title: BET1L and TNRC6B associate with uterine fibroid risk among European Americans.
abstract: Uterine fibroid (UFs) affect 77 % of women by menopause and account for $9.4 billion in healthcare costs each year. Although UFs are heritable, genetic risk is poorly understood. The first genome-wide association study (GWAS) of UFs was recently performed in a Japanese population, with reported genome-wide significance for single nucleotide polymorphisms (SNPs) across three chromosomal regions. We tested these SNPs for association with UFs in US cohorts. Women were enrolled in the Right from the Start (RFTS) cohort and the BioVU DNA repository. UF status in both cohorts was determined by pelvic imaging. We tested 65 candidate and haplotype-tagging SNPs for association with UFs presence using logistic regression in RFTS and the top three GWAS-associated SNPs in BioVU. We also combined association results from both cohorts using meta-analysis. 1,086 European American (EA) cases and 1,549 controls were examined. Two SNP associations replicated [blocked early in transport 1 homolog (BET1L) rs2280543, RFTS-BioVU meta-odds ratio (OR) = 0.67 95 % confidence interval (CI) 0.38-0.96, Q = 0.70, I = 0, p = 6.9 × 10⁻³; trinucleotide repeat containing 6B (TNRC6B) rs12484776, RFTS-BioVU meta-OR = 1.21, 95 % CI 1.07-1.35, Q = 0.24, I = 28.37, p = 8.7 × 10⁻³). Meta-analyses combining evidence from RFTS, BioVU, and prior GWAS showed little heterogeneity in effect sizes across studies, with meta-p values between 7.45 × 10⁻⁸ and 3.89 × 10⁻⁹, which were stronger than prior GWAS and supported associations observed for all previously identified loci. These data suggest common variants increase risk for UF in both EA and Japanese populations. However, further research is needed to assess the role of these genes across other racial groups.
authors.affiliation: Vanderbilt Epidemiology Center, Vanderbilt University, 2525 West End Ave., Suite 600 6th Floor, Nashville, TN 37203, USA.
authors.forename: Todd L
authors.initials: TL
authors.lastname: Edwards
authors.forename: Kara A
authors.initials: KA
authors.lastname: Michels
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Hartmann
authors.forename: Digna R
authors.initials: DR
authors.lastname: Velez Edwards
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007889:Leiomyoma / Q000209:etiology* / Q000473:pathology; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D050767:Qc-SNARE Proteins / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000235:genetics*; D012307:Risk Factors; D044465:White People
chemical_list: C107588:BET1L protein, human; D050767:Qc-SNARE Proteins; D016601:RNA-Binding Proteins; C542384:TNRC6B protein, human