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African genetic ancestry interacts with body mass index to modify risk for uterine fibroids.

ABSTRACT: Race, specifically African ancestry, and obesity are important risk factors for uterine fibroids, and likely interact to provide the right conditions for fibroid growth. However, existing studies largely focus on the main-effects rather than their interaction. Here, we firstly provide evidence for interaction between categories of body mass index (BMI) and reported-race in relation to uterine fibroids. We then investigate whether the association between inferred local European ancestry and fibroid risk is modified by BMI in African American (AA) women in the Vanderbilt University Medical Center bio-repository (BioVU) (539 cases and 794 controls) and the Coronary Artery Risk Development in Young Adults study (CARDIA, 264 cases and 173 controls). We used multiple logistic regression to evaluate interactions between local European ancestry and BMI in relation to fibroid risk, then performed fixed effects meta-analysis. Statistical significance threshold for local-ancestry and BMI interactions was empirically estimated with 10,000 permutations (p-value = 1.18x10-4). Admixture mapping detected an association between European ancestry and fibroid risk which was modified by BMI (continuous-interaction p-value = 3.75x10-5) around ADTRP (chromosome 6p24); the strongest association was found in the obese category (ancestry odds ratio (AOR) = 0.51, p-value = 2.23x10-5). Evaluation of interaction between genotyped/imputed variants and BMI in this targeted region suggested race-specific interaction, present in AAs only; strongest evidence was found for insertion/deletion variant (6:11946435), again in the obese category (OR = 1.66, p-value = 1.72x10-6). We found nominal evidence for interaction between local ancestry and BMI at a previously reported region in chromosome 2q31-32, which includes COL5A2, and TFPI, an immediate downstream target of ADTRP. Interactions between BMI and SNPs (single nucleotide polymorphisms) found in this region in AA women were also detected in an independent European American population of 1,195 cases and 1,164 controls. Findings from our study provide an example of how modifiable and non-modifiable factors may interact to influence fibroid risk and suggest a biological role for BMI in fibroid etiology.

SUBMITTER: Giri A

PROVIDER: S-EPMC5536439 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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African genetic ancestry interacts with body mass index to modify risk for uterine fibroids.

Giri Ayush A Edwards Todd L TL Hartmann Katherine E KE Torstenson Eric S ES Wellons Melissa M Schreiner Pamela J PJ Velez Edwards Digna R DR

PLoS genetics 20170717 7

Race, specifically African ancestry, and obesity are important risk factors for uterine fibroids, and likely interact to provide the right conditions for fibroid growth. However, existing studies largely focus on the main-effects rather than their interaction. Here, we firstly provide evidence for interaction between categories of body mass index (BMI) and reported-race in relation to uterine fibroids. We then investigate whether the association between inferred local European ancestry and fibro ...[more]

PMID: 28715450

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Project description:BackgroundAfrican ancestry (AA) and obesity are associated with worse survival in early-stage breast cancer. Obesity disproportionately affects women of AA; however, the intersection between ancestry and obesity on breast cancer outcomes remains unclear.MethodsA total of 2854 patients in the adjuvant trial E5103 were analyzed. Genetic ancestry was determined using principal components from a genome-wide array. The impact of continuous or binary body mass index (BMI) on disease-free survival (DFS) and overall survival (OS) was evaluated by multivariable Cox proportional hazards models in AA patients and European ancestry (EA) patients.ResultsThere were 2471 EA patients and 383 AA patients. Higher BMI was significantly associated with worse DFS and OS only in AA patients (DFS hazard ratio [HR], 1.25; 95% CI, 1.07-1.46; OS HR, 1.38; 95% CI, 1.10-1.73), not in EA patients (DFS HR, 0.97; 95% CI, 0.90-1.05; OS HR, 1.03; 95% CI, 0.93-1.14). Severe obesity (BMI ≥40) was significantly associated with worse survival in AA patients (DFS HR, 2.04; 95% CI, 1.21-3.43; OS HR, 2.21; 95% CI, 1.03-4.75) but had no impact on that of EA patients. In the estrogen receptor-positive (ER+) and triple-negative breast cancer subgroups, BMI was significantly associated with worse outcomes only in those AA patients with ER+ disease. Within the AA group, BMI remained associated with worse survival regardless of the AA proportion.ConclusionsHigher BMI was statistically significantly associated with worse breast cancer outcomes in AA but not EA patients. This association was most significant for severe obesity and those with ER+ disease. These observations help define optimal populations for weight change interventions designed to affect disparities and survival in early-stage breast cancer.Lay summaryAfrican ancestry and obesity are both risk factors for worse survival after early-stage breast cancer. Women of African descent are also disproportionately affected by obesity; however, it is unclear what impact body weight has on racial disparities in breast cancer. Data from a large phase 3 clinical trial in high-risk, early-stage breast cancer were used to determine how body weight affects survival outcomes in European versus African Americans. Study results demonstrate that a higher body mass index is associated with increased risk of breast cancer recurrence and worse survival in women of African ancestry but not in women of European ancestry.

Project description:BACKGROUND:Obesity is a complex trait with both environmental and genetic contributors. Genome-wide association studies have identified several variants that are robustly associated with obesity and body mass index (BMI), many of which are found within genes involved in appetite regulation. Currently, genetic association data for obesity are lacking in Africans-a single genome-wide association study and a few replication studies have been published in West Africa, but none have been performed in a South African population. OBJECTIVE:To assess the association of candidate loci with BMI in black South Africans. The authors focused on single nucleotide polymorphisms (SNPs) in the FTO, LEP, LEPR, MC4R, NPY2R and POMC genes. DESIGN:A genetic association study. PARTICIPANTS:990 randomly selected individuals from the larger Birth to Twenty cohort (a longitudinal birth cohort study of health and development in Africans). MEASURES:The authors genotyped 44 SNPs within the six candidate genes that included known BMI-associated SNPs and tagSNPs based on linkage disequilibrium in an African population for FTO, LEP and NPY2R. To assess population substructure, the authors included 18 ancestry informative markers. Weight, height, sex, sex-specific pubertal stage and exact age collected during adolescence (13 years) were used to identify loci that predispose to obesity early in life. RESULTS:Sex, sex-specific pubertal stage and exact age together explain 14.3% of the variation in log(BMI) at age 13. After adjustment for these factors, four SNPs were individually significantly associated with BMI: FTO rs17817449 (p=0.022), LEP rs10954174 (p=0.0004), LEP rs6966536 (p=0.012) and MC4R rs17782313 (p=0.045). Together the four SNPs account for 2.1% of the variation in log(BMI). Each risk allele was associated with an estimated average increase of 2.5% in BMI. CONCLUSIONS:The study highlighted SNPs in FTO and MC4R as potential genetic markers of obesity risk in South Africans. The association with two SNPs in the 3' untranslated region of the LEP gene is novel.

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African genetic ancestry interacts with body mass index to modify risk for uterine fibroids.

Publications

African genetic ancestry interacts with body mass index to modify risk for uterine fibroids.

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