Dataset Information

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?? and 3.89 × 10??, 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.

SUBMITTER: Edwards TL

PROVIDER: S-EPMC3715562 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

BET1L and TNRC6B associate with uterine fibroid risk among European Americans.

Edwards Todd L TL Michels Kara A KA Hartmann Katherine E KE Velez Edwards Digna R DR

Human genetics 20130419 8

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 ...[more]

PMID: 23604678

Similar Datasets

Project description:BackgroundUterine fibroids are common. Symptoms are debilitating for many, leading to high medical and societal costs. Indirect data suggest that compared with white women, African Americans develop fibroids at least 10 years earlier on average, and their higher health burden has been well documented.ObjectiveThe objective of the study was to directly measure fibroid incidence and growth in a large, community-based cohort of young African-American women.Study designThis observational, community-based, prospective study enrolled 1693 African-American women, aged 23-35 years with no prior diagnosis of fibroids. Standardized transvaginal ultrasound examinations at enrollment and after approximately 18 months were conducted to identify and measure fibroids ≥0.5 cm in diameter. Fibroid growth (change in natural log volume per 18 months) was analyzed with mixed-model regression (n = 344 fibroids from 251 women whose baseline ultrasound revealed already existing fibroids).ResultsAmong the 1123 fibroid-free women with follow-up data (88% were followed up), incidence was 9.4% (95% confidence interval, 7.7-11.2) and increased with age (Ptrend < .0001), from 6% (confidence interval, 3-9) for 23-25 year olds to 13% (confidence interval, 9-17) for 32-35 year olds. The chance of any new fibroid development was greater than twice as high for women with existing fibroids compared with women who were fibroid free at baseline (age-adjusted relative risk = 2.3 (confidence interval, 1.7-3.0). The uterine position of most incident fibroids (60%) was intramural corpus. Average fibroid growth was 89% per 18 months (confidence interval, 74-104%) but varied by baseline fibroid size (P < .0001). Fibroids ≥2 cm in diameter had average growth rates well under 100%. In contrast, small fibroids (<1 cm diameter) had an average growth rate of nearly 200% (188%, confidence interval, 145-238%). However, these small fibroids also had a high estimated rate of disappearance (23%).ConclusionThis is the first study to directly measure age-specific fibroid incidence with a standardized ultrasound protocol and to measure fibroid growth in a large community-based sample. Findings indicate that very small fibroids are very dynamic in their growth, with rapid growth, but a high chance of loss. Larger fibroids grow more slowly. For example, a 2-cm fibroid is likely to take 4-5 years to double its diameter. Detailed data on fibroid incidence confirm an early onset in African-American women.

Project description:BackgroundHeritability estimates (including twin and single nucleotide polymorphism [SNP]-based heritability studies) for fibroids have been inconsistent across prior studies ranging between 9 and 69%. These inconsistencies are due to variations in study design and included populations. A major design issue has been lack of imaging confirmation to identify controls, where asymptomatic women without imaging confirmation may be misclassified as controls leading to an attenuation of heritability estimates. To reconcile the differences in prior heritability estimates and the impact of misclassification of controls on heritability, we determined SNP-based heritability and characterized the genetic architecture of pelvic image-confirmed fibroid cases and controls.MethodsAnalyses were performed among women of European American descent using genome-wide SNP data from BioVU, a clinical database composed of DNA linked to de-identified electronic health records. We estimated the genetic variance explained by all SNPs using Genome-Wide Complex Trait Analysis on imputed data. Fibroid cases and controls were identified using a previously reported phenotyping algorithm that required pelvic imaging confirmation.ResultsIn total, we used 1,067 image-confirmed fibroid cases and 1,042 image-confirmed fibroid controls. The SNP-based heritability estimate for fibroid risk was h2 = 0.33 ± 0.18 (p = 0.040). We investigated the relationship between heritability per chromosome and chromosome length (r2 < 1%), with chromosome 8 explaining the highest proportion of variance for fibroid risk. There was no enrichment for intergenic or genic SNPs for the fibroid SNP-based heritability. Excluding loci previously associated with fibroid risk from genome-wide association study did not attenuate fibroid heritability suggesting that loci associating with fibroid risk are yet to be discovered.ConclusionsWe observed that fibroid SNP-based heritability was higher than the previous estimate using genome-wide SNP data that relied on self-reported outcomes, but within the range of prior twin pair studies. Furthermore, these data support that imprecise phenotyping can significantly affect the ability to estimate heritability using genotype data.

Project description:BackgroundUterine fibroids are a common cause of heavy menstrual bleeding and pain. Treatment with the combination of relugolix (an oral gonadotropin-releasing hormone-receptor antagonist), estradiol, and norethindrone acetate, administered once daily, may have efficacy in women with uterine fibroids and heavy bleeding while avoiding hypoestrogenic effects.MethodsWe conducted two replicate international, double-blind, 24-week, phase 3 trials involving women with fibroid-associated heavy menstrual bleeding. Participants were randomly assigned in a 1:1:1 ratio to receive once-daily placebo, relugolix combination therapy (40 mg of relugolix, 1 mg of estradiol, and 0.5 mg of norethindrone acetate), or delayed relugolix combination therapy (40 mg of relugolix monotherapy, followed by relugolix combination therapy, each for 12 weeks). The primary efficacy end point in each trial was the percentage of participants with a response (volume of menstrual blood loss <80 ml and a ≥50% reduction in volume from baseline) in the relugolix combination therapy group, as compared with the placebo group. Key secondary end points were amenorrhea, volume of menstrual blood loss, distress from bleeding and pelvic discomfort, anemia, pain, fibroid volume, and uterine volume. Safety and bone mineral density were assessed.ResultsA total of 388 women in trial L1 and 382 in trial L2 underwent randomization. A total of 73% of the participants in the relugolix combination therapy group in trial L1 and 71% of those in trial L2 had a response (primary end point), as compared with 19% and 15%, respectively, of those in the placebo groups (P<0.001 for both comparisons). Both relugolix combination therapy groups had significant improvements, as compared with the placebo groups, in six of seven key secondary end points, including measures of menstrual blood loss (including amenorrhea), pain, distress from bleeding and pelvic discomfort, anemia, and uterine volume, but not fibroid volume. The incidence of adverse events was similar with relugolix combination therapy and placebo. Bone mineral density was similar with relugolix combination therapy and placebo but decreased with relugolix monotherapy.ConclusionsOnce-daily relugolix combination therapy resulted in a significant reduction in menstrual bleeding, as compared with placebo, and preserved bone mineral density in women with uterine fibroids. (Funded by Myovant Sciences; LIBERTY 1 [L1] and LIBERTY 2 [L2] ClinicalTrials.gov numbers, NCT03049735 and NCT03103087, respectively.).

Project description:Background: Women with uterine fibroids often seek uterine-preserving treatments, rather than hysterectomy. Imaging-defined endpoints following nonsurgical treatments for fibroids are limited. Materials and Methods: Fibroid Interventions: Reducing Symptoms Today and Tomorrow (FIRSTT), a randomized controlled trial of uterine artery embolization (UAE) versus magnetic resonance imaging-guided focused ultrasound surgery (MRgFUS), enrolled premenopausal women with symptomatic uterine fibroids. In this subanalysis, we report imaging results up to 36 months after UAE or MRgFUS. Magnetic resonance imaging (MRI) was performed at baseline for all women and during the 36 months after treatment if they did not meet other study endpoints. The main outcome of this subanalysis was fibroid volume reduction (defined both in terms of total fibroid load and volume of the largest fibroid), uterine volume reduction, and nonperfused volume. Results: During 2010-2014, 25 of the 37 women who were randomized and treated at Mayo Clinic had a 24-month follow-up MRI (11 UAE; 14 MRgFUS); among these women, 15 (7 UAE and 8 MRgFUS) had a 36-month follow-up MRI. Average age for the cohort was 44.1 (standard deviation, SD = 4.4) years. Nine patients had a second fibroid procedure by 36 months (seven in the MRgFUS arm and two in UAE arm). Median total fibroid load reduction was ∼50% in both treatment arms at both 24- and 36-month follow-up. Volume of the largest fibroid decreased more in the MRgFUS arm, whereas uterine volume decreased more in the UAE arm (neither reached statistical significance). At 24 months, median nonperfused volume was higher in the UAE arm (92%) than the MRgFUS arm (10%). Conclusions: Similar fibroid volume reduction was seen for the MRgFUS and UAE treatments in this comparative effectiveness study. Nonperfused volume 24 months after the procedure was higher in the UAE arm than in the MRgFUS arm. Clinical Trial Registration Number: NCT00995878, clinicaltrials.gov.

Dataset Information

BET1L and TNRC6B associate with uterine fibroid risk among European Americans.

Publications

BET1L and TNRC6B associate with uterine fibroid risk among European Americans.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets