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

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.

种族（尤其是非裔血统）与肥胖均为子宫肌瘤的重要危险因素，且二者可能存在交互作用，为肌瘤生长营造适宜环境。然而现有研究大多仅关注主效应，而非二者的交互作用。本研究首先针对子宫肌瘤的发病风险，提供了体重指数（Body Mass Index，BMI）分类与自述种族之间存在交互作用的证据。随后，我们在范德堡大学医学中心生物样本库（BioVU，包含539例病例与794例对照）以及青年冠状动脉风险发展研究（CARDIA，包含264例病例与173例对照）的非裔美国女性队列中，探究了推断的局部欧洲血统与肌瘤发病风险之间的关联是否受BMI的修饰。本研究采用多元logistic回归分析评估局部欧洲血统与BMI对肌瘤发病风险的交互作用，并开展固定效应元分析。通过10000次置换检验经验性确定了局部血统与BMI交互作用的统计学显著性阈值（p值=1.18×10^-4）。混合映射分析在ADTRP基因区域（6号染色体p24）检测到欧洲血统与肌瘤发病风险的关联受BMI修饰（连续型交互作用p值=3.75×10^-5）；其中肥胖亚组的关联最强（血统优势比[AOR]=0.51，p值=2.23×10^-5）。对该目标区域内基因型/填充变异与BMI的交互作用进行评估后发现，仅在非裔美国人中存在种族特异性的交互作用；其中插入/缺失变异（6:11946435）的交互作用证据最强，且同样见于肥胖亚组（优势比[OR]=1.66，p值=1.72×10^-6）。本研究在既往报道的2号染色体q31-32区域（包含COL5A2基因以及ADTRP的直接下游靶基因TFPI）中，发现局部血统与BMI之间存在名义显著性的交互作用证据。在包含1195例病例与1164例对照的独立欧裔美国人群队列中，同样检测到非裔美国女性该区域内发现的单核苷酸多态性（Single Nucleotide Polymorphisms，SNPs）与BMI的交互作用。本研究结果阐明了可干预与不可干预因素如何通过交互作用影响肌瘤发病风险，同时提示BMI在子宫肌瘤发病机制中发挥生物学作用。