617 controls) provided increased support, ORs for BMI and WHR were 1.26 (95% CI: 1.10-1.44, P=7.7 × 10(-4)) and 1.40 (95% CI: 1.14-1.72, P=1.2 × 10(-3)), respectively. CONCLUSIONS:These data provide further evidence for a strong causal relationship between adiposity and the risk of developing CRC highlighting the urgent need for prevention and treatment of adiposity.

SUBMITTER: Jarvis D

PROVIDER: S-EPMC4947703 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Mendelian randomisation analysis strongly implicates adiposity with risk of developing colorectal cancer.

Jarvis David D Mitchell Jonathan S JS Law Philip J PJ Palin Kimmo K Tuupanen Sari S Gylfe Alexandra A Hänninen Ulrika A UA Cajuso Tatiana T Tanskanen Tomas T Kondelin Johanna J Kaasinen Eevi E Sarin Antti-Pekka AP Kaprio Jaakko J Eriksson Johan G JG Rissanen Harri H Knekt Paul P Pukkala Eero E Jousilahti Pekka P Salomaa Veikko V Ripatti Samuli S Palotie Aarno A Järvinen Heikki H Renkonen-Sinisalo Laura L Lepistö Anna A Böhm Jan J Meklin Jukka-Pekka JP Al-Tassan Nada A NA Palles Claire C Martin Lynn L Barclay Ella E Farrington Susan M SM Timofeeva Maria N MN Meyer Brian F BF Wakil Salma M SM Campbell Harry H Smith Christopher G CG Idziaszczyk Shelley S Maughan Timothy S TS Kaplan Richard R Kerr Rachel R Kerr David D Buchanan Daniel D DD Win Aung K AK Hopper John L JL Jenkins Mark A MA Lindor Noralane M NM Newcomb Polly A PA Gallinger Steve S Conti David D Schumacher Fred F Casey Graham G Taipale Jussi J Aaltonen Lauri A LA Cheadle Jeremy P JP Dunlop Malcolm G MG Tomlinson Ian P IP Houlston Richard S RS

British journal of cancer 20160623 2

<h4>Background</h4>Observational studies have associated adiposity with an increased risk of colorectal cancer (CRC). However, such studies do not establish a causal relationship. To minimise bias from confounding we performed a Mendelian randomisation (MR) analysis to examine the relationship between adiposity and CRC.<h4>Methods</h4>We used SNPs associated with adult body mass index (BMI), waist-hip ratio (WHR), childhood obesity and birth weight as instrumental variables in a MR analysis of 9 ...[more]

PMID: 27336604

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Project description:BackgroundEpidemiological studies have linked lifestyle, cardiometabolic, reproductive, developmental, and inflammatory factors to the risk of colorectal cancer. However, which specific factors affect risk and the strength of these effects are unknown. We aimed to examine the relationship between potentially modifiable risk factors and colorectal cancer.MethodsWe used a random-effects model to examine the relationship between 39 potentially modifiable risk factors and colorectal cancer in 26 397 patients with colorectal cancer and 41 481 controls (ie, people without colorectal cancer). These population data came from a genome-wide association study of people of European ancestry, which was amended to exclude UK BioBank data. In the model, we used genetic variants as instruments via two-sample mendelian randomisation to limit bias from confounding and reverse causation. We calculated odds ratios per genetically predicted SD unit increase in each putative risk factor (ORSD) for colorectal cancer risk. We did mendelian randomisation Egger regressions to identify evidence of potential violations of mendelian randomisation assumptions. A Bonferroni-corrected threshold of p=1·3 × 10-3 was considered significant, and p values less than 0·05 were considered to be suggestive of an association.FindingsNo putative risk factors were significantly associated with colorectal cancer risk after correction for multiple testing. However, suggestive associations with increased risk were noted for genetically predicted body fat percentage (ORSD 1·14 [95% CI 1·03-1·25]; p=0·0086), body-mass index (1·09 [1·01-1·17]; p=0·023), waist circumference (1·13 [1·02-1·26]; p=0·018), basal metabolic rate (1·10 [1·03-1·18]; p=0·0079), and concentrations of LDL cholesterol (1·14 [1·04-1·25]; p=0·0056), total cholesterol (1·09 [1·01-1·18]; p=0·025), circulating serum iron (1·17 [1·00-1·36]; p=0·049), and serum vitamin B12 (1·21 [1·04-1·42]; p=0·016), although potential pleiotropy among genetic variants used as instruments for vitamin B12 constrains the finding. A suggestive association was also noted between adult height and increased risk of colorectal cancer (ORSD 1·04 [95% CI 1·00-1·08]; p=0·032). Low blood selenium concentration had a suggestive association with decreased risk of colorectal cancer (ORSD 0·85 [95% CI 0·75-0·96]; p=0·0078) based on a single variant, as did plasma concentrations of interleukin-6 receptor subunit α (also based on a single variant; 0·98 [0·96-1·00]; p=0·035). Risk of colorectal cancer was not associated with any sex hormone or reproductive factor, serum calcium, or circulating 25-hydroxyvitamin D concentrations.InterpretationThis analysis identified several modifiable targets for primary prevention of colorectal cancer, including lifestyle, obesity, and cardiometabolic factors, that should inform public health policy.FundingCancer Research UK, UK Medical Research Council Human Genetics Unit Centre, DJ Fielding Medical Research Trust, EU COST Action, and the US National Cancer Institute.

Project description:BackgroundHigher adiposity increases the risk of colorectal cancer (CRC), but whether this relationship varies by anatomical sub-site or by sex is unclear. Further, the metabolic alterations mediating the effects of adiposity on CRC are not fully understood.MethodsWe examined sex- and site-specific associations of adiposity with CRC risk and whether adiposity-associated metabolites explain the associations of adiposity with CRC. Genetic variants from genome-wide association studies of body mass index (BMI) and waist-to-hip ratio (WHR, unadjusted for BMI; N = 806,810), and 123 metabolites from targeted nuclear magnetic resonance metabolomics (N = 24,925), were used as instruments. Sex-combined and sex-specific Mendelian randomization (MR) was conducted for BMI and WHR with CRC risk (58,221 cases and 67,694 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry). Sex-combined MR was conducted for BMI and WHR with metabolites, for metabolites with CRC, and for BMI and WHR with CRC adjusted for metabolite classes in multivariable models.ResultsIn sex-specific MR analyses, higher BMI (per 4.2 kg/m2) was associated with 1.23 (95% confidence interval (CI) = 1.08, 1.38) times higher CRC odds among men (inverse-variance-weighted (IVW) model); among women, higher BMI (per 5.2 kg/m2) was associated with 1.09 (95% CI = 0.97, 1.22) times higher CRC odds. WHR (per 0.07 higher) was more strongly associated with CRC risk among women (IVW OR = 1.25, 95% CI = 1.08, 1.43) than men (IVW OR = 1.05, 95% CI = 0.81, 1.36). BMI or WHR was associated with 104/123 metabolites at false discovery rate-corrected P ≤ 0.05; several metabolites were associated with CRC, but not in directions that were consistent with the mediation of positive adiposity-CRC relations. In multivariable MR analyses, associations of BMI and WHR with CRC were not attenuated following adjustment for representative metabolite classes, e.g., the univariable IVW OR for BMI with CRC was 1.12 (95% CI = 1.00, 1.26), and this became 1.11 (95% CI = 0.99, 1.26) when adjusting for cholesterol in low-density lipoprotein particles.ConclusionsOur results suggest that higher BMI more greatly raises CRC risk among men, whereas higher WHR more greatly raises CRC risk among women. Adiposity was associated with numerous metabolic alterations, but none of these explained associations between adiposity and CRC. More detailed metabolomic measures are likely needed to clarify the mechanistic pathways.

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Mendelian randomisation analysis strongly implicates adiposity with risk of developing colorectal cancer.

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Mendelian randomisation analysis strongly implicates adiposity with risk of developing colorectal cancer.

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