Mendelian randomisation implicates hyperlipidaemia as a risk factor for colorectal cancer

Rodriguez-Broadbent, Henry; Law, Philip; Sud, Amit; Palin, Kimmo; Tuupanen, Sari; Gylfe, Alexandra E.; Hänninen, Ulrika A.; Cajuso, Tatiana; Tanskanen, Tomas; Kondelin, Johanna; Kaasinen, Eevi; Sarin, Antti‐Pekka; Ripatti, Samuli; Eriksson, Johan G.; Rissanen, Harri; Knekt, Paul; Pukkala, Eero; Jousilahti, Pekka; Salomaa, Veikko; Palotie, Aarno; Renkonen–Sinisalo, Laura; Lepistö, Anna; Böhm, Jan; Mecklin∥, Jukka–Pekka; Tassan, Nada Al; Palles, Claire; Martin, Lynn; Barclay, Ella; Farrington, Susan M.; Timofeeva, Maria; Meyer, Brian F.; Wakil, Salma M.; Campbell, Harry; Smith, Christopher G.; Idziaszczyk, Shelley; Maughan, T; Kaplan, Richard; Kerr, Rachel; Kerr, David; Passarelli, Michael N.; Figueiredo, Jane C.; Buchanan, Daniel D.; Win, Aung Ko; Hopper, John L.; Jenkins, Mark A.; Lindor, Noralane M.; Newcomb, Polly A.; Gallinger, Steven; Conti, David V.; Schumacher, Fredrick; Casey, Graham; Aaltonen, Lauri A.; Cheadle, Jeremy P.; Tomlinson, Ian; Dunlop, Malcolm G.; Houlston, Richard S.

doi:10.1002/ijc.30709

Cited by 78 publications

(78 citation statements)

References 37 publications

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“…Metabolic factors related to the metabolic syndrome other than body fatness, such as blood pressure and blood lipids, are associated with CRC risk, independently of BMI . While the evidence for causality for these factors is limited compared to for body fatness, there is genetic evidence supporting a causal, BMI‐independent, role for total cholesterol . To our knowledge, no previous study has investigated whether metabolic factors related to the metabolic syndrome demonstrate subtype‐specific relationships with CRC risk …”

Section: Introductionsupporting

confidence: 90%

“…This was, to our knowledge, the first molecular pathological epidemiology study of CRC and several metabolic factors other than BMI. By studying several metabolic factors, we were able to assess several aspects of metabolic health, which do not always co‐exist with obesity, and are independently associated with CRC risk . The prospective cohort design with long follow‐up (up to 31 years) reduces the risk of recall bias and reverse causation.…”

Section: Discussionmentioning

confidence: 99%

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Metabolic factors and the risk of colorectal cancer by KRAS and BRAF mutation status

Myte

Gylling

Häggström

et al. 2019

Intl Journal of Cancer

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Factors related to energy metabolism and the metabolic syndrome, such as higher body mass index (BMI), blood glucose, or blood lipids, and blood pressure, are associated with an increased risk of colorectal cancer (CRC). However, CRC is a heterogeneous disease, developing through distinct pathways with differences in molecular characteristics and prognosis, and possibly also in risk factors. For subtypes defined by KRAS and BRAF mutation status, BMI is the only metabolic factor previously studied, with inconsistent findings. We investigated whether associations between BMI, blood glucose, blood lipids, and blood pressure and CRC risk differed by tumor KRAS and BRAF mutation status in 117,687 participants from two population‐based cohorts within the Northern Sweden Health and Disease Study (NSHDS). Hazard ratios (HRs) for overall CRC and CRC subtypes by metabolic factors were estimated with Cox proportional hazards regression, using multiple imputation to handle missing exposure and tumor data. During a median follow‐up of 15.6 years, we acquired 1,250 prospective CRC cases, of which 766 cases had complete baseline and molecular tumor data. Consistent with previous evidence, higher BMI, total cholesterol, triglyceride levels, and blood pressure were associated with an increased risk of overall CRC (HRs per 1 standard deviation increase: 1.07 to 1.12). These associations were similar regardless of CRC subtype by KRAS and BRAF mutation status (all pheterogeneity > 0.05). The same was true for subtypes based on microsatellite instability status. Poor metabolic health may therefore be a universal mechanism for colorectal cancer, acting across multiple developmental pathways.

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Section: Introductionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Metabolic factors and the risk of colorectal cancer by KRAS and BRAF mutation status

Myte

Gylling

Häggström

et al. 2019

Intl Journal of Cancer

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“…Finally, a case–control CRC study from Croatia consisting of 764 cases and 460 population-based controls was also included in the analysis. Details of study genotyping, quality control procedures and imputations are presented in Additional file 1 and elsewhere [ 30 , 31 ]. A total of 9940 cases and 22,848 controls with genotyping data were included after extensive quality control procedures (Additional file 1 ).…”

Section: Methodsmentioning

confidence: 99%

Exploring causality in the association between circulating 25-hydroxyvitamin D and colorectal cancer risk: a large Mendelian randomisation study

Timofeeva

Farrington

et al. 2018

BMC Med

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BackgroundWhilst observational studies establish that lower plasma 25-hydroxyvitamin D (25-OHD) levels are associated with higher risk of colorectal cancer (CRC), establishing causality has proven challenging. Since vitamin D is modifiable, these observations have substantial clinical and public health implications. Indeed, many health agencies already recommend supplemental vitamin D. Here, we explore causality in a large Mendelian randomisation (MR) study using an improved genetic instrument for circulating 25-OHD.MethodsWe developed a weighted genetic score for circulating 25-OHD using six genetic variants that we recently reported to be associated with circulating 25-OHD in a large genome-wide association study (GWAS) meta-analysis. Using this score as instrumental variable in MR analyses, we sought to determine whether circulating 25-OHD is causally linked with CRC risk. We conducted MR analysis using individual-level data from 10,725 CRC cases and 30,794 controls (Scotland, UK Biobank and Croatia). We then applied estimates from meta-analysis of 11 GWAS of CRC risk (18,967 cases; 48,168 controls) in a summary statistics MR approach.ResultsThe new genetic score for 25-OHD was strongly associated with measured plasma 25-OHD levels in 2821 healthy Scottish controls (P = 1.47 × 10− 11), improving upon previous genetic instruments (F-statistic 46.0 vs. 13.0). However, individual-level MR revealed no association between 25-OHD score and CRC risk (OR 1.03/unit log-transformed circulating 25-OHD, 95% CI 0.51–2.07, P = 0.93). Similarly, we found no evidence for a causal relationship between 25-OHD and CRC risk using summary statistics MR analysis (OR 0.91, 95% CI 0.69–1.19, P = 0.48).ConclusionsDespite the scale of this study and employing an improved score capturing more of the genetic contribution to circulating 25-OHD, we found no evidence for a causal relationship between circulating 25-OHD and CRC risk. Although the magnitude of effect for vitamin D suggested by observational studies can confidently be excluded, smaller effects sizes and non-linear relationships remain plausible. Circulating vitamin D may be a CRC biomarker, but a causal effect on CRC risk remains unproven.Electronic supplementary materialThe online version of this article (10.1186/s12916-018-1119-2) contains supplementary material, which is available to authorized users.

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“…A limited number of Mendelian randomization studies have investigated the relationship between HMGCR inhibition and cancer [37][38][39][40][41] , with protective associations observed for prostate cancer 37 , colorectal cancer 38 , breast cancer 39,40 , and ovarian cancer 41 . However, no comprehensive Mendelian randomization investigation has evaluated the predicted impact of HMGCR inhibition or the causal role of specific lipid fractions on the risk of many of the most common site-specific cancers.…”

mentioning

confidence: 99%

Predicting the effect of statins on cancer risk using genetic variants: a Mendelian randomization study in UK Biobank

Carter

Vithayathil

Kar

et al. 2020

Preprint

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Laboratory studies have suggested oncogenic roles of lipids, as well as anticarcinogenic effects of statins. We here assess the potential effect of statin therapy on cancer risk in Mendelian randomization analyses. We obtained genetic associations with the risk of overall and 22 site-specific cancers for 367,703 individuals in UK Biobank. In total, 75,037 individuals had a cancer event. Variants in the HMGCR gene region, which represent proxies for statin treatment, were associated with overall cancer risk (OR per 1 standard deviation increase in LDL-cholesterol 1.32, 95% CI 1.13-1.53, p=0.0003), but variants in gene regions representing alternative lipid-lowering treatment targets (PCSK9, LDLR, NPC1L1, APOC3, LPL) were not. Genetically-predicted LDL-cholesterol was not associated with overall cancer risk (OR 1.01, 95% CI 0.98-1.05, p=0.50). Our results predict that statins reduce cancer risk, but other lipid-lowering treatments do not. This suggests that statins reduce cancer risk through a cholesterol independent pathway.

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Mendelian randomisation implicates hyperlipidaemia as a risk factor for colorectal cancer

Cited by 78 publications

References 37 publications

Metabolic factors and the risk of colorectal cancer by KRAS and BRAF mutation status

Metabolic factors and the risk of colorectal cancer by KRAS and BRAF mutation status

Exploring causality in the association between circulating 25-hydroxyvitamin D and colorectal cancer risk: a large Mendelian randomisation study

Predicting the effect of statins on cancer risk using genetic variants: a Mendelian randomization study in UK Biobank

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