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The influence of obesity-related factors in the etiology of renal cell carcinoma-A mendelian randomization study.

ABSTRACT: BACKGROUND:Several obesity-related factors have been associated with renal cell carcinoma (RCC), but it is unclear which individual factors directly influence risk. We addressed this question using genetic markers as proxies for putative risk factors and evaluated their relation to RCC risk in a mendelian randomization (MR) framework. This methodology limits bias due to confounding and is not affected by reverse causation. METHODS AND FINDINGS:Genetic markers associated with obesity measures, blood pressure, lipids, type 2 diabetes, insulin, and glucose were initially identified as instrumental variables, and their association with RCC risk was subsequently evaluated in a genome-wide association study (GWAS) of 10,784 RCC patients and 20,406 control participants in a 2-sample MR framework. The effect on RCC risk was estimated by calculating odds ratios (ORSD) for a standard deviation (SD) increment in each risk factor. The MR analysis indicated that higher body mass index increases the risk of RCC (ORSD: 1.56, 95% confidence interval [CI] 1.44-1.70), with comparable results for waist-to-hip ratio (ORSD: 1.63, 95% CI 1.40-1.90) and body fat percentage (ORSD: 1.66, 95% CI 1.44-1.90). This analysis further indicated that higher fasting insulin (ORSD: 1.82, 95% CI 1.30-2.55) and diastolic blood pressure (DBP; ORSD: 1.28, 95% CI 1.11-1.47), but not systolic blood pressure (ORSD: 0.98, 95% CI 0.84-1.14), increase the risk for RCC. No association with RCC risk was seen for lipids, overall type 2 diabetes, or fasting glucose. CONCLUSIONS:This study provides novel evidence for an etiological role of insulin in RCC, as well as confirmatory evidence that obesity and DBP influence RCC risk.

SUBMITTER: Johansson M

PROVIDER: S-EPMC6317776 | biostudies-other | 2019 Jan

REPOSITORIES: biostudies-other

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The influence of obesity-related factors in the etiology of renal cell carcinoma-A mendelian randomization study.

Johansson Mattias M Carreras-Torres Robert R Scelo Ghislaine G Purdue Mark P MP Mariosa Daniela D Muller David C DC Timpson Nicolas J NJ Haycock Philip C PC Brown Kevin M KM Wang Zhaoming Z Ye Yuanqing Y Hofmann Jonathan N JN Foll Matthieu M Gaborieau Valerie V Machiela Mitchell J MJ Colli Leandro M LM Li Peng P Garnier Jean-Guillaume JG Blanche Helene H Boland Anne A Burdette Laurie L Prokhortchouk Egor E Skryabin Konstantin G KG Yeager Meredith M Radojevic-Skodric Sanja S Ognjanovic Simona S Foretova Lenka L Holcatova Ivana I Janout Vladimir V Mates Dana D Mukeriya Anush A Rascu Stefan S Zaridze David D Bencko Vladimir V Cybulski Cezary C Fabianova Eleonora E Jinga Viorel V Lissowska Jolanta J Lubinski Jan J Navratilova Marie M Rudnai Peter P Benhamou Simone S Cancel-Tassin Geraldine G Cussenot Olivier O Weiderpass Elisabete E Ljungberg Börje B Tumkur Sitaram Raviprakash R Häggström Christel C Bruinsma Fiona F Jordan Susan J SJ Severi Gianluca G Winship Ingrid I Hveem Kristian K Vatten Lars J LJ Fletcher Tony T Larsson Susanna C SC Wolk Alicja A Banks Rosamonde E RE Selby Peter J PJ Easton Douglas F DF Andreotti Gabriella G Beane Freeman Laura E LE Koutros Stella S Männistö Satu S Weinstein Stephanie S Clark Peter E PE Edwards Todd L TL Lipworth Loren L Gapstur Susan M SM Stevens Victoria L VL Carol Hallie H Freedman Matthew L ML Pomerantz Mark M MM Cho Eunyoung E Wilson Kathryn M KM Gaziano J Michael JM Sesso Howard D HD Freedman Neal D ND Parker Alexander S AS Eckel-Passow Jeanette E JE Huang Wen-Yi WY Kahnoski Richard J RJ Lane Brian R BR Noyes Sabrina L SL Petillo David D Teh Bin Tean BT Peters Ulrike U White Emily E Anderson Garnet L GL Johnson Lisa L Luo Juhua J Buring Julie J Lee I-Min IM Chow Wong-Ho WH Moore Lee E LE Eisen Timothy T Henrion Marc M Larkin James J Barman Poulami P Leibovich Bradley C BC Choueiri Toni K TK Lathrop G Mark GM Deleuze Jean-Francois JF Gunter Marc M McKay James D JD Wu Xifeng X Houlston Richard S RS Chanock Stephen J SJ Relton Caroline C Richards J Brent JB Martin Richard M RM Davey Smith George G Brennan Paul P

PLoS medicine 20190103 1

<h4>Background</h4>Several obesity-related factors have been associated with renal cell carcinoma (RCC), but it is unclear which individual factors directly influence risk. We addressed this question using genetic markers as proxies for putative risk factors and evaluated their relation to RCC risk in a mendelian randomization (MR) framework. This methodology limits bias due to confounding and is not affected by reverse causation.<h4>Methods and findings</h4>Genetic markers associated with obesi ...[more]

PMID: 30605491

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Project description:Observational studies have reported an association between obesity, as measured by elevated body mass index (BMI), in early adulthood and risk of multiple sclerosis (MS). However, bias potentially introduced by confounding and reverse causation may have influenced these findings. Therefore, we elected to perform Mendelian randomization (MR) analyses to evaluate whether genetically increased BMI is associated with an increased risk of MS.Employing a two-sample MR approach, we used summary statistics from the Genetic Investigation of Anthropometric Traits (GIANT) consortium and the International MS Genetics Consortium (IMSGC), the largest genome-wide association studies for BMI and MS, respectively (GIANT: n = 322,105; IMSGC: n = 14,498 cases and 24,091 controls). Seventy single nucleotide polymorphisms (SNPs) were genome-wide significant (p < 5 x 10-8) for BMI in GIANT (n = 322,105) and were investigated for their association with MS risk in the IMSGC. The effect of each SNP on MS was weighted by its effect on BMI, and estimates were pooled to provide a summary measure for the effect of increased BMI upon risk of MS. Our results suggest that increased BMI influences MS susceptibility, where a 1 standard deviation increase in genetically determined BMI (kg/m2) increased odds of MS by 41% (odds ratio [OR]: 1.41, 95% CI 1.20-1.66, p = 2.7 x 10-5, I2 = 0%, 95% CI 0-29). Sensitivity analyses, including MR-Egger regression, and the weighted median approach provided no evidence of pleiotropic effects. The main study limitations are that, while these sensitivity analyses reduce the possibility that pleiotropy influenced our results, residual pleiotropy is difficult to exclude entirely.Genetically elevated BMI is associated with risk of MS, providing evidence for a causal role for obesity in MS etiology. While obesity has been associated with many late-life outcomes, these findings suggest an important consequence of childhood and/or early adulthood obesity.

Project description:BackgroundAssessing the relationship between lung cancer and metabolic conditions is challenging because of the confounding effect of tobacco. Mendelian randomization (MR), or the use of genetic instrumental variables to assess causality, may help to identify the metabolic drivers of lung cancer.Methods and findingsWe identified genetic instruments for potential metabolic risk factors and evaluated these in relation to risk using 29,266 lung cancer cases (including 11,273 adenocarcinomas, 7,426 squamous cell and 2,664 small cell cases) and 56,450 controls. The MR risk analysis suggested a causal effect of body mass index (BMI) on lung cancer risk for two of the three major histological subtypes, with evidence of a risk increase for squamous cell carcinoma (odds ratio (OR) [95% confidence interval (CI)] = 1.20 [1.01-1.43] and for small cell lung cancer (OR [95%CI] = 1.52 [1.15-2.00]) for each standard deviation (SD) increase in BMI [4.6 kg/m2]), but not for adenocarcinoma (OR [95%CI] = 0.93 [0.79-1.08]) (Pheterogeneity = 4.3x10-3). Additional analysis using a genetic instrument for BMI showed that each SD increase in BMI increased cigarette consumption by 1.27 cigarettes per day (P = 2.1x10-3), providing novel evidence that a genetic susceptibility to obesity influences smoking patterns. There was also evidence that low-density lipoprotein cholesterol was inversely associated with lung cancer overall risk (OR [95%CI] = 0.90 [0.84-0.97] per SD of 38 mg/dl), while fasting insulin was positively associated (OR [95%CI] = 1.63 [1.25-2.13] per SD of 44.4 pmol/l). Sensitivity analyses including a weighted-median approach and MR-Egger test did not detect other pleiotropic effects biasing the main results.ConclusionsOur results are consistent with a causal role of fasting insulin and low-density lipoprotein cholesterol in lung cancer etiology, as well as for BMI in squamous cell and small cell carcinoma. The latter relation may be mediated by a previously unrecognized effect of obesity on smoking behavior.

Project description:PurposeUndertake a systematic investigation into associations between genetic predictors of lipid fractions and age-related macular degeneration (AMD) risk.DesignTwo-sample Mendelian randomization investigation using published data.ParticipantsA total of 33 526 individuals (16 144 cases, 17 832 controls) predominantly of European ancestry from the International Age-related Macular Degeneration Genomics Consortium.MethodsWe consider 185 variants previously demonstrated to be associated with at least 1 of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, or triglycerides at a genome-wide level of significance, and test their associations with AMD. We particularly focus on variants in gene regions that are proxies for specific pharmacologic agents for lipid therapy. We then conduct a 2-sample Mendelian randomization investigation to assess the causal roles of LDL-cholesterol, HDL-cholesterol, and triglycerides on AMD risk. We also conduct parallel investigations for coronary artery disease (CAD) (viewed as a positive control) and Alzheimer's disease (a negative control) for comparison.Main outcome measuresDiagnosis of AMD.ResultsWe find evidence that HDL-cholesterol is a causal risk factor for AMD, with an odds ratio (OR) estimate of 1.22 (95% confidence interval [CI], 1.03-1.44) per 1 standard deviation increase in HDL-cholesterol. No causal effect of LDL-cholesterol or triglycerides was found. Variants in the CETP gene region associated with increased circulating HDL-cholesterol also associate with increased AMD risk, although variants in the LIPC gene region that increase circulating HDL-cholesterol have the opposite direction of association with AMD risk. Parallel analyses suggest that lipids have a greater role for AMD compared with Alzheimer's disease, but a lesser role than for CAD.ConclusionsSome genetic evidence suggests that HDL-cholesterol is a causal risk factor for AMD risk and that increasing HDL-cholesterol (particularly via CETP inhibition) will increase AMD risk.

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The influence of obesity-related factors in the etiology of renal cell carcinoma-A mendelian randomization study.

Publications

The influence of obesity-related factors in the etiology of renal cell carcinoma-A mendelian randomization study.

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