Impact of FTO genotypes on BMI and weight in polycystic ovary syndrome: a systematic review and meta-analysis

Abstract

Aims/hypothesisFTO gene single nucleotide polymorphisms (SNPs) have been shown to be associated with obesity-related traits and type 2 diabetes. Several small studies have suggested a greater than expected effect of the FTO rs9939609 SNP on weight in polycystic ovary syndrome (PCOS). We therefore aimed to examine the impact of FTO genotype on BMI and weight in PCOS.MethodsA systematic search of medical databases (PubMed, EMBASE and Cochrane CENTRAL) was conducted up to the end of April 2011. Seven studies describing eight distinct PCOS cohorts were retrieved; seven were genotyped for SNP rs9939609 and one for SNP rs1421085. The per allele effect on BMI and body weight increase was calculated and subjected to meta-analysis.ResultsA total of 2,548 women with PCOS were included in the study; 762 were TT homozygotes, 1,253 had an AT/CT genotype, and 533 were AA/CC homozygotes. Each additional copy of the effect allele (A/C) increased the BMI by a mean of 0.19 z score units (95% CI 0.13, 0.24; p = 2.26 × 10−11) and body weight by a mean of 0.20 z score units (95% CI 0.14, 0.26; p = 1.02 × 10−10). This translated into an approximately 3.3 kg/m2 increase in BMI and an approximately 9.6 kg gain in body weight between TT and AA/CC homozygotes. The association between FTO genotypes and BMI was stronger in the cohorts with PCOS than in the general female populations from large genome-wide association studies. Deviation from an additive genetic model was observed in heavier populations.Conclusions/interpretationThe effect of FTO SNPs on obesity-related traits in PCOS seems to be more than two times greater than the effect found in large population-based studies. This suggests an interaction between FTO and the metabolic context or polygenic background of PCOS.

Influence of a positive family history of both type 2 diabetes and PCOS on metabolic and endocrine parameters in a large cohort of PCOS women

“…Those women differ from women without a positive FHx of T2DM, which might be related to either genetic or environmental factors. Of note, it has been shown that T2DM-related genetic variants are also associated with PCOS phenotype and risk (3,15). To our knowledge, it has not been investigated so far whether PCOS women with a positive FHx of T2DM have a higher prevalence of T2DM-related genetic variants than PCOS women with a negative T2DM FHx.…”

“…Total testosterone, insulin, prolactin, TSH, fT 3 , fT 4 and cortisol (Siemens, Erlangen, Germany) were measured by luminescence immunoassay (intra-and interassay coefficients of variation (CV values) of !10%). SHBG was measured by luminescence immunoassay (Roche) with an intra-and interassay CV of 1.3 and 2.1% respectively.…”

“…There are several lines of evidence suggesting a strong genetic background of PCOS, which is also reflected by a familial accumulation of PCOS cases (2,3,4,5). Thus, a positive FHx of PCOS is considered as a risk factor for PCOS development.…”

“…Further, there is evidence showing that a positive family history (FHx) of T2DM, as a reflection of genetic risk, is associated with an increased risk of the development of T2DM in PCOS women (12,13,14). In PCOS women, obesity and T2DM-related genes (3,15) as well as genetic polymorphisms related to hyperandrogenism (16) have been shown to be associated with PCOS phenotype, suggesting an important genetic background. Apart from this, it has not been investigated so far whether a positive FHx of T2DM and PCOS contribute equally to metabolic and endocrine disturbances in PCOS women or whether there are differences regarding the impact of T2DM and PCOS FHx on metabolic and endocrine parameters.…”

MECHANISMS IN ENDOCRINOLOGY: Thyroid and polycystic ovary syndrome

“…In Dutch twins, a tetrachoric correlation of 0.71 and 0.38 in monozygotic twin sisters and in dizygotic twins and other sisters, respectively, was established (31). Several candidate genes have been studied for PCOS, such as those coding for fibrillin 3 (FBN3), INS, INS receptor, insulin receptor substrate 1, transcription factor 7-like 2, calpain 10, the fat mass and obesity associated protein (38,39), SHBG (32), and VDR (40). Results of a large number of candidate gene studies were mostly inconclusive (32).…”