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.
Highlights
Uterine leiomyomata, referred to as fibroids, are benign growths arising from myometrial smooth muscle cells
It is postulated that obesity and non-modifiable risk factors such as race or genetic ancestry may interact to jointly influence uterine fibroid growth, most existing studies have not evaluated their interaction
We first show that the association between reported/third-party identified-race (African American (AA) and European American (EA)) and fibroid risk is modified by body mass index (BMI) categories
Summary
Referred to as fibroids, are benign growths arising from myometrial smooth muscle cells. As the most common pelvic tumor in women, prevalence of fibroids ranges from 20 to 77% [1,2,3,4,5], and accounts for $9.4-$34 billion dollars annually in healthcare costs [5,6,7]. Compared with European American (EA) women, African American (AA) women are two to three times more likely to be diagnosed with fibroids [2;3], which are larger in size and greater in number [2;3;9]. The role of genetic predisposition in this disparity is supported by two admixture mapping studies of AAs which demonstrated that greater proportion of European ancestry was inversely associated with fibroids in AA women [11;12]
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