Epidemiological studies have linked adult height with breast cancer risk in women. However, the magnitude of the association, particularly by subtypes of breast cancer, has not been established.
Furthermore, the mechanisms of the association remain unclear. We performed a meta-analysis to investigate associations between height and breast cancer risk using data from prospective cohorts totaling women, including events. In a consortium with individual-level data from case patients and control subjects, we conducted a Mendelian randomization analysis using a genetic score that comprised height-associated variants as an instrument.
This association was further evaluated in a second consortium using summary statistics data from case patients and control subjects. The pooled relative risk of breast cancer was 1. In Mendelian randomization analysis, the odds ratio of breast cancer per 10cm increase in genetically predicted height was 1. The association was found in both premenopausal and postmenopausal women but restricted to hormone receptor—positive breast cancer.
Analyses of height-associated variants identified eight new loci associated with breast cancer risk after adjusting for multiple comparisons, including three loci at 1q Our study provides strong evidence that adult height is a risk factor for breast cancer in women and certain genetic factors and biological pathways affecting adult height have an important role in the etiology of breast cancer.
Diabetes mellitus and the risk of gastrointestinal cancer in women compared with men: a meta-analysis of cohort studies
Breast cancer is a leading cause of cancer morbidity and mortality among women worldwide 1. Adult height has been found to be positively related to breast cancer risk in many epidemiological studies 2—30reporting mostly a linear dose-response relationship. from studies, however, have been inconsistent, particularly with regard to the magnitude of the association and the association by subtypes of breast cancer. For example, relative risks of breast cancer associated with per 10cm increase in adult height ranged from 1.
Furthermore, it remains unclear whether adult height is causally related to breast cancer risk through shared underlying genetic factors and biological pathways or serves only as a surrogate measure of certain environmental and lifestyle exposures that contribute to breast cancer risk.
Answers to these questions may provide additional insight into breast tumorigenesis and strengthen the basis for classifying height as a breast cancer risk factor.
Mendelian randomization analysis can be used to minimize potential biases encountered in conventional observational studies and to determine the causal association of a given exposure with disease risk The causal association can also be manifested by common genetic and biological pathways that determine two sequentially developed phenotypes, such as adult height and breast cancer risk. Adult height is a classic quantitative trait determined, to a large extent, by genetic factors Sincegenome-wide association studies GWAS have identified single-nucleotide polymorphisms SNPs in approximately loci related to adult height 33— Women looking for sex ban hui krot alleles associated with adult height should be randomly ased to offspring from parents during mitosis, a process analogous to a random asment of subjects to an exposure of interest in randomized clinical trials.
Thus, a genetic score summarizing the effects of these height-associated SNPs can serve as an instrumental variable in a Mendelian randomization analysis of adult height and breast cancer risk Here we comprehensively assessed epidemiologic evidence from conventional observational studies regarding the association between height and breast cancer risk by performing a meta-analysis of prospective cohorts including more than five million women of European ancestry. To determine the nature of the association, we conducted two Mendelian randomization analyses using data from two large consortia totaling breast cancer case patients and control subjects.
The regulation of mitochondrial replacement techniques around the world
We searched electronic databases to identify prospective studies that investigated the association between height and breast cancer risk among women of European ancestry published before December Supplementary Figure 1available online. We combined relative risks RRs of breast cancer with per 10cm increase in height from each of the included studies using a random effects meta-analysis We also performed subgroup meta-analyses based on method of height assessment measured or self-reportedas well as menopausal, estrogen receptor ERand progesterone receptor PR status. Sensitivity analyses were performed to evaluate the robustness of the.
We considered P values of less than. All tests were two-sided, with the exception of tests of heterogeneity and publication bias. Details of literature searches, study inclusion criteria, and meta-analysis are presented in the Supplementary Methods available online. In BCAC, we included individual-level data for breast cancer case patients and control subjects of European ancestry from 39 studies Supplementary Table 1. In DRIVE, only summary statistics data were available to our study, and these data were obtained from breast cancer case patients and control subjects of Women looking for sex ban hui krot ancestry from 11 studies Supplementary Table 2available online.
Study descriptions and methods for SNP selection, genotyping, and imputation are presented in the Supplementary Methods available online. We examined associations between the SNPs and adult height in cm in the BCAC using general linear models with adjustment for age and principal components. We converted all effect alleles to correspond to taller height in the SNP-based analyses and construction of the wHGS. All analyses were performed for each study separately, and summary statistics were obtained using a fixed-effects meta-analysis.
In the first Mendelian randomization analysis, we estimated the potential causal association between height X and breast cancer risk Y by using the wHGS G as an instrumental variable. Sensitivity analyses were performed Supplementary Table 3available onlineand the strength of instrumental variables was evaluated using F statistic The second Mendelian randomization analysis was conducted using the inverse-variance weighted method for summary statistics data to further evaluate the association Details of methodology for statistical analyses are presented in the Supplementary Methods available online.
Analyses were performed using SAS version 9. All tests were two-sided, and P values of less than. We identified 26 articles 5—30containing information from prospective cohorts that were eligible for inclusion in our meta-analyses Table 1. Of these, 22 articles reported from individual cohorts, while the remaining four articles provided from combined analyses of two to cohorts. After excluding overlapping cohorts, participants of European ancestry were included in our analyses, including women with breast cancer.
Height and breast cancer risk: evidence from prospective studies and mendelian randomization
Figure 1 presents relative risks RRs of breast cancer associated with per 10cm increase in height for each of the published studies, all studies combined, and study subgroups. Removal of the smallest, the largest, the first ificant, or the study with adjustment only for age did not change the pooled risk estimate.
Meta-analysis of associations between height and risk of breast cancer in prospective cohort studies. All tests for meta-analyses were two-sided.
Of the height-associated variants, showed an association with height at P values of less than. A clear relation between the wHGS and height was found in the study Table 2. The wHGS was associated, at a P value of. No association was observed between wHGS and other risk factors for breast cancer.
The mean wHGS was higher in case patients than in control subjects This positive association between breast cancer risk and wHGS remained essentially unchanged after adjustment for breast cancer risk factors, including age at menarche, age at menopause, parity, family history of breast cancer, age at the first live birth, breast feeding, and use of oral contraceptive or postmenopausal hormone data not shown.
Associations of the weighted height genetic score with height and traditional breast cancer risk factors. All tests were two-sided.
Covid pandemic ()
Association of the weighted height genetic score with breast cancer risk in the Breast Cancer Association Consortium. Table 3 presents associations of breast cancer risk with adult height as predicted using the wHGS as the instrument in Mendelian randomization analysis. As a comparison, derived from the meta-analysis of prospective studies and the meta-analysis of studies included in BCAC are also presented.
The association, however, was restricted primarily to hormone receptor—positive breast cancer. For example, the odds ratios were 1. Sensitivity analyses similar to those performed in the analysis of data from BCAC described above yielded similar data not shown.
Sensitivity analyses for associations between genetically predicted height and breast cancer risk in the Breast Cancer Association Consortium. Statistically ificant associations with breast cancer at P values of less than. In the combined analysis of data from both consortia, 25 SNPs were associated with breast cancer risk at P value sof less than.
These three loci have not been ly reported in GWAS to be associated with breast cancer risk. Three loci 1q Regional association plots of the three new loci associated with breast cancer risk in the Breast Cancer Association Consortium. The three plots represent: A 1q The association between adult height and breast cancer risk in women has been investigated in many epidemiological studies 2—4. However, the magnitude of this association, particularly for subtypes of breast cancer, has not been established.
History of lesbianism in the united states
The association was stronger in the meta-analysis of studies with measured height than in meta-analysis of studies with self-reported height. The weaker association observed in the meta-analysis of cohort studies was expected because some of these conventional observational studies may have suffered from possible biases, including confounding biases and measurement errors.
In both meta-analysis of prospective studies and Mendelian randomization analysis, the association between height and breast cancer risk was observed in both premenopausal and postmenopausal women but was limited primarily to hormone receptor—positive breast cancer.
Using the Mendelian randomization approach, our study provides strong evidence for a possible causal association between adult height and breast cancer risk. from this study have clarified the nature of the height and breast cancer association and provided additional insight into the genetic and biological basis of breast cancer development. Indeed, this is what we observed in the study. It has been reported that in addition to genetic factors, adult height is influenced by energy intake and socioeconomic status during growth spurts It has been suggested that certain nutritional factors during childhood and adolescence may be related to breast cancer risk 2—4.