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Gene variants associated with age at menopause are also associated with polycystic ovary syndrome, gonadotrophins and ovarian volume.

ABSTRACT: Is there a relationship between the genetic risk for polycystic ovary syndrome (PCOS) and genetic variants that influence timing of menopause?The genetic risk score, which sums the contribution of variants at all menopause loci, was associated with PCOS.Ovarian parameters and anti-Mullerian hormone levels suggest that women with PCOS should have a later age at menopause.The study was a case-control examination of genetic variants associated with age at menopause in a discovery cohort of women with PCOS (n = 485) and controls (n = 407) from Boston recruited from 2003 to 2012. Replication was performed in women from Greece (cases, n = 884 and controls, n = 311).PCOS was defined by the National Institutes of Health criteria in Boston and Greece (n = 783), with additional subjects fulfilling the Rotterdam criteria (hyperandrogenism, polycystic ovary morphology and regular menses) in Greece (n = 101). Controls in Boston and Greece had regular menstrual cycles and no hyperandrogenism. Allele frequencies for variants previously associated with age at menopause were examined in PCOS cases and controls, along with the relationship to quantitative traits.The variant rs11668344-G was associated with decreased risk of PCOS (odds ratio: 0.77 [0.59-0.93]; P = 0.004). There was a strong relationship between the late menopause allele rs12294104-T and increased LH levels (? ± SE; 0.26 ± 0.06; P = 5.2 × 10(-5)) and the LH:FSH ratio (0.28 ± 0.06; P = 2.7 × 10(-6)). The minor allele at rs10852344-T was associated with smaller ovarian volume (-0.16 ± 0.05; P = 0.0012). A genetic risk score calculated from 16 independent variants associated with age at menopause was also associated with PCOS (P < 0.02), LH and the LH:FSH ratio (both P < 0.05).The variant rs11668344 was not associated with PCOS in the Greek cohort, but results exhibited the same direction of effect as the Boston cohort. However, it is possible that the individual association was a false positive in the Boston cohort.The study demonstrates that gene variants known to influence age at menopause are also associated with risk for PCOS. Further, our data suggest that the relationship between age at menopause and PCOS may be explained, at least in part, by effects on LH levels and follicle number. The data point to opposing influences of the genetic variants on both menopausal age and PCOS.The project was supported by award number R01HD065029 from the Eunice Kennedy Shriver National Institute of Child Health & Human Development, award number 1 UL1 RR025758, Harvard Clinical and Translational Science Center, from the National Center for Research Resources and award 1-10-CT-57 from the American Diabetes Association. C.K.W. is a consultant for Takeda Pharmaceuticals.NCT00166569.

SUBMITTER: Saxena R

PROVIDER: S-EPMC4472323 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Gene variants associated with age at menopause are also associated with polycystic ovary syndrome, gonadotrophins and ovarian volume.

Saxena R R Bjonnes A C AC Georgopoulos N A NA Koika V V Panidis D D Welt C K CK

Human reproduction (Oxford, England) 20150520 7

<h4>Study question</h4>Is there a relationship between the genetic risk for polycystic ovary syndrome (PCOS) and genetic variants that influence timing of menopause?<h4>Summary answer</h4>The genetic risk score, which sums the contribution of variants at all menopause loci, was associated with PCOS.<h4>What is already known</h4>Ovarian parameters and anti-Mullerian hormone levels suggest that women with PCOS should have a later age at menopause.<h4>Study design, size, duration</h4>The study was ...[more]

PMID: 25994816

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Project description:IntroductionAge, polycystic ovary syndrome (PCOS), low body mass index (BMI), high antral follicle count (AFC), increased anti-Muller hormone (AMH) levels, and elevated serum estradiol (E2) concentrations are risk factors for ovarian hyperstimulation syndrome (OHSS). However, data on the relationship between risk factors and OHSS severity in patients with PCOS are rare.ObjectiveThis retrospective study examined the risk factors for OHSS and their effect on OHSS severity in patients with PCOS undergoing in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI).MethodThe records of 2,699 women were reviewed and included in this study. These women were diagnosed with PCOS during their first IVF/ICSI cycle between January 2010 and December 2017. We analyzed the association between each of the interrogated risk factors (including female age, BMI, AFC, basal serum E2, and the number of oocytes retrieved) and OHSS. The effects of each risk factor on OHSS severity were further explored. Logistic regression was performed as part of the above analysis.ResultsOf the 2,699 women with PCOS who underwent assisted reproductive technology (ART), 75.2% had a normal response to controlled ovarian hyperstimulation (COH), while 24.8% developed OHSS. All OHSS patients were younger and had lower BMIs and basal serum follicle-stimulating hormone (FSH) and E2 levels but higher AFCs than those in the normal group. AFC demonstrated a strong correlation with OHSS, with a cutoff value of 24 in patients with PCOS. A total of 19.5% of the patients had mild OHSS, while 80.5% had moderate OHSS. Compared with those in the moderate OHSS group, those in the mild OHSS group were older and had higher basal serum FSH levels and lower serum E2 and T levels. However, BMI and AFC were not different between the mild and moderate OHSS groups. Basal serum E2 showed a strong correlation with OHSS severity, with a cutoff value of 37.94 pg/ml.ConclusionsAFC is a strong marker of OHSS, and basal serum E2 is the best predictor of OHSS severity in women with PCOS undergoing IVF treatment.

Project description:BACKGROUND:Polycystic ovary syndrome (PCOS) is a common endocrine disorder in reproductive-age women. Multiple susceptible gene as well as environmental factors and their interaction each other are contributed to the PCOS risk. Several case-control studies have researched the associations of the vitamin D receptor gene (VDR) polymorphisms with PCOS susceptibility, but the jury is still out. Here, we carried out a meta-analysis to clarify polymorphisms between ApaI (C/A) (rs7975232), BsmI (G/A) (rs1544410), FokI (C/T) (rs10735810), TaqI (T/C) (rs731236) and Tru9I (G/A) (rs757343) in the VDR gene and PCOS susceptibility based on relative lager sample size. METHODS:English database of PubMed and Embase, and Chinese database of Wanfang and China National Knowledge Infrastructure (CNKI) databases were retrivaled for the relationship between VDR gene variates and PCOS susceptibility published before 31th, May 2018. Crude odds ratios (ORs) and its 95% confidence intervals (95% CIs) in different comparisons were used to detected the strength of the association. All the statistical analyses of the present meta-analysis were performed by STATA version 12.0 software. RESULTS:Totally, 3587 (PCOS group 1922; control group 1665) participants from 13 studies were included which met our inclusion criteria. A statistically significant association between VDR ApaI (rs7975232) polymorphism and PCOS susceptibility (C vs. A: OR?=?1.19, 95%CI?=?1.06~1.34, P?=?0.004) was found in the overall population. After stratified by ethnicity, we showed that there is a significant association between VDR ApaI (rs7975232) polymorphism and susceptibility to PCOS in the Asian (C vs. A: OR?=?1.21, 95%CI?=?1.04~1.42, P?=?0.016) population, but this association was not found in the Caucasian population. Additionally, a significant relationship between VDR BsmI (rs1544410) variates with PCOS susceptibility in the Asian (G vs. A: OR?=?1.27, 95%CI?=?1.06~1.53, P?=?0.011) population, but this association was not found in the Caucasian population. We didn't find any association between VDR FokI (rs2228570), VDR TaqI (rs731236), VDR Tru9I (rs757343) and PCOS susceptibility in the overall and the subgroup populations. CONCLUSIONS:Our findings demonstrated that VDR ApaI (rs7975232) and VDR BsmI (rs1544410) polymorphisms are correlated with susceptibility to PCOS in the Asian population and VDR TaqI (rs731236), VDR FokI (rs2228570), VDR Tru9I (rs757343) did not reveal a relationship with the PCOS susceptibility.

Project description:ContextA genome-wide association study has identified three loci (five independent signals) that confer risk for polycystic ovary syndrome (PCOS) in Han Chinese women. Replication is necessary to determine whether the same variants confer risk for PCOS in women of European ancestry.ObjectiveThe objective of the study was to test whether these PCOS risk variants in Han Chinese women confer risk for PCOS in women of European ancestry.DesignThis was a case-control study.SettingThe study was conducted at deCODE Genetics in Iceland and two academic medical centers in the United States.PatientsCases were 376 Icelandic women and 565 and 203 women from Boston, MA, and Chicago, IL, respectively, all diagnosed with PCOS by the National Institutes of Health criteria. Controls were 16,947, 483, and 189 women not known to have PCOS from Iceland, Boston, and Chicago, respectively.InterventionThere were no interventions.Main outcomesMain outcomes were allele frequencies for seven variants in PCOS cases and controls.ResultsTwo strongly correlated Han Chinese PCOS risk variants on chromosome 9q33.3, rs10986105[C], and rs10818854[A], were replicated in samples of European ancestry with odds ratio of 1.68 (P = 0.00033) and odds ratio of 1.53 (P = 0.0019), respectively. Other risk variants at 2p16.3 (rs13405728), 2p21 (rs12468394, rs12478601, and rs13429458), and 9q33.3 (rs2479106), or variants correlated with them, did not associate with PCOS. The same allele of rs10986105 that increased the risk of PCOS also increased the risk of hyperandrogenism in women without PCOS from Iceland and demonstrated a stronger risk for PCOS defined by the National Institutes of Health criteria than the Rotterdam criteria.ConclusionsWe replicated one of the five Chinese PCOS association signals, represented by rs10986105 and rs10818854 on 9q33, in individuals of European ancestry. Examination of the subjects meeting at least one of the Rotterdam criteria for PCOS suggests that the variant may be involved in the hyperandrogenism and possibly the irregular menses of PCOS.

Dataset Information

Gene variants associated with age at menopause are also associated with polycystic ovary syndrome, gonadotrophins and ovarian volume.

Publications

Gene variants associated with age at menopause are also associated with polycystic ovary syndrome, gonadotrophins and ovarian volume.

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