Genetic polymorphisms of GnRH and gonadotrophic hormone receptors affect the phenotype of polycystic ovary syndrome

Valkenburg, Olivier; Uitterlinden, André G.; Piersma, Djura; Hofman, Albert; Themmen, Axel P. N.; Jong, Frank H. de; Fauser, Bart C.J.M.; Laven, Joop S.E.

doi:10.1093/humrep/dep113

Cited by 111 publications

(97 citation statements)

References 33 publications

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“…In our study, rs13405728 was not associated with PCOS among Bahraini Arab subjects, which was in agreement with recent studies on Dutch [19], and USA women of European ancestry [18,20], but in sharp contrast to two independent Chinese studies, which confirmed its strong association with PCOS in Chinese [6] and in Han Chinese [17] subjects. In addition to rs13405728, rs2293275 was not associated with PCOS among Bahraini Arab (this study) and Dutch [25] subjects, with comparable case:control MAF recorded for Bahraini Arab (0.34:0.34) and Dutch (0.40:0.42) cases and controls.…”

Section: Discussionsupporting

confidence: 66%

“…We analyzed the association of PCOS with 11 SNPs from LHCGR and FSHR previously tested for their association with PCOS in European [18][19][20]25], and non-European [17,[26][27][28][29] populations. This case-control sample included 203 women with PCOS and 211 age-and ethnically-matched (Bahraini Arab) control women.…”

Section: Discussionmentioning

confidence: 99%

“…Recent GWAS studies on Han Chinese [6,28] and women of European ancestry [10] identified FSHR as PCOS susceptibility locus. FSHR gene variants were linked with and PCOS according to some [27,28], but not all [19,25,30], studies. This was largely due to the ethnic/racial background of studied participant, supported by the association of rs2268361 with PCOS in Chinese [28], but not Dutch [19] PCOS cases, and by the association of rs6166 with PCOS in Chinese [27], but not Dutch [19], UK [31], or Turkish [30] women.…”

Section: Discussionmentioning

confidence: 99%

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Leutinizing hormone/choriogonadotropin receptor and follicle stimulating hormone receptor gene variants in polycystic ovary syndrome

Almawi

Hubail

Arekat

et al. 2015

J Assist Reprod Genet

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Purpose Previous studies identified follicle-stimulating hormone receptor (FSHR) and luteinizing hormone/ choriogonadotropin receptor (LHCGR) genes as polycystic ovary syndrome (PCOS) susceptibility loci, which was dependent on the racial/ethnic background of studied population. We investigated the association of genetic variants in FSHR and LHCGR with PCOS in Bahraini Arab women. Methods A retrospective case-control study, involving 203 women with PCOS, and 211 age-and ethnically-matched control women. FSHR and LHCGR genotyping was done by allelic exclusion method (real-time PCR).Results Significantly lower frequencies of heterozygous LHCGR rs7371084 and FSHR rs11692782 genotype carriers were seen between women with PCOS vs. controls, and increased frequency of heterozygous homozygous LHCGR rs4953616 genotype carriers were detected between women with PCOS compared to control women. Limited linkage disequilibrium was noted among LHCGR and FSHR SNPs, and 2 blocks were constructed: the first (Block 1) spanning 61 kb contained the six tested LHCGR SNPs, and the second (Block 2) spanning 298 kb contained four of the five tested FSHR SNPs. Higher frequency of LHCGR GTCAAG haplotype was seen in women with PCOS compared to controls; the frequencies of the remaining LHCGR haplotypes, and all FSHR haplotypes were similar between cases and controls. Conclusion This is the first study to confirm the association of novel LHCGR (rs7371084, rs4953616) and FSHR (rs11692782) SNPs with PCOS. The differential association of LHCGR and FSHR variants with PCOS confirms the racial/ ethnic contribution to their association with PCOS.

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Section: Discussionsupporting

confidence: 66%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Leutinizing hormone/choriogonadotropin receptor and follicle stimulating hormone receptor gene variants in polycystic ovary syndrome

Almawi

Hubail

Arekat

et al. 2015

J Assist Reprod Genet

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“…A significant association between the polymorphism Ala307Thr and PCOS was also reported by a recent study on Chinese women [11]. In contrast, the existence of significant differences in the allele distribution of FSH-R polymorphysm 307 in women with PCOS was not confirmed among Turkish adolescent girls [12], and on women of Caucasian origin [13]. We studied herein an homogeneous population of women with "full" PCOS and a control population of IVF patients with normal ovary.…”

Section: Discussionmentioning

confidence: 61%

“…A couple of studies have been published, one showing that normo-ovulatory women with homozygous Ala307 have the best responsiveness to exogenous FSH [8], the other showing no 307 variant-linked changes in the responsiveness to FSH in chronic anovulatory subjects [9]. A significant increase in the Ala307Thr genotype frequency among women with PCOS was also reported [9][10][11], but not confirmed by other studies [12,13].…”

Section: Introductionmentioning

confidence: 93%

FSH-receptor Ala307Thr polymorphism is associated to polycystic ovary syndrome and to a higher responsiveness to exogenous FSH in Italian women

Dolfin

Guani

Lussiana

et al. 2011

J Assist Reprod Genet

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Objective Herein we analyzed FSH-R polymorphism at position 307 aiming (a) to assess the prevalence of the three allelic variants (Ala307Ala, Ala307Thr and Thr307Thr) in relation to the type of ovary and (b) to clarify if the allelic variant could influence the responsiveness to exogenous FSH. Study design We prospectively studied a group of 106 Italian women undergoing in vitro fertilization (IVF), among which 40 were subjects with polycystic ovary syndrome (PCOS) and 66 were normo-ovulatory women with a normal ovarian morphology at transvaginal ultrasound. DNA extraction, denaturing high-performance liquid chromatography (dHPLC) and DNA sequencing were used to detect the FSH-R 307 polymorphic genotype and the whole exon 10 was analyzed. Results The heterozygote variant Ala307Thr was significantly more frequent than the homozygote variants in women with PCOS, whereas in normo-ovulatory women with normal ovary the three allelic variants had a comparable prevalence. Women bearing the Ala307Thr variant showed a higher ovarian responsiveness to exogenous FSH than normo-ovulatory subjects. Conclusions The heterozygote FSH-R polymorphism Ala307Thr is significantly more frequent in women with PCOS than in normo-ovulatory subjects and is more frequently associated with a higher ovarian responsiveness to exogenous FSH.

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Association between genes encoding components of the Leutinizing hormone/Luteinizing hormone–choriogonadotrophin receptor pathway and polycystic ovary syndrome in Egyptian women

et al. 2015

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Polycystic ovary syndrome (PCOS) is one of the most common endocrine-metabolic disorders; however, its pathophysiology is still unclear. Certain polymorphisms of luteinizing hormone betasubunit (LHb) and LH/choriogonadotrophin receptor (LHCGR) genes may lead to changes in the bioactivity of this hormone. We aimed to investigate possible associations between polymorphisms in the LHb and LHCGR genes and PCOS among Egyptian women. We also aimed to shed light on the impact of these polymorphisms on LH level, hormonal, and metabolic features of PCOS. A case-control study included unrelated 210 patients with PCOS and 200 healthy controls, and they were stratified according to their body mass index into two subgroups: lean and obese. Polymorphisms of LHb G1502A and LHCGR [G935A, and ins18LQ] genes were genotyped using polymerase chain reaction-restriction fragment length polymorphism. Our results revealed that LHb G1052A GA genotype and A allele, LHCGR G935A GA, AA genotypes, or A allele were significantly associated with PCOS risk, while the LHCGR ins18LQ polymorphism was not. Additionally, there is a synergism between LHb G1052A minor A and minor A allele of LHCGR G935A or minor ins allele of LHCGR ins18LQ and susceptibility to PCOS. When we stratified PCOS women or controls into obese and lean subjects, we found that LHb G1502A GA genotype and A allele being more frequent in the obese group when compared with lean patients with PCOS [The odds ratio and 95% confidence interval were 5.6 (1.30-24.56) and 5.15 (1.21-21.90), respectively, P 5 0.01, for each group.] These results suggested that LHb G1052A and LHCGR G935A genes polymorphisms are associated with increased risk of PCOS in Egyptian women especially in obese cases. There was a synergism between LHb G1052A minor A allele and of LHCGR G935A minor A or minor ins alleles of LHCGR ins18LQ and PCOS risk. V C 2015 IUBMB Life, 68(1): [23][24][25][26][27][28][29][30][31][32][33][34][35][36] 2016

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Genetic polymorphisms of GnRH and gonadotrophic hormone receptors affect the phenotype of polycystic ovary syndrome

Cited by 111 publications

References 33 publications

Leutinizing hormone/choriogonadotropin receptor and follicle stimulating hormone receptor gene variants in polycystic ovary syndrome

Leutinizing hormone/choriogonadotropin receptor and follicle stimulating hormone receptor gene variants in polycystic ovary syndrome

FSH-receptor Ala307Thr polymorphism is associated to polycystic ovary syndrome and to a higher responsiveness to exogenous FSH in Italian women

Association between genes encoding components of the Leutinizing hormone/Luteinizing hormone–choriogonadotrophin receptor pathway and polycystic ovary syndrome in Egyptian women

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