Dataset Information

Height and Body Mass Index as Modifiers of Breast Cancer Risk in BRCA1/2 Mutation Carriers: A Mendelian Randomization Study.

ABSTRACT: BACKGROUND:BRCA1/2 mutations confer high lifetime risk of breast cancer, although other factors may modify this risk. Whether height or body mass index (BMI) modifies breast cancer risk in BRCA1/2 mutation carriers remains unclear. METHODS:We used Mendelian randomization approaches to evaluate the association of height and BMI on breast cancer risk, using data from the Consortium of Investigators of Modifiers of BRCA1/2 with 14 676 BRCA1 and 7912 BRCA2 mutation carriers, including 11 451 cases of breast cancer. We created a height genetic score using 586 height-associated variants and a BMI genetic score using 93 BMI-associated variants. We examined both observed and genetically determined height and BMI with breast cancer risk using weighted Cox models. All statistical tests were two-sided. RESULTS:Observed height was positively associated with breast cancer risk (HR = 1.09 per 10?cm increase, 95% confidence interval [CI] = 1.0 to 1.17; P?=?1.17). Height genetic score was positively associated with breast cancer, although this was not statistically significant (per 10?cm increase in genetically predicted height, HR = 1.04, 95% CI = 0.93 to 1.17; P?=?.47). Observed BMI was inversely associated with breast cancer risk (per 5?kg/m2 increase, HR = 0.94, 95% CI = 0.90 to 0.98; P?=?.007). BMI genetic score was also inversely associated with breast cancer risk (per 5?kg/m2 increase in genetically predicted BMI, HR = 0.87, 95% CI = 0.76 to 0.98; P?=?.02). BMI was primarily associated with premenopausal breast cancer. CONCLUSION:Height is associated with overall breast cancer and BMI is associated with premenopausal breast cancer in BRCA1/2 mutation carriers. Incorporating height and BMI, particularly genetic score, into risk assessment may improve cancer management.

SUBMITTER: Qian F

PROVIDER: S-EPMC6449171 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Height and Body Mass Index as Modifiers of Breast Cancer Risk in BRCA1/2 Mutation Carriers: A Mendelian Randomization Study.

Qian Frank F Wang Shengfeng S Mitchell Jonathan J McGuffog Lesley L Barrowdale Daniel D Leslie Goska G Oosterwijk Jan C JC Chung Wendy K WK Evans D Gareth DG Engel Christoph C Kast Karin K Aalfs Cora M CM Adank Muriel A MA Adlard Julian J Agnarsson Bjarni A BA Aittomäki Kristiina K Alducci Elisa E Andrulis Irene L IL Arun Banu K BK Ausems Margreet G E M MGEM Azzollini Jacopo J Barouk-Simonet Emmanuelle E Barwell Julian J Belotti Muriel M Benitez Javier J Berger Andreas A Borg Ake A Bradbury Angela R AR Brunet Joan J Buys Saundra S SS Caldes Trinidad T Caligo Maria A MA Campbell Ian I Caputo Sandrine M SM Chiquette Jocelyne J Claes Kathleen B M KBM Margriet Collée J J Couch Fergus J FJ Coupier Isabelle I Daly Mary B MB Davidson Rosemarie R Diez Orland O Domchek Susan M SM Donaldson Alan A Dorfling Cecilia M CM Eeles Ros R Feliubadaló Lidia L Foretova Lenka L Fowler Jeffrey J Friedman Eitan E Frost Debra D Ganz Patricia A PA Garber Judy J Garcia-Barberan Vanesa V Glendon Gord G Godwin Andrew K AK Gómez Garcia Encarna B EB Gronwald Jacek J Hahnen Eric E Hamann Ute U Henderson Alex A Hendricks Carolyn B CB Hopper John L JL Hulick Peter J PJ Imyanitov Evgeny N EN Isaacs Claudine C Izatt Louise L Izquierdo Ángel Á Jakubowska Anna A Kaczmarek Katarzyna K Kang Eunyoung E Karlan Beth Y BY Kets Carolien M CM Kim Sung-Won SW Kim Zisun Z Kwong Ava A Laitman Yael Y Lasset Christine C Hyuk Lee Min M Won Lee Jong J Lee Jihyoun J Lester Jenny J Lesueur Fabienne F Loud Jennifer T JT Lubinski Jan J Mebirouk Noura N Meijers-Heijboer Hanne E J HEJ Meindl Alfons A Miller Austin A Montagna Marco M Mooij Thea M TM Morrison Patrick J PJ Mouret-Fourme Emmanuelle E Nathanson Katherine L KL Neuhausen Susan L SL Nevanlinna Heli H Niederacher Dieter D Nielsen Finn C FC Nussbaum Robert L RL Offit Kenneth K Olah Edith E Ong Kai-Ren KR Ottini Laura L Park Sue K SK Peterlongo Paolo P Pfeiler Georg G Phelan Catherine M CM Poppe Bruce B Pradhan Nisha N Radice Paolo P Ramus Susan J SJ Rantala Johanna J Robson Mark M Rodriguez Gustavo C GC Schmutzler Rita K RK Hutten Selkirk Christina G CG Shah Payal D PD Simard Jacques J Singer Christian F CF Sokolowska Johanna J Stoppa-Lyonnet Dominique D Sutter Christian C Yen Tan Yen Y Teixeira R Manuel RM Teo Soo H SH Terry Mary Beth MB Thomassen Mads M Tischkowitz Marc M Toland Amanda E AE Tucker Katherine M KM Tung Nadine N van Asperen Christi J CJ van Engelen Klaartje K van Rensburg Elizabeth J EJ Wang-Gohrke Shan S Wappenschmidt Barbara B Weitzel Jeffrey N JN Yannoukakos Drakoulis D Greene Mark H MH Rookus Matti A MA Easton Douglas F DF Chenevix-Trench Georgia G Antoniou Antonis C AC Goldgar David E DE Olopade Olufunmilayo I OI Rebbeck Timothy R TR Huo Dezheng D

Journal of the National Cancer Institute 20190401 4

<h4>Background</h4>BRCA1/2 mutations confer high lifetime risk of breast cancer, although other factors may modify this risk. Whether height or body mass index (BMI) modifies breast cancer risk in BRCA1/2 mutation carriers remains unclear.<h4>Methods</h4>We used Mendelian randomization approaches to evaluate the association of height and BMI on breast cancer risk, using data from the Consortium of Investigators of Modifiers of BRCA1/2 with 14 676 BRCA1 and 7912 BRCA2 mutation carriers, including ...[more]

PMID: 30312457

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Project description:ObjectiveTo determine whether height and body mass index (BMI) have a causal role in five measures of socioeconomic status.DesignMendelian randomisation study to test for causal effects of differences in stature and BMI on five measures of socioeconomic status. Mendelian randomisation exploits the fact that genotypes are randomly assigned at conception and thus not confounded by non-genetic factors.SettingUK Biobank.Participants119,669 men and women of British ancestry, aged between 37 and 73 years.Main outcome measuresAge completed full time education, degree level education, job class, annual household income, and Townsend deprivation index.ResultsIn the UK Biobank study, shorter stature and higher BMI were observationally associated with several measures of lower socioeconomic status. The associations between shorter stature and lower socioeconomic status tended to be stronger in men, and the associations between higher BMI and lower socioeconomic status tended to be stronger in women. For example, a 1 standard deviation (SD) higher BMI was associated with a £210 (€276; $300; 95% confidence interval £84 to £420; P=6 × 10(-3)) lower annual household income in men and a £1890 (£1680 to £2100; P=6 × 10(-15)) lower annual household income in women. Genetic analysis provided evidence that these associations were partly causal. A genetically determined 1 SD (6.3 cm) taller stature caused a 0.06 (0.02 to 0.09) year older age of completing full time education (P=0.01), a 1.12 (1.07 to 1.18) times higher odds of working in a skilled profession (P=6 × 10(-7)), and a £1130 (£680 to £1580) higher annual household income (P=4 × 10(-8)). Associations were stronger in men. A genetically determined 1 SD higher BMI (4.6 kg/m(2)) caused a £2940 (£1680 to £4200; P=1 × 10(-5)) lower annual household income and a 0.10 (0.04 to 0.16) SD (P=0.001) higher level of deprivation in women only.ConclusionsThese data support evidence that height and BMI play an important partial role in determining several aspects of a person's socioeconomic status, especially women's BMI for income and deprivation and men's height for education, income, and job class. These findings have important social and health implications, supporting evidence that overweight people, especially women, are at a disadvantage and that taller people, especially men, are at an advantage.

Project description:BackgroundRecent studies have reported associations between body mass index (BMI) and various autoimmune disorders. However, it is still uncertain whether there exists a direct cause-and-effect relationship between BMI and autoimmune thyroiditis (AIT). The aim of our study is to investigate the causal association between BMI and AIT.MethodsWe conducted a two-sample summary data Mendelian randomization (MR) analysis using genome-wide association studies (GWAS) summary statistics data related to BMI as exposure, and GWAS summary statistic data sets for AIT as the outcome. Robustly associated single-nucleotide polymorphisms (SNPs) for BMI were selected as instrumental variables (IVs). We used the inverse variance weighted (IVW) method as the primary method and performed other MR methods such as MR-Egger regression, weighted median, simple mode, and weighted mode analyses for further validation. The slope of MR-Egger regression was used to correct for pleiotropy and provide estimates of causality. The p-value for the intercept in MR-Egger was utilized to detect any directional pleiotropic effects. Heterogeneity and sensitivity analyses were performed to assess the robustness of our findings.ResultsSeventy-eight SNPs were selected from GWAS on BMI as the IVs. Our MR analysis using the IVW method showed a potential causal association between BMI and AIT (OR = 3.071, 95% CI 1.324-7.118). Findings from other MR methods are non-significant, although the direction of effect is consistent. There was no evidence that the result was affected by genetic pleiotropy (MR-Egger regression intercept = 0.01, SE = 0.00025, p = 0.719). Heterogeneity and sensitivity analyses revealed no significant heterogeneity among SNPs, and no single SNP drove the observed associations.ConclusionOur findings suggest a potential causal association between BMI and AIT, which may provide a basis for further investigation into the relationship between BMI and AIT. Further studies are required as only the IVW method shows significant results, and the case sample size is small.

Dataset Information

Height and Body Mass Index as Modifiers of Breast Cancer Risk in BRCA1/2 Mutation Carriers: A Mendelian Randomization Study.

Publications

Height and Body Mass Index as Modifiers of Breast Cancer Risk in BRCA1/2 Mutation Carriers: A Mendelian Randomization Study.

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