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Mendelian randomization analyses suggest a role for cholesterol in the development of endometrial cancer.

ABSTRACT: Blood lipids have been associated with the development of a range of cancers, including breast, lung and colorectal cancer. For endometrial cancer, observational studies have reported inconsistent associations between blood lipids and cancer risk. To reduce biases from unmeasured confounding, we performed a bidirectional, two-sample Mendelian randomization analysis to investigate the relationship between levels of three blood lipids (low-density lipoprotein [LDL] and high-density lipoprotein [HDL] cholesterol, and triglycerides) and endometrial cancer risk. Genetic variants associated with each of these blood lipid levels (P?-8 ) were identified as instrumental variables, and assessed using genome-wide association study data from the Endometrial Cancer Association Consortium (12?906 cases and 108?979 controls) and the Global Lipids Genetic Consortium (n = 188?578). Mendelian randomization analyses found genetically raised LDL cholesterol levels to be associated with lower risks of endometrial cancer of all histologies combined, and of endometrioid and non-endometrioid subtypes. Conversely, higher genetically predicted HDL cholesterol levels were associated with increased risk of non-endometrioid endometrial cancer. After accounting for the potential confounding role of obesity (as measured by genetic variants associated with body mass index), the association between genetically predicted increased LDL cholesterol levels and lower endometrial cancer risk remained significant, especially for non-endometrioid endometrial cancer. There was no evidence to support a role for triglycerides in endometrial cancer development. Our study supports a role for LDL and HDL cholesterol in the development of non-endometrioid endometrial cancer. Further studies are required to understand the mechanisms underlying these findings.

SUBMITTER: Kho PF

PROVIDER: S-EPMC7757859 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Mendelian randomization analyses suggest a role for cholesterol in the development of endometrial cancer.

Kho Pik-Fang PF Amant Frederic F Annibali Daniela D Ashton Katie K Attia John J Auer Paul L PL Beckmann Matthias W MW Black Amanda A Brinton Louise L Buchanan Daniel D DD Chanock Stephen J SJ Chen Chu C Chen Maxine M MM Cheng Timothy H T THT Cook Linda S LS Crous-Bous Marta M Czene Kamila K De Vivo Immaculata I Dennis Joe J Dörk Thilo T Dowdy Sean C SC Dunning Alison M AM Dürst Matthias M Easton Douglas F DF Ekici Arif B AB Fasching Peter A PA Fridley Brooke L BL Friedenreich Christine M CM García-Closas Montserrat M Gaudet Mia M MM Giles Graham G GG Goode Ellen L EL Gorman Maggie M Haiman Christopher A CA Hall Per P Hankinson Susan E SE Hein Alexander A Hillemanns Peter P Hodgson Shirley S Hoivik Erling A EA Holliday Elizabeth G EG Hunter David J DJ Jones Angela A Kraft Peter P Krakstad Camilla C Lambrechts Diether D Le Marchand Loic L Liang Xiaolin X Lindblom Annika A Lissowska Jolanta J Long Jirong J Lu Lingeng L Magliocco Anthony M AM Martin Lynn L McEvoy Mark M Milne Roger L RL Mints Miriam M Nassir Rami R Otton Geoffrey G Palles Claire C Pooler Loreall L Proietto Tony T Rebbeck Timothy R TR Renner Stefan P SP Risch Harvey A HA Rübner Matthias M Runnebaum Ingo I Sacerdote Carlotta C Sarto Gloria E GE Schumacher Fredrick F Scott Rodney J RJ Setiawan V Wendy VW Shah Mitul M Sheng Xin X Shu Xiao-Ou XO Southey Melissa C MC Tham Emma E Tomlinson Ian I Trovik Jone J Turman Constance C Tyrer Jonathan P JP Van Den Berg David D Wang Zhaoming Z Wentzensen Nicolas N Xia Lucy L Xiang Yong-Bing YB Yang Hannah P HP Yu Herbert H Zheng Wei W Webb Penelope M PM Thompson Deborah J DJ Spurdle Amanda B AB Glubb Dylan M DM O'Mara Tracy A TA

International journal of cancer 20200807 2

Blood lipids have been associated with the development of a range of cancers, including breast, lung and colorectal cancer. For endometrial cancer, observational studies have reported inconsistent associations between blood lipids and cancer risk. To reduce biases from unmeasured confounding, we performed a bidirectional, two-sample Mendelian randomization analysis to investigate the relationship between levels of three blood lipids (low-density lipoprotein [LDL] and high-density lipoprotein [HD ...[more]

PMID: 32851660

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Project description:BackgroundBilirubin, a byproduct of hemoglobin breakdown and purported anti-oxidant, is thought to be cancer preventive. We conducted complementary serological and Mendelian randomization (MR) analyses to investigate whether alterations in circulating levels of bilirubin are associated with risk of colorectal cancer (CRC). We decided a priori to perform analyses separately in men and women based on suggestive evidence that associations may differ by sex.MethodsIn a case-control study nested in the European Prospective Investigation into Cancer and Nutrition (EPIC), pre-diagnostic unconjugated bilirubin (UCB, the main component of total bilirubin) concentrations were measured by high-performance liquid chromatography in plasma samples of 1386 CRC cases and their individually matched controls. Additionally, 115 single-nucleotide polymorphisms (SNPs) robustly associated (P < 5 × 10-8) with circulating total bilirubin were instrumented in a 2-sample MR to test for a potential causal effect of bilirubin on CRC risk in 52,775 CRC cases and 45,940 matched controls in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colon Cancer Family Registry (CCFR), and the Colorectal Transdisciplinary (CORECT) study.ResultsThe associations between circulating UCB levels and CRC risk differed by sex (Pheterogeneity = 0.008). Among men, higher levels of UCB were positively associated with CRC risk (odds ratio [OR] = 1.19, 95% confidence interval [CI] = 1.04-1.36; per 1-SD increment of log-UCB). In women, an inverse association was observed (OR = 0.86 (0.76-0.97)). In the MR analysis of the main UGT1A1 SNP (rs6431625), genetically predicted higher levels of total bilirubin were associated with a 7% increase in CRC risk in men (OR = 1.07 (1.02-1.12); P = 0.006; per 1-SD increment of total bilirubin), while there was no association in women (OR = 1.01 (0.96-1.06); P = 0.73). Raised bilirubin levels, predicted by instrumental variables excluding rs6431625, were suggestive of an inverse association with CRC in men, but not in women. These differences by sex did not reach formal statistical significance (Pheterogeneity ≥ 0.2).ConclusionsAdditional insight into the relationship between circulating bilirubin and CRC is needed in order to conclude on a potential causal role of bilirubin in CRC development.

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Mendelian randomization analyses suggest a role for cholesterol in the development of endometrial cancer.

Publications

Mendelian randomization analyses suggest a role for cholesterol in the development of endometrial cancer.

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