Dataset Information

Genetic determinants of uterine fibroid size in the multiethnic NIEHS uterine fibroid study.

ABSTRACT: We conducted a follow-up association study across extended candidate chromosomal regions for uterine leiomyoma (UL), or fibroids, to search for loci influencing the size of UL in 916 premenopausal North American women participants to the NIEHS uterine fibroid study. Proportional odds models with adjustments for confounders were fitted to evaluate the association of a final set of 2,484 single nucleotide polymorphisms (SNPs) with the size of uterine fibroids measured by transabdominal and transvaginal ultrasounds. SNP association with UL size was tested in a case-only design comparing three categories of tumor size (small, medium and large tumors) and in a design that included UL-free controls as the lowest category of a four-level ordinal outcome to account for misclassifications due to small, undetected tumors. In the case-only design, rs2285789 in SORCS2 (sortilin-related VPS10 domain containing receptor 2) was the sole variant that remained significant after correction for multiple testing (Bonferroni-adjusted P=0.037). Several other SNPs, namely those located in MYT1L, TMCC1 and BRCA1, reached promising associations. In the design that included the controls, several genes of potential relevance to UL pathogenesis were associated (Bonferroni-unadjusted P < 0.01) with tumor size, particularly LIFR-AS1 (leukemia inhibitory factor receptor alpha-antisense RNA 1), which showed the strongest association (Bonferroni-unadjusted P=0.0006) among the genes with regulated expression in UL. In conclusion, SORCS2, a known GWAS candidate for circulating IGF-I and IGFBP-3, may act through IGF-I signaling to affect the size of fibroids. Through down-regulation of LIFR, LIFR-AS1 may mediate the inhibitory action of LIF (leukemia inhibitory factor), a cytokine involved in embryonic uterine development. Replication analyses are needed to substantiate our reported associations of SORCS2 and LIFR-AS1 with the size of fibroids.

SUBMITTER: Aissani B

PROVIDER: S-EPMC4572088 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Genetic determinants of uterine fibroid size in the multiethnic NIEHS uterine fibroid study.

Aissani Brahim B Zhang Kui K Wiener Howard H

International journal of molecular epidemiology and genetics 20150909 1

We conducted a follow-up association study across extended candidate chromosomal regions for uterine leiomyoma (UL), or fibroids, to search for loci influencing the size of UL in 916 premenopausal North American women participants to the NIEHS uterine fibroid study. Proportional odds models with adjustments for confounders were fitted to evaluate the association of a final set of 2,484 single nucleotide polymorphisms (SNPs) with the size of uterine fibroids measured by transabdominal and transva ...[more]

PMID: 26417400

Similar Datasets

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: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:OBJECTIVES:To examine the association between phthalate exposure and two measures of uterine fibroid burden: diameter of largest fibroid and uterine volume. DESIGN:Pilot, cross-sectional study. SETTING:Academic medical center. PATIENT(S):Fifty-seven premenopausal women undergoing either hysterectomy or myomectomy for fibroids. INTERVENTION(S):None. MAIN OUTCOME MEASURE(S):The diameter of the largest fibroid and uterine dimensions were abstracted from medical records. Spot urine samples were analyzed for 14 phthalate biomarkers using mass spectrometry. We estimated associations between fibroid outcomes and individual phthalate metabolites, sum of di(2-ethylhexyl) phthalate metabolites (?DEHP), and a weighted sum of anti-androgenic phthalate metabolites (?AA Phthalates) using linear regression, adjusting for age, race/ethnicity, and body mass index. Fibroid outcomes were also examined dichotomously (divided at the median) using logistic regression. RESULTS:Most women were of black ethnicity, overweight or obese, and college educated. In multivariable models, higher levels of mono-hydroxyisobutyl phthalate, monocarboxyoctyl phthalate, monocarboxynonyl phthalate, mono(2-ethylhexyl) phthalate, mono(2-ethyl-5-hydroxyhexyl phthalate) (MEHHP), mono(2-ethyl-5-oxohexyl) phthalate (MEOHP), and mono(2-ethyl-5-carboxypentyl) phthalate (MECPP), ?DEHP, and ?AA Phthalates were positively associated with uterine volume. Associations were most pronounced for individual DEHP metabolites (MEHHP, MEOHP, MECPP), ?DEHP, and ?AA Phthalates. For example, a doubling in ?DEHP and ?AA Phthalates was associated with 33.2% (95% confidence interval 6.6-66.5) and 26.8% (95% confidence interval 2.2-57.4) increase in uterine volume, respectively. There were few associations between phthalate biomarkers and fibroid size. CONCLUSIONS:Exposure to some phthalate biomarkers was positively associated with uterine volume, which further supports the hypothesis that phthalate exposures may be associated with fibroid outcomes. Additional studies are needed to confirm these relationships.

Dataset Information

Genetic determinants of uterine fibroid size in the multiethnic NIEHS uterine fibroid study.

Publications

Genetic determinants of uterine fibroid size in the multiethnic NIEHS uterine fibroid study.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets