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 U.S. 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 to 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 to 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 to 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.

Race‐specific molecular alterations correlate with differential outcomes for black and white endometrioid endometrial cancer patients

“…genome-wide association studies investigating variants associated with the formation of uterine fibroids identified a single-nucleotide polymorphism in the 3 0untranslated region of the BET1L gene directly associated with a decreased risk for developing uterine fibroids in women of European American descent. 24,25 FAM228B, a black-specific PFS candidate associated with better PFS, is a theoretical protein-coding gene encoded on chromosome 2p23.3 that is otherwise largely of unknown function. Furthermore, LIG3, observed as being associated with poor PFS for black patients but improved PFS for white patients, regulates a highly error-prone subtype of alternative nonhomologous end joining DNA repair, termed microhomology-mediated end joining, that can result in an elevated risk of genome instability and increased cancer risk.…”

Follow-up to genome-wide linkage and admixture mapping studies implicates components of the extracellular matrix in susceptibility to and size of uterine fibroids

“…Furthermore, genome-wide linkage scan in the affected sister study (ASP) (8) and fine association mapping across the FH -linked region in the NIEHS cohort (16) suggested the presence of a candidate 1q43 gene affecting the risk and size of UL. More recently, epidemiologic studies of UL in American women enrolled in the Right from the Start (RFTS) cohort and the BioVU DNA repository replicated the results of GWAS in a Japanese population for two of the three most significantly associated genes encoding BET1L (blocked early in transport 1 homolog) and TNRC6B (trinucleotide repeat containing 6B) (17, 18). …”

Epidemiology of Uterine Fibroids

“…A subsequent GWAS in women of European descent found that SNPs in the FASN gene were associated with UL, but did not replicate the Japanese GWAS findings [188], nor did the BWHS among African Americans [189]. However, the BioVU and Right From the Start cohorts replicated two SNP associations from the Japanese GWAS among European Americans (blocked early in transport 1 homolog (BET1L) rs2280543, and trinucleotide repeat containing 6B (TNRC6B) rs12484776) [190, 191]. In the BWHS, admixture mapping analyses showed suggestive evidence of association at chromosomes 2, 4, and 10 (2q37, 4p16.1, and 10q26) [189], with the region in chromosome 2 being replicated in the UFS [192].…”