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

<div><p>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 <i>ADTRP</i> (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 <i>COL5A2</i>, and <i>TFPI</i>, an immediate downstream target of <i>ADTRP</i>. 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.</p></div

Summary of empirically inferred local ancestry x BMI interaction analyses at top chromosome 2q31-32 SNP rs12999125: Continuous and stratified by BMI categories.

<p>Summary of empirically inferred local ancestry x BMI interaction analyses at top chromosome 2q31-32 SNP rs12999125: Continuous and stratified by BMI categories.</p

Box plot of average European ancestry estimates in women from BioVU and CARDIA.

<p>Con = Controls; Ca = Cases; NW = normal-weight; OW = over-weight; Ob = obese; Average European ancestry by case control status in (a) BioVU, and (b) CARDIA; Average European ancestry by case-control status across BMI categories in (c) BioVU and (d) CARDIA.</p

Association between race/ethnicity and fibroid presence by categories of BMI in the Vanderbilt University SD and CARDIA.

<p>Association between race/ethnicity and fibroid presence by categories of BMI in the Vanderbilt University SD and CARDIA.</p

Characteristics of fibroid cases and controls in the Vanderbilt University Synthetic Derivative (SD) and CARDIA.

<p>Characteristics of fibroid cases and controls in the Vanderbilt University Synthetic Derivative (SD) and CARDIA.</p

Regional association plots for SNP x BMI (continuous) interaction p-values for targeted region in chromosome 6 before and after meta-analysis with European American women.

<p>Plotted p-values are for BMI x SNP interaction term in the following scenarios: a) chromosome 6 region meta-analysis in BioVU AA and CARDIA AA; b) chromosome 6 region meta-analysis in BioVU AA and CARDIA AA + BIOVU EA.</p

Summary of empirically inferred local ancestry x BMI interaction analyses at top <i>ADTRP</i> SNP rs6457825 from 6p24: Continuous and stratified by BMI categories.

<p>Summary of empirically inferred local ancestry x BMI interaction analyses at top <i>ADTRP</i> SNP rs6457825 from 6p24: Continuous and stratified by BMI categories.</p

Summary of strongest SNP (rs71430182) association from BMI category and SNP interactions from 2q31-32.

<p>Summary of strongest SNP (rs71430182) association from BMI category and SNP interactions from 2q31-32.</p

Meta-analysis of genome-wide local ancestry and BMI (continuous) interaction in African American women in BioVU and CARDIA.

<p>Negative log(10) p-values for fibroids modeled against local European ancestry and BMI with continuous interaction term (BMI x Local ancestry); y-axis reflects–log10(p) for the interaction term.</p

Association between body fat composition measures and anthropometry by sex in MESA.

<p>Regression equation for body fat composition by anthropometry and sex: Ln body fat composition = β0₁ + β0₂(sex) + β1(X) + β2(X²) + β3(sex*X). Intercept = β0₁ + β0₂, Linear = β1 <b>+</b> β3, Quadratic = β2, P-value for difference by sex = p-value for β3. Centering: height—160cm, weight—50kg, BMI—20 kg/m², waist—100cm, hip—100cm, waist to hip—0.7, waist to height—0.4.</p><p>Association between body fat composition measures and anthropometry by sex in MESA.</p