Evaluation of GWAS candidate susceptibility loci for uterine leiomyoma in the multi-ethnic NIEHS uterine fibroid study

Aissani, Brahim; Zhang, Kui; Wiener, Howard W.

doi:10.3389/fgene.2015.00241

Cited by 18 publications

(12 citation statements)

References 44 publications

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“…The observation of an association between rs4247357 and UL risk among women with ≥40% European ancestry supports findings from the recent 2012 GWAS among women of European descent (8). Our results do not agree with those from a smaller ultrasound screening study of European and African American women (9). The average percent European ancestry among African American women is about 20%.…”

Section: Discussioncontrasting

confidence: 99%

“…It is unknown whether any of these SNPs are causally associated with UL or whether they are in LD with the causal variant. The National Institute of Environmental Health Sciences Uterine Fibroid Study (6), which analyzed 574 African American and 394 non-Hispanic European American women aged 35–51 with DNA, did not replicate FASN findings in either ethnic group (9) but power was low to detect an association.…”

Section: Introductionmentioning

confidence: 99%

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FASN, dietary fat intake, and risk of uterine leiomyomata in the Black Women's Health Study

Wise

Palmer

Rosenberg

et al. 2016

Fertility and Sterility

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Objective To replicate results from a previous genome-wide association study (GWAS) of European ancestry women, in which a positive association was found between uterine leiomyomata (UL) and rs4247357, a single nucleotide polymorphism (SNP) located near the fatty-acid synthase (FASN) gene. Design Prospective cohort study. Setting United States. Patients African American women aged 23–50 years, who were premenopausal and had an intact uterus in 1997. Interventions None. Main outcome measures We genotyped rs4247357 among 2,301 incident UL cases and 3,005 controls from the Black Women’s Health Study (BWHS). Odds ratios (ORs) and 95% confidence intervals (CI) were estimated using logistic regression with control for age, geographic region of residence, and percent European ancestry using a panel of validated ancestry informative markers. Results Overall, rs4247357 was not associated with UL risk. Relative to the CC genotype, ORs were 1.04 (95% CI: 0.92–1.19) for the AC genotype and 1.09 (95% CI: 0.93–1.29) for the AA genotype (P-trend=0.281). A positive association was found, however, among those with higher European ancestry (≥40%). Relative to the CC genotype, ORs were 2.03 (95% CI: 1.12–3.69) for the AC genotype and 2.44 (95% CI: 1.20–4.96) for the AA genotype (P-trend=0.012; P-interaction=0.136). Dietary fat intake also appeared to modify the FASN-UL association. Conclusions Although there was little overall association between rs4247357 and UL risk, a positive association was observed among women with ≥40% European ancestry. Direct sequencing of this genomic region might be warranted to determine whether rs4247357, or some other variant, is causally related to UL.

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Section: Discussioncontrasting

confidence: 99%

Section: Introductionmentioning

confidence: 99%

FASN, dietary fat intake, and risk of uterine leiomyomata in the Black Women's Health Study

Wise

Palmer

Rosenberg

et al. 2016

Fertility and Sterility

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“…Genome-wide linkage and follow-up association studies in a meta-analysis of EA women implicated an additional locus for risk of fibroid diagnosis (Eggert et al 2012 ). The loci implicated in these previous studies ( SLK , BET1 , TNRC6B , and FASN/CCDC57 ) have been replicated among EAs (Aissani et al 2015a ; Edwards et al 2013b ), which have been evaluated but failed to replicate in AAs (Aissani et al 2015b ; Wise et al 2012 ). The predominant studies conducted among AA subjects have involved admixture mapping, which has shown significant regions of increased African ancestry in cases, particularly at 1q42.2 (Zhang et al 2015 ), 4p16, and 10q26 (Wise et al 2012 ).…”

Section: Introductionmentioning

confidence: 95%

A multi-stage genome-wide association study of uterine fibroids in African Americans

et al. 2017

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Uterine fibroids are benign tumors of the uterus affecting up to 77% of women by menopause. They are the leading indication for hysterectomy, and account for $34 billion annually in the United States. Race/ethnicity and age are the strongest known risk factors. African American (AA) women have higher prevalence, earlier onset, and larger and more numerous fibroids than European American women. We conducted a multi-stage genome-wide association study (GWAS) of fibroid risk among AA women followed by in silico genetically predicted gene expression profiling of top hits. In Stage 1, cases and controls were confirmed by pelvic imaging, genotyped and imputed to 1000 Genomes. Stage 2 used self-reported fibroid and GWAS data from 23andMe, Inc. and the Black Women’s Health Study. Associations with fibroid risk were modeled using logistic regression adjusted for principal components, followed by meta-analysis of results. We observed a significant association among 3399 AA cases and 4764 AA controls at rs739187 (risk-allele frequency = 0.27) in CYTH4 (OR (95% confidence interval) = 1.23 (1.16–1.30), p value = 7.82 × 10−9). Evaluation of the genetic association results with MetaXcan identified lower predicted gene expression of CYTH4 in thyroid tissue as significantly associated with fibroid risk (p value = 5.86 × 10−8). In this first multi-stage GWAS for fibroids among AA women, we identified a novel risk locus for fibroids within CYTH4 that impacts gene expression in thyroid and has potential biological relevance for fibroids.Electronic supplementary materialThe online version of this article (doi:10.1007/s00439-017-1836-1) contains supplementary material, which is available to authorized users.

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“…Genome‐wide analyses such as exome sequencing may elucidate an additional candidate gene(s) possibly contributing to tumorigenesis. Although, the molecular mechanism of tumorigenesis in ovarian leiomyoma remains unknown, Aissani et al provided independent evidence for association of SNP of TNRC6B with both the risk and the size of uterine leiomyoma [Aissani et al, ]. However, TNRC6B resides on 22q13.1, a location different from that of PTCH1 .…”

Section: Discussionmentioning

confidence: 99%

Gorlin syndrome with an ovarian leiomyoma associated with a PTCH1 second hit

Akizawa

Miyashita

Sasaki

et al. 2016

American J of Med Genetics Pt A

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We describe a Gorlin syndrome (GS) case with two different second hit mutations of PTCH1, one in a keratocystic odontogenic tumor (KCOT) and the other in an ovarian leiomyoma. GS is a rare genetic condition manifesting as multiple basal cell nevi associated with other features such as medulloblastomas, skeletal abnormalities, and ovarian fibromas. A 21-year-old Japanese woman with a history of two KCOTs was diagnosed with GS according to clinical criteria. A PTCH1 mutation, c.1427del T, was detected in peripheral blood. A novel PTCH1 mutation, c.264_265insAATA, had been found in the maxillary KCOT as a second hit mutation. More recently, the ovarian tumor was detected during a gynecological examination. Laparoscopic adnexectomy was performed, and the pathological diagnosis of the ovarian tumor was leiomyoma. Interestingly, another novel mutation, loss of heterozygosity spanning from 9q22.32 to 9q31.2, including PTCH1 and 89 other genes, was detected in this ovarian tumor, providing evidence of a second hit mutation. This is the first report describing a GS-associated ovarian tumor carrying a second hit in the PTCH1 region. We anticipate that accumulation of more cases will clarify the importance of second hit mutations in ovarian tumor formation in GS.

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Evaluation of GWAS candidate susceptibility loci for uterine leiomyoma in the multi-ethnic NIEHS uterine fibroid study

Cited by 18 publications

References 44 publications

FASN, dietary fat intake, and risk of uterine leiomyomata in the Black Women's Health Study

FASN, dietary fat intake, and risk of uterine leiomyomata in the Black Women's Health Study

A multi-stage genome-wide association study of uterine fibroids in African Americans

Gorlin syndrome with an ovarian leiomyoma associated with a PTCH1 second hit

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