The peroxisome proliferator activated receptor gamma Pro12Ala polymorphism is associated with a lower hirsutism score and increased insulin sensitivity in women with polycystic ovary syndrome

Hahn, Susanne; Fingerhut, Anja; Khomtsiv, Ulyana; Khomtsiv, Liliya; Tan, Susanne; Quadbeck, B.; Herrmann, Benedikt; Knebel, Birgit; Müller‐Wieland, Dirk; Mann, Klaus; Janßen, Onno E.

doi:10.1111/j.1365-2265.2005.02261.x

Cited by 61 publications

(70 citation statements)

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“…Whereas most studies (9)(10)(11)(12)14,15), present study included, reported no association between Pro12Ala genotype and PCOS diagnosis, a few reported that the Pro12Ala G allele was significantly less frequent in PCOS versus control women (13,16). Additionally, some studies reported significant increases in insulin sensitivity (decreased HOMA-IR) and decreases in fasting insulin and glucose levels (8-10) and lower hirsutism score (9) in PCOS women with the Pro12Ala G allele; whereas others (7,11,14), including this study, reported no association with fasting glucose and insulin or changes in HOMA-IR in those with PCOS. Only a subset of the subjects in our study was phenotyped for insulin-related traits, which may explain why we did not observe association with these traits in subjects with PCOS; however, this subset was still greater in number than each of the reports that did find an effect of Pro12Ala on insulin-related traits.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, a polymorphism in exon 2 of the PPARγ2 isoform, resulting in a Pro12Ala substitution, influences the risk of type 2 diabetes with the rarer Ala allele associated with a lower incidence of diabetes (6). Several small studies have looked at the effects of the Pro12Ala and a silent exon 6 polymorphism (His447His) in association with PCOS, though they have produced conflicting results (7)(8)(9)(10)(11)(12)(13)(14)(15)(16). To better understand the role of these polymorphisms in PCOS, we examined the Pro12Ala and silent exon 6 polymorphism in a cohort of 285 women with PCOS and 187 controls, the largest sample size of all published reports of PPARG in PCOS to date.…”

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confidence: 99%

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Genetic variants in peroxisome proliferator-activated receptor gamma influence insulin resistance and testosterone levels in normal women, but not those with polycystic ovary syndrome

Antoine

Pall

Trader

et al. 2007

Fertility and Sterility

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Polymorphisms in PPARG implicated in previous studies of metabolic traits do not appear to influence component phenotypes of PCOS, but do affect androgens and insulin resistance in the general population.Objective-To investigate the relationship of the PPARG Pro12Ala and silent exon 6 (His447His) polymorphisms with the clinical features of polycystic ovary syndrome (PCOS).Design-PCOS and control subjects were genotyped for Pro12Ala and His447His; associations between genotype, diagnosis, and hormonal/metabolic parameters were assessed.Setting-Subjects were recruited from the reproductive endocrinology clinic at the University of Alabama at Birmingham; control subjects were recruited from the surrounding community. Genotyping was performed at Cedars-Sinai Medical Center in Los Angeles.Reprint Request: Mark O. Goodarzi, M.D., Ph.D., Cedars-Sinai Medical Center, Division of Endocrinology, Diabetes and Metabolism, 8700 Beverly Blvd., Los Angeles, CA 90048, email: mark.goodarzi@cshs.org Presented in part at the 87 th Annual Meeting of the Endocrine Society, San Diego, June 4-7, 2005 Supported by:This study was supported in part by the Helping Hand of Los Angeles, and by grants R01-HD29364 and K24-HD01346 from the National Institutes of Health (to RA). Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Result(s)-Pro12Ala and His447His did not influence risk of PCOS or its component phenotypes in PCOS patients. In controls, Pro12Ala did not influence measures of insulin resistance or androgen production; however, carriers of the His447His T allele had significantly decreased free and total testosterone levels and HOMA-IR. Furthermore, haplotypes in controls bearing the His447His T allele were also associated with decreased testosterone. Conflict of Interest NIH Public AccessConclusion(s)-does not appear to be an important modifier gene in PCOS. In controls, however, the His447His T allele may be in linkage disequilibrium with a functional variant that influences insulin resistance and testosterone production. Keywordsperoxisome proliferator activated receptor gamma; polycystic ovary syndrome; single nucleotide polymorphism; testosterone; insulin resistance Polycystic ovary syndrome (PCOS) is a common disorder affecting 6-8% of reproductive aged women (1) and clinically manifests as menstrual irregularities, hyperandrogenism, polycystic ovaries, and often obesity. Several studies demonstrate substantial familial aggregation of PCOS with most showing significantly higher rates of PCOS among first-degree relatives when compared to the general population (2,3). Fifty to s...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Genetic variants in peroxisome proliferator-activated receptor gamma influence insulin resistance and testosterone levels in normal women, but not those with polycystic ovary syndrome

Antoine

Pall

Trader

et al. 2007

Fertility and Sterility

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“…It is well established that Ala allele, enhances insulin sensitivity and protects against development of T2DM [28]. Increased insulin sensitivity, decreased fasting insulin levels, HOMA-IR, [13,14,17,30,34] basal metabolic rate [16] and increased HDL-C levels [4] were observed in women with PCOS who were carriers of Ala alleles. Consistently we too observed that the variant genotype carriers had significantly lower 2 h glucose levels than wild genotype carriers in PCOS group but not in controls.…”

Section: Association Of Pparγ Pro12ala C/g Polymorphism With Pcos Andmentioning

confidence: 99%

“…However, in our study with increased sample size of PCOS women (n=450) and controls (n=300), a significant difference in both allelic and genotypic frequency were found; and further logistic regression analysis also revealed a stronger association of Pro12Ala polymorphism with reduced susceptibility to PCOS. Other studies with Italian [20,21], German [13], Chinese [32], Caucasian [1], Korean [4], Greek [5,33], Spanish [23] and Polish [3] women with PCOS failed to find any such association. It is well established that Ala allele, enhances insulin sensitivity and protects against development of T2DM [28].…”

Section: Association Of Pparγ Pro12ala C/g Polymorphism With Pcos Andmentioning

confidence: 99%

Peroxisome proliferator activated receptor gamma gene variants influence susceptibility and insulin related traits in Indian women with polycystic ovary syndrome

Shaikh

Mukherjee

Shah³

et al. 2013

J Assist Reprod Genet

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Purpose Peroxisome proliferator activated receptor gamma (PPARγ), a transcription factor involved in glucose and lipid metabolism is one of the candidate genes associated with polycystic ovary syndrome (PCOS). We investigated individual and combined associations of Pro12Ala and His447His polymorphisms of PPARγ with PCOS susceptibility and its related traits (hyperinsulinemia, hyperandrogenemia and lipid parameters) in Indian women.Method Genotyping of PPARγ polymorphisms in this casecontrol study was performed in PCOS (n=450) and agematched controls (n=300) by direct sequencing. Clinical, anthropometric, hormonal and metabolic parameters were estimated in 275 women with PCOS and 169 controls. Chisquare test was used to compare the categorical data while regression analysis was used to evaluate association of genotypes with PCOS as well as its related phenotypes. Results The frequencies of CC and CG+GG genotypes of Pro12Ala (χ 2 =15.3, p<0.0001) and CC and CT+TT genotypes of His447His (χ 2 =12.7, p=0.0004) polymorphisms were significantly different between PCOS and controls. Logistic regression analysis revealed a significant association of PCOS with Pro12Ala but not the His447His polymorphism. Carriers of variant genotypes at both PPARγ loci showed significantly reduced 2 h glucose levels while carriers of variant His447His genotype showed lower fasting insulin and HOMA-IR levels in PCOS women. Conclusions Pro12Ala polymorphism of PPARγ showed significant association with decreased PCOS susceptibility. Both polymorphisms influenced insulin related traits (2 h glucose, fasting insulin and HOMA-IR) and improved glucose metabolism in these women. This is the first report to establish that variations in PPARγ gene influence the insulin resistance pathophysiology in Indian women with PCOS.

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“…Associations of PCOS with mutations in a variety of candidate genes involved in pathways regulating steroid hormone synthesis (2,3) or insulin metabolism have been analyzed, without evidence of a single common defect. In women with PCOS, the impairment of insulin metabolism is thought to be influenced by both environmental (4) and genetic factors (5,6). Recently published studies from the Czech Republic (7) and Finland (8) have shown that insulin resistance and metabolic abnormalities are related to obesity rather than to PCOS per se.…”

Section: Introductionmentioning

confidence: 99%

The CC genotype of the GNAS T393C polymorphism is associated with obesity and insulin resistance in women with polycystic ovary syndrome

Hahn¹,

Frey²,

Siffert³

et al. 2006

eur j endocrinol

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Objective: Variants in the Gs protein a subunit gene (GNAS1) are known to be involved in the pathogenesis of several endocrine and metabolic disorders. To understand genetic determinants of androgen excess, insulin resistance, and obesity in polycystic ovary syndrome (PCOS), we investigated the effect of the common GNAS1 T393C polymorphism on the phenotype of German PCOS women. Design: Two hundred and seventy-eight PCOS women and 820 Caucasian controls were genotyped for the common T393C polymorphism in GNAS1. To this end, genomic DNA was amplified by PCR with specific oligonucleotides and genotypes were determined using the restriction enzyme FokI. In addition, we evaluated whether the T393C polymorphism had an influence on the response to 6 months metformin treatment in a subgroup of 105 PCOS women. Methods: Anthropometric variables, metabolic parameters including indices of insulin resistance measured by oral glucose tolerance testing, and endocrine biochemical as well as clinical parameters were measured in all PCOS subjects. Results: GNAS1 genotype distributions were not significantly different between PCOS women and controls. In PCOS women, no significant differences in endocrine clinical and biochemical variables were found between the genotypes. However, the C-allele carrier group had significantly higher mean body weight, body mass index, leptin levels, and higher indices of insulin resistance compared with women with GNAS1 TT-genotype. Metformin treatment significantly improved hyperandrogenism, menstrual cyclicity, body weight, and insulin resistance independent of GNAS1 genotype. The major determinant of weight loss was body weight before treatment. Conclusion: The T393C polymorphism is not associated with PCOS in Caucasian women, but may represent a genetic marker for increased susceptibility for obesity in this cohort.

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The peroxisome proliferator activated receptor gamma Pro12Ala polymorphism is associated with a lower hirsutism score and increased insulin sensitivity in women with polycystic ovary syndrome

Abstract: The Pro12Ala polymorphism of the PPARgamma gene is associated with increased insulin sensitivity and lower hirsutism scores in PCOS women.

Cited by 61 publications

References 59 publications

Genetic variants in peroxisome proliferator-activated receptor gamma influence insulin resistance and testosterone levels in normal women, but not those with polycystic ovary syndrome

Genetic variants in peroxisome proliferator-activated receptor gamma influence insulin resistance and testosterone levels in normal women, but not those with polycystic ovary syndrome

Peroxisome proliferator activated receptor gamma gene variants influence susceptibility and insulin related traits in Indian women with polycystic ovary syndrome

The CC genotype of the GNAS T393C polymorphism is associated with obesity and insulin resistance in women with polycystic ovary syndrome

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