Body size and composition and risk of site-specific cancers in the UK Biobank and large international consortia: A mendelian randomisation study

Evidence for the impact of body size and composition on cancer risk is limited. This mendelian randomisation (MR) study investigates evidence supporting causal relationships of body mass index (BMI), fat mass index (FMI), fat-free mass index (FFMI), and height with cancer risk. Single nucleotide pol...

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Veröffentlicht in:PLoS medicine 2021-07, Vol.18 (7), p.e1003706
Hauptverfasser: Vithayathil, Mathew, Carter, Paul, Kar, Siddhartha, Mason, Amy M, Burgess, Stephen, Larsson, Susanna C
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Carter, Paul
Kar, Siddhartha
Mason, Amy M
Burgess, Stephen
Larsson, Susanna C
description Evidence for the impact of body size and composition on cancer risk is limited. This mendelian randomisation (MR) study investigates evidence supporting causal relationships of body mass index (BMI), fat mass index (FMI), fat-free mass index (FFMI), and height with cancer risk. Single nucleotide polymorphisms (SNPs) were used as instrumental variables for BMI (312 SNPs), FMI (577 SNPs), FFMI (577 SNPs), and height (293 SNPs). Associations of the genetic variants with 22 site-specific cancers and overall cancer were estimated in 367,561 individuals from the UK Biobank (UKBB) and with lung, breast, ovarian, uterine, and prostate cancer in large international consortia. In the UKBB, genetically predicted BMI was positively associated with overall cancer (odds ratio [OR] per 1 kg/m.sup.2 increase 1.01, 95% confidence interval [CI] 1.00-1.02; p = 0.043); several digestive system cancers: stomach (OR 1.13, 95% CI 1.06-1.21; p < 0.001), esophagus (OR 1.10, 95% CI 1.03, 1.17; p = 0.003), liver (OR 1.13, 95% CI 1.03-1.25; p = 0.012), and pancreas (OR 1.06, 95% CI 1.01-1.12; p = 0.016); and lung cancer (OR 1.08, 95% CI 1.04-1.12; p < 0.001). For sex-specific cancers, genetically predicted elevated BMI was associated with an increased risk of uterine cancer (OR 1.10, 95% CI 1.05-1.15; p < 0.001) and with a lower risk of prostate cancer (OR 0.97, 95% CI 0.94-0.99; p = 0.009). When dividing cancers into digestive system versus non-digestive system, genetically predicted BMI was positively associated with digestive system cancers (OR 1.04, 95% CI 1.02-1.06; p < 0.001) but not with non-digestive system cancers (OR 1.01, 95% CI 0.99-1.02; p = 0.369). Genetically predicted FMI was positively associated with liver, pancreatic, and lung cancer and inversely associated with melanoma and prostate cancer. Genetically predicted FFMI was positively associated with non-Hodgkin lymphoma and melanoma. Genetically predicted height was associated with increased risk of overall cancer (OR per 1 standard deviation increase 1.09; 95% CI 1.05-1.12; p < 0.001) and multiple site-specific cancers. Similar results were observed in analyses using the weighted median and MR-Egger methods. Results based on consortium data confirmed the positive associations between BMI and lung and uterine cancer risk as well as the inverse association between BMI and prostate cancer, and, additionally, showed an inverse association between genetically predicted BMI and breast cancer. The main limitations are th
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This mendelian randomisation (MR) study investigates evidence supporting causal relationships of body mass index (BMI), fat mass index (FMI), fat-free mass index (FFMI), and height with cancer risk. Single nucleotide polymorphisms (SNPs) were used as instrumental variables for BMI (312 SNPs), FMI (577 SNPs), FFMI (577 SNPs), and height (293 SNPs). Associations of the genetic variants with 22 site-specific cancers and overall cancer were estimated in 367,561 individuals from the UK Biobank (UKBB) and with lung, breast, ovarian, uterine, and prostate cancer in large international consortia. In the UKBB, genetically predicted BMI was positively associated with overall cancer (odds ratio [OR] per 1 kg/m.sup.2 increase 1.01, 95% confidence interval [CI] 1.00-1.02; p = 0.043); several digestive system cancers: stomach (OR 1.13, 95% CI 1.06-1.21; p &lt; 0.001), esophagus (OR 1.10, 95% CI 1.03, 1.17; p = 0.003), liver (OR 1.13, 95% CI 1.03-1.25; p = 0.012), and pancreas (OR 1.06, 95% CI 1.01-1.12; p = 0.016); and lung cancer (OR 1.08, 95% CI 1.04-1.12; p &lt; 0.001). For sex-specific cancers, genetically predicted elevated BMI was associated with an increased risk of uterine cancer (OR 1.10, 95% CI 1.05-1.15; p &lt; 0.001) and with a lower risk of prostate cancer (OR 0.97, 95% CI 0.94-0.99; p = 0.009). When dividing cancers into digestive system versus non-digestive system, genetically predicted BMI was positively associated with digestive system cancers (OR 1.04, 95% CI 1.02-1.06; p &lt; 0.001) but not with non-digestive system cancers (OR 1.01, 95% CI 0.99-1.02; p = 0.369). Genetically predicted FMI was positively associated with liver, pancreatic, and lung cancer and inversely associated with melanoma and prostate cancer. Genetically predicted FFMI was positively associated with non-Hodgkin lymphoma and melanoma. Genetically predicted height was associated with increased risk of overall cancer (OR per 1 standard deviation increase 1.09; 95% CI 1.05-1.12; p &lt; 0.001) and multiple site-specific cancers. Similar results were observed in analyses using the weighted median and MR-Egger methods. Results based on consortium data confirmed the positive associations between BMI and lung and uterine cancer risk as well as the inverse association between BMI and prostate cancer, and, additionally, showed an inverse association between genetically predicted BMI and breast cancer. The main limitations are the assumption that genetic associations with cancer outcomes are mediated via the proposed risk factors and that estimates for some lower frequency cancer types are subject to low precision. Our results show that the evidence for BMI as a causal risk factor for cancer is mixed. We find that BMI has a consistent causal role in increasing risk of digestive system cancers and a role for sex-specific cancers with inconsistent directions of effect. 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This mendelian randomisation (MR) study investigates evidence supporting causal relationships of body mass index (BMI), fat mass index (FMI), fat-free mass index (FFMI), and height with cancer risk. Single nucleotide polymorphisms (SNPs) were used as instrumental variables for BMI (312 SNPs), FMI (577 SNPs), FFMI (577 SNPs), and height (293 SNPs). Associations of the genetic variants with 22 site-specific cancers and overall cancer were estimated in 367,561 individuals from the UK Biobank (UKBB) and with lung, breast, ovarian, uterine, and prostate cancer in large international consortia. In the UKBB, genetically predicted BMI was positively associated with overall cancer (odds ratio [OR] per 1 kg/m.sup.2 increase 1.01, 95% confidence interval [CI] 1.00-1.02; p = 0.043); several digestive system cancers: stomach (OR 1.13, 95% CI 1.06-1.21; p &lt; 0.001), esophagus (OR 1.10, 95% CI 1.03, 1.17; p = 0.003), liver (OR 1.13, 95% CI 1.03-1.25; p = 0.012), and pancreas (OR 1.06, 95% CI 1.01-1.12; p = 0.016); and lung cancer (OR 1.08, 95% CI 1.04-1.12; p &lt; 0.001). For sex-specific cancers, genetically predicted elevated BMI was associated with an increased risk of uterine cancer (OR 1.10, 95% CI 1.05-1.15; p &lt; 0.001) and with a lower risk of prostate cancer (OR 0.97, 95% CI 0.94-0.99; p = 0.009). When dividing cancers into digestive system versus non-digestive system, genetically predicted BMI was positively associated with digestive system cancers (OR 1.04, 95% CI 1.02-1.06; p &lt; 0.001) but not with non-digestive system cancers (OR 1.01, 95% CI 0.99-1.02; p = 0.369). Genetically predicted FMI was positively associated with liver, pancreatic, and lung cancer and inversely associated with melanoma and prostate cancer. Genetically predicted FFMI was positively associated with non-Hodgkin lymphoma and melanoma. Genetically predicted height was associated with increased risk of overall cancer (OR per 1 standard deviation increase 1.09; 95% CI 1.05-1.12; p &lt; 0.001) and multiple site-specific cancers. Similar results were observed in analyses using the weighted median and MR-Egger methods. Results based on consortium data confirmed the positive associations between BMI and lung and uterine cancer risk as well as the inverse association between BMI and prostate cancer, and, additionally, showed an inverse association between genetically predicted BMI and breast cancer. The main limitations are the assumption that genetic associations with cancer outcomes are mediated via the proposed risk factors and that estimates for some lower frequency cancer types are subject to low precision. Our results show that the evidence for BMI as a causal risk factor for cancer is mixed. We find that BMI has a consistent causal role in increasing risk of digestive system cancers and a role for sex-specific cancers with inconsistent directions of effect. In contrast, increased height appears to have a consistent risk-increasing effect on overall and site-specific cancers.</description><subject>Analysis</subject><subject>Biobanks</subject><subject>Biology and Life Sciences</subject><subject>Body composition</subject><subject>Body fat</subject><subject>Body mass index</subject><subject>Body size</subject><subject>Breast cancer</subject><subject>Cancer</subject><subject>Confidence intervals</subject><subject>Consortia</subject><subject>Digestive system</subject><subject>Disease</subject><subject>Epidemiology</subject><subject>Esophageal cancer</subject><subject>Esophagus</subject><subject>Estrogens</subject><subject>Fat-free body mass</subject><subject>Genetic aspects</subject><subject>Genetic diversity</subject><subject>Genetic variance</subject><subject>Health aspects</subject><subject>Hodgkin's disease</subject><subject>Liver</subject><subject>Liver cancer</subject><subject>Lung cancer</subject><subject>Medicin och hälsovetenskap</subject><subject>Medicine and Health Sciences</subject><subject>Melanoma</subject><subject>Non-Hodgkin's lymphoma</subject><subject>Obesity</subject><subject>Ovarian cancer</subject><subject>Ovaries</subject><subject>Pancreas</subject><subject>Pancreatic cancer</subject><subject>Physiological aspects</subject><subject>Prostate cancer</subject><subject>Risk factors</subject><subject>Single-nucleotide polymorphism</subject><subject>Uterine cancer</subject><issn>1549-1676</issn><issn>1549-1277</issn><issn>1549-1676</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>D8T</sourceid><sourceid>DOA</sourceid><recordid>eNqVlN9u0zAUxiMEYmPwBkhYQkJCosWOHSfmAqkb_yYmJgHbreU4J63b1A52Aoyn4JFx24wt0iaBfBHn-Pd9Pj5OTpI8JnhKaE5eLl3vrWqm7RqqKcGY5pjfSfZJxsSE8JzfvTbfSx6EsMQ4FVjg-8keZTRlrOD7ye9DV12gYH4BUrZC2q1bF0xnnN2-exNWyNUR6GASWtCmNhppZTX4gIxF3QLQ2Ud0aFyp7GqraZSfQ1zrIOa3cVJN9LXB-c6oV2iG1mAraIyyyEferU3YYih0fXXxMLlXqybAo-F5kJy9e_v16MPk5PT98dHsZKJzwbtJRoqaK821ykmKWUFyXoqMg65VVmZZxXLAkOa8ghKEyBTUFGtcspzWBLAo6UHyZOfbNi7IoZhBphknggpOcSSOd0Tl1FK23qyVv5BOGbkNOD-XKh5JNyCpFqwqSlxCKVimC0UyCpXGlJZVWhASvSY7r_AD2r4cuQ2hVZyBZBwTLiIvbuVb76or0aWQxKPxOFjUvrhV-8acz7aZ971kWUrSTWqvh0L0ZfyUNNjOq2a842jFmoWcu--yoCkWYmPwdDDw7lsPobulmgM1V7FgxtYumul491rOeE6IYLjAV3UaUXOwEHd2FmoTwyN-egMfRwVro28UPB8JItPBz26u-hDk8ZfP_8F--nf29HzMPrvGLkA13SK4pt_8BGEMsh2ovQvBQ_33VgiWmyZwWWm5aQJyaAL0Dwh5T7M</recordid><startdate>20210729</startdate><enddate>20210729</enddate><creator>Vithayathil, Mathew</creator><creator>Carter, Paul</creator><creator>Kar, Siddhartha</creator><creator>Mason, Amy M</creator><creator>Burgess, Stephen</creator><creator>Larsson, Susanna C</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISN</scope><scope>ISR</scope><scope>3V.</scope><scope>7TK</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>5PM</scope><scope>ACNBI</scope><scope>ADTPV</scope><scope>AOWAS</scope><scope>D8T</scope><scope>DF2</scope><scope>ZZAVC</scope><scope>DOA</scope><scope>CZK</scope><orcidid>https://orcid.org/0000-0002-9146-7540</orcidid><orcidid>https://orcid.org/0000-0003-0118-0341</orcidid><orcidid>https://orcid.org/0000-0002-8019-0777</orcidid><orcidid>https://orcid.org/0000-0002-1457-4385</orcidid><orcidid>https://orcid.org/0000-0002-2314-1426</orcidid></search><sort><creationdate>20210729</creationdate><title>Body size and composition and risk of site-specific cancers in the UK Biobank and large international consortia: A mendelian randomisation study</title><author>Vithayathil, Mathew ; Carter, Paul ; Kar, Siddhartha ; Mason, Amy M ; Burgess, Stephen ; Larsson, Susanna C</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c796t-518f6ac6ca712048176b956ecfa5b55d47e0e276debe995aef30c0b473f1e09b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Analysis</topic><topic>Biobanks</topic><topic>Biology and Life Sciences</topic><topic>Body composition</topic><topic>Body fat</topic><topic>Body mass index</topic><topic>Body size</topic><topic>Breast cancer</topic><topic>Cancer</topic><topic>Confidence intervals</topic><topic>Consortia</topic><topic>Digestive system</topic><topic>Disease</topic><topic>Epidemiology</topic><topic>Esophageal cancer</topic><topic>Esophagus</topic><topic>Estrogens</topic><topic>Fat-free body mass</topic><topic>Genetic aspects</topic><topic>Genetic diversity</topic><topic>Genetic variance</topic><topic>Health aspects</topic><topic>Hodgkin's disease</topic><topic>Liver</topic><topic>Liver cancer</topic><topic>Lung cancer</topic><topic>Medicin och hälsovetenskap</topic><topic>Medicine and Health Sciences</topic><topic>Melanoma</topic><topic>Non-Hodgkin's lymphoma</topic><topic>Obesity</topic><topic>Ovarian cancer</topic><topic>Ovaries</topic><topic>Pancreas</topic><topic>Pancreatic cancer</topic><topic>Physiological aspects</topic><topic>Prostate cancer</topic><topic>Risk factors</topic><topic>Single-nucleotide polymorphism</topic><topic>Uterine cancer</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Vithayathil, Mathew</creatorcontrib><creatorcontrib>Carter, Paul</creatorcontrib><creatorcontrib>Kar, Siddhartha</creatorcontrib><creatorcontrib>Mason, Amy M</creatorcontrib><creatorcontrib>Burgess, Stephen</creatorcontrib><creatorcontrib>Larsson, Susanna C</creatorcontrib><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Canada</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Neurosciences Abstracts</collection><collection>Health &amp; 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This mendelian randomisation (MR) study investigates evidence supporting causal relationships of body mass index (BMI), fat mass index (FMI), fat-free mass index (FFMI), and height with cancer risk. Single nucleotide polymorphisms (SNPs) were used as instrumental variables for BMI (312 SNPs), FMI (577 SNPs), FFMI (577 SNPs), and height (293 SNPs). Associations of the genetic variants with 22 site-specific cancers and overall cancer were estimated in 367,561 individuals from the UK Biobank (UKBB) and with lung, breast, ovarian, uterine, and prostate cancer in large international consortia. In the UKBB, genetically predicted BMI was positively associated with overall cancer (odds ratio [OR] per 1 kg/m.sup.2 increase 1.01, 95% confidence interval [CI] 1.00-1.02; p = 0.043); several digestive system cancers: stomach (OR 1.13, 95% CI 1.06-1.21; p &lt; 0.001), esophagus (OR 1.10, 95% CI 1.03, 1.17; p = 0.003), liver (OR 1.13, 95% CI 1.03-1.25; p = 0.012), and pancreas (OR 1.06, 95% CI 1.01-1.12; p = 0.016); and lung cancer (OR 1.08, 95% CI 1.04-1.12; p &lt; 0.001). For sex-specific cancers, genetically predicted elevated BMI was associated with an increased risk of uterine cancer (OR 1.10, 95% CI 1.05-1.15; p &lt; 0.001) and with a lower risk of prostate cancer (OR 0.97, 95% CI 0.94-0.99; p = 0.009). When dividing cancers into digestive system versus non-digestive system, genetically predicted BMI was positively associated with digestive system cancers (OR 1.04, 95% CI 1.02-1.06; p &lt; 0.001) but not with non-digestive system cancers (OR 1.01, 95% CI 0.99-1.02; p = 0.369). Genetically predicted FMI was positively associated with liver, pancreatic, and lung cancer and inversely associated with melanoma and prostate cancer. Genetically predicted FFMI was positively associated with non-Hodgkin lymphoma and melanoma. Genetically predicted height was associated with increased risk of overall cancer (OR per 1 standard deviation increase 1.09; 95% CI 1.05-1.12; p &lt; 0.001) and multiple site-specific cancers. Similar results were observed in analyses using the weighted median and MR-Egger methods. Results based on consortium data confirmed the positive associations between BMI and lung and uterine cancer risk as well as the inverse association between BMI and prostate cancer, and, additionally, showed an inverse association between genetically predicted BMI and breast cancer. The main limitations are the assumption that genetic associations with cancer outcomes are mediated via the proposed risk factors and that estimates for some lower frequency cancer types are subject to low precision. Our results show that the evidence for BMI as a causal risk factor for cancer is mixed. We find that BMI has a consistent causal role in increasing risk of digestive system cancers and a role for sex-specific cancers with inconsistent directions of effect. In contrast, increased height appears to have a consistent risk-increasing effect on overall and site-specific cancers.</abstract><cop>San Francisco</cop><pub>Public Library of Science</pub><pmid>34324486</pmid><doi>10.1371/journal.pmed.1003706</doi><orcidid>https://orcid.org/0000-0002-9146-7540</orcidid><orcidid>https://orcid.org/0000-0003-0118-0341</orcidid><orcidid>https://orcid.org/0000-0002-8019-0777</orcidid><orcidid>https://orcid.org/0000-0002-1457-4385</orcidid><orcidid>https://orcid.org/0000-0002-2314-1426</orcidid><oa>free_for_read</oa></addata></record>
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subjects Analysis
Biobanks
Biology and Life Sciences
Body composition
Body fat
Body mass index
Body size
Breast cancer
Cancer
Confidence intervals
Consortia
Digestive system
Disease
Epidemiology
Esophageal cancer
Esophagus
Estrogens
Fat-free body mass
Genetic aspects
Genetic diversity
Genetic variance
Health aspects
Hodgkin's disease
Liver
Liver cancer
Lung cancer
Medicin och hälsovetenskap
Medicine and Health Sciences
Melanoma
Non-Hodgkin's lymphoma
Obesity
Ovarian cancer
Ovaries
Pancreas
Pancreatic cancer
Physiological aspects
Prostate cancer
Risk factors
Single-nucleotide polymorphism
Uterine cancer
title Body size and composition and risk of site-specific cancers in the UK Biobank and large international consortia: A mendelian randomisation study
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