Polymorphism analysis of the Gly972Arg IRS-1 and Gly1057Asp IRS-2 genes in obese pregnant women

Genes encoding insulin receptor substrates IRS-1 and IRS-2 perform key functions in the insulin pathway. Numerous authors have suggested that single-nucleotide polymorphism (SNP) changes in the DNA sequence may be associated with the development of obesity, insulin resistance and type 2 diabetes. The Gly972Arg polymorphism of the IRS-1 gene and the Gly1057Asp polymorphism of the IRS-2 gene are believed to be associated with the occurrence of insulin resistance and obesity according to many sources. The aim of our study was to investigate the influence of these polymorphisms on the clinical parameters and to assess their correlations in obese Polish pregnant women. A total of 154 pregnant Caucasian women from the Wielkopolska region were analyzed: 78 diagnosed with overweight or obesity (study group) and 76 with normal body mass (controls). The analysis of the polymorphisms was performed using the PCR-restriction fragment length polymorphism (PCR-RFLP) method. The IRS-2 Gly1057Asp polymorphism revealed no significant correlations with excessive weight gain during pregnancy. The analysis of the IRS-1 Gly972Arg polymorphism showed an association with obesity between the study and control groups (GG-80.77%, GR-17.95%, RR-1.28% vs GG-94.74%, GR-5.26%; p = 0.023). We also observed slightly increased BMI values ​​and higher values ​​of the waist and hip circumference before pregnancy in the case of the IRS-1 Gly972Arg polymorphism. The analysis of the clinical and anthropometric parameters demonstrated no significant relationships between the genotypes of the polymorphic variants of the IRS-1 and IRS-2 genes but suggested an association between the IRS-1 Gly972Arg polymorphism and the risk for obesity.     

Polymorphisms in the IRS-1 and PPAR-γ genes and their association with polycystic ovary syndrome among South Indian women

Polycystic ovary syndrome is known to be characterized by metabolic abnormalities such as hyperinsulinemia, adiposity and dyslipidemia. Both insulin receptor substrate-1 and peroxisome proliferator-activated receptor-γ have emerged as significant candidate genes in the pathogenesis of PCOS. In this study, we report for the first time, the association pattern of these genes with PCOS among South Indian women. Two hundred fifty PCOS cases and 299 controls were sequenced for IRS-1 exon1 and PPAR-γ exon 2 and exon 6 to study the already reported SNPs in other ethnic groups and to identify any novel SNP in these exonic regions specific to the Indian population. We did not find any novel SNP in our population except for those already reported- two IRS-1 polymorphisms (Gly972Arg and G2323A) and two PPAR-γ polymorphisms (Pro12Ala and His447His). While the IRS-1 polymorphic alleles had a similar distribution between cases and controls, the PPAR-γ exon 2 Ala allele and exon 6 His447His T allele were significantly more in the controls than in the cases (p≤0.05). Haplotype association analysis also suggests that both IRS-1 and PPAR-γ haplotypes with mutations depicted reduced frequency of hyperandrogenic and metabolic traits in PCOS compared to the haplotype with only wild type alleles. Our study on Indian women suggests that while IRS-1, contrary to the earlier findings in other ethnic groups, seems to have a probable protective role against development of specific PCOS sub-phenotypes, the evidence for a probable protective role of PPAR-γ is reaffirmed in our study.     

The polymorphism in insulin receptor substrate-1 gene and birth weight in neonates at term

BACKGROUND: The mutation of the IRS-1 gene is one of the genetic risk factors which, it is speculated, is associated with insulin resistance or predisposition to type 2 diabetes. The aim of our study was to evaluate the association between the Gly972Arg polymorphism in the IRS-1 gene and birth weight in newborn children with adequate gestational age. MATERIAL AND METHODS: 100 newborn children with adequate gestational age (38-42 weeks), whose mother had no disorders during pregnancy, were studied. Genomic DNA was extracted from umbilical cord blood leukocytes, and Gly972Arg polymorphism in the IRS-1 gene was genotyped using the PCR-based method. RESULTS: Birth weight was significantly lower in the newborn with the IRS-1 Gly972Arg polymorphism compared with a control group (3161.75 +/- 380.86 g vs. 3427.92 +/- 468.86 g). Body length and head circumference at birth were also lower in the neonates with that polymorphism (54.38 +/- 3.13 cm vs. 52.69 +/- 2.91 cm, and 34.08 +/- 1.47 vs. 33.63 +/- 0.81, respectively). CONCLUSIONS: The results suggest that the Gly972Arg genotype is associated with lower birth weight, body length and head circumference in neonates with adequate gestational age.     

Insulin sensitivity is not affected by mutation of codon 972 of the human IRS-1 gene

We investigated the relationship of codon 972 polymorphism of the insulin receptor substrate-1 (IRS-1) gene with insulin resistance in the Japanese population. Among 130 patients with type-2 diabetes mellitus (DM), we identified 6 who were heterozygous for the Gly972Arg mutation. Among 144 healthy subjects, 6 were heterozygous and 1 was homozygous for the mutation. A hyperinsulinemic euglycemic clamp study was performed in 3 of 6 diabetic patients with the heterozygous Gly972Arg mutation and in 60 without it. Both groups showed almost the same levels of insulin sensitivity (glucose infusion rate, GIR = 50.2 +/- 3.0 vs. 51.3 +/- 12.1 micromol/kg/min). Similarly, there was no difference in insulin sensitivity between healthy subjects with and without the mutation using the homeostasis model assessment (HOMA index = 1.14 +/- 0.50 vs. 1.02 +/- 0.63). The frequency of the Gly972Arg allele was not increased in diabetic patients compared with control subjects even in aged (>50 years old) or obese (BMI >/=25) subjects. Among healthy subjects, we identified a 25-year-old male with the homozygous Gly972Arg allele. He was slightly obese (BMI = 25.5) but showed relatively high insulin sensitivity, almost equal to that of healthy subjects without the mutation (GIR = 67.2 vs. 71.8 +/- 22.0 micromol/kg/min). Because the GIR in healthy subjects was significantly higher compared with that in type-2 DM patients, we speculate that another genetic or environmental factor producing a more deleterious effect on insulin sensitivity may exist in diabetic patients. We conclude that this gene abnormality does not play a role in the pathogenesis of insulin resistance and type-2 DM.     

The common Arg972 polymorphism in insulin receptor substrate-1 causes apoptosis of human pancreatic islets.

Molecular scanning of human IRS-1 gene revealed a common polymorphism causing Gly-->Arg972 change. Diabetic and pre-diabetic carriers of Arg972 IRS-1 are characterized by low fasting levels of insulin and C-peptide. To investigate directly whether the Arg 972 IRS-1 affects human islet cells survival, we took advantage of the unique opportunity to analyze pancreatic islets isolated from three donors heterozygous for the Arg972 and six donors carrying wild-type IRS-1. Islets from carriers of Arg972 IRS-1 showed a two-fold increase in the number of apoptotic cells as compared with wild-type. IRS-1-associated PI3-kinase activity was decreased in islets from carriers of Arg972 IRS-1. Same results were reproduced in RIN rat b-cell lines stably expressing wild-type IRS-1 or Arg972 IRS-1. Using these cells, we characterized the downstream pathway by which Arg972 IRS-1 impairs b-cell survival. RIN-Arg972 cells exhibited a marked impairment in the sequential activation of PI3-kinase, Akt, and BAD as compared with RI N-WT. Impaired BAD phosphorylation resulted in increased binding to Bcl-XL instead of 14-3-3 protein, thus sequestering the Bcl-XL antiapoptotic protein to promote survival. Both caspase-9 and caspase-3 activities were increased in RIN-Arg972 cells. The results show that the common Arg972 polymorphism in IRS-1 impairs human b-cell survival and causes resistance to antiapoptotic effects of insulin by affecting the PI3-kinase/Akt survival pathway. These findings establish an important role for the insulin signaling in human b-cell survival and suggest that genetic defects in early steps of insulin signaling may contribute to b-cell failure.     

Lack of Arg972 polymorphism in the IRS1 gene in Parakanã Brazilian Indians

Several polymorphisms in the insulin receptor substrate-1 (IRS1) gene have been reported in the last years. The most common IRS1 variant, a Gly --> Arg substitution at codon 972 (Arg972 IRS1), is more prevalent among subjects who have features of insulin resistance syndrome associated, or not, with type 2 diabetes in European populations. To determine whether the absence of IRS1 polymorphism is a more general characteristic of Paleo-Indian-derived populations, we examined the Arg972 IRS1 polymorphism in Parakan? Indians and found a lack of this polymorphism in the Parakan? population.     

中国汉族人群ENPP1基因K121Q多态与2型糖尿病的关联及Meta分析

多个欧洲白人的Meta分析表明核苷酸焦磷酸酶1(Ectonucleotide pyrophosphatase/phosphodiesterase 1, ENPP1)基因K121Q多态与2型糖尿病相关联, 但在日本人、韩国人和中国台湾人的研究中没有发现相关性, 而在中国大陆人群中二者的关联研究结果不尽一致。文章调查了湖北地区539例2型糖尿病患者和404名正常人ENPP1基因K121Q多态性。基因型及等位基因频率在病例组和对照组间没有显著差异(P＞0.05), 但经性别、年龄和体重指数调整后的Logistic回归分析揭示XQ基因型与2型糖尿病显著相关(OR=1.5, 95%CI: 1.39~1.62, P<0.001)。对性别进行的亚组分析显示, 女性病例组Q等位基因和XQ基因型的频率显著高于对照组(Q: 12.4% vs. 6.1%, P=0.001; XQ: 23.7% vs. 11.7%, P=0.001)。结果表明ENPP1基因K121Q多态与湖北汉族人2型糖尿病的关联存在性别差异, 在女性中更明显。文章是对中国大陆人群进行的第一个Meta分析, 结果显示Q等位基因增加2型糖尿病的发病风险(OR=1.42, P=0.042)。     

Human insulin receptor substrate-1 (IRS-1) polymorphism G972R causes IRS-1 to associate with the insulin receptor and inhibit receptor autophosphorylation

The most commonly detected polymorphism in human insulin receptor substrate-1 (IRS-1), a glycine to arginine change at codon 972 (G972R), is associated with an increased risk of Type 2 diabetes and insulin resistance. To determine the molecular mechanism by which this polymorphism may be linked to insulin resistance, we produced recombinant peptides comprising amino acid residues 925-1008 from IRS-1 that contain either a glycine or arginine at codon 972 and the two nearby tyrosine phosphorylation consensus sites (EY(941)MLM and DY(989)MTM), which are known binding sites for the p85alpha regulatory subunit of phosphatidylinositol 3-kinase. The wild type peptide could be phosphorylated at these sites in vitro by purified insulin receptor. Introduction of the G972R polymorphism into the peptide reduced the amount of tyrosine phosphorylation by >60%. Pull-down experiments indicated that there was an association between the IRS-1-(925-1008) peptide and the insulin receptor that was markedly enhanced by the presence of the G972R polymorphism. The use of additional overlapping fragments localized this interaction to domains between residues 950-986 of IRS-1 and residues 966-1271 of the insulin receptor, containing the tyrosine kinase domain of the receptor. In addition, the IRS-1-(925-1008) G972R peptide acted as a competitive inhibitor of insulin receptor and insulin-like growth factor-1 receptor autophosphorylation. Taken together, these data indicate that the G972R naturally occurring polymorphism of IRS-1 not only reduces phosphorylation of the substrate but allows IRS-1 to act as an inhibitor of the insulin receptor kinase, producing global insulin resistance.     

The ENPP1 K121Q polymorphism is not associated with type 2 diabetes and related metabolic traits in an Iranian population

The K121Q polymorphism of the ectoenzyme nucleotide pyrophosphate phosphodiesterase 1 (ENPP1) gene has been variably associated with insulin resistance and type 2 diabetes (T2D) in several populations. However, this association has not been studied in Iranian subjects and we hypothesized that the K121Q variant might be associated with T2D and related metabolic traits in this population. The K121Q genotypes were determined by PCR-restriction fragment length polymorphism in 377 normoglycemic controls and 155 T2D patients. T2D patients had significantly higher values for systolic and diastolic blood pressure, BMI, glucose, cholesterol, triglyceride, LDL, apoB, insulin, and HOMA-IR, and lower levels of HDL than the normoglycemic subjects. The frequency of the Q allele did not differ between T2D and normoglycemic subjects (OR 0.96, 95% CI 0.90-2.00, P?=?0.70). The Q allele frequency was 16.5% in T2D and 15.2% in normoglycemic subjects. The ENPP1 genotype (KQ?+?QQ) was not associated with the systolic and diastolic blood pressure, glucose, triglyceride, cholesterol, LDL-C and HDL-C, apo B, BMI, HOMA-IR, and insulin levels in both normoglycemic and T2D groups. Our results suggest that the ENPP1 121Q allele might not be associated with T2D and related metabolic traits among Iranian subjects.     

Association of ��2-adrenergic receptor and insulin receptor substrate-1 polymorphisms with obesity in a Northern Indian population

BACKGROUND:

Imbalance in hormonal levels, regulated by host genetic factors, are known to be a major cause of obesity. Therefore, we aimed to evaluate association of genetic polymorphisms of β₂-adrenergic receptor (β₂-AR) and insulin receptor substrate-1 (IRS-1) with hormonal levels in northern Indian obese.

METHODS:

A total of 111 obese and 89 age matched non-obese subjects were studied after taking detailed clinical profile. Hormonal assays in serum/plasma for different hormones were done using IRMA and RIA kits. Genetic analysis of β₂-AR (-47 and -20, T to C) and IRS-1 (Arg972Gly) was done using PCR-RFLP.

STATISTICAL ANALYSIS:

Statistical analysis was performed by SPSS (version 11.5) software. All continuous variables were expressed as mean ± SD and tested by ANOVA test. Comparisons of categorical variables were assessed using X² tests or Fisher''s exact test. P-value <0.05 was considered as significant.

RESULTS:

Analysis showed that obese subjects had significantly higher value of blood pressure (systolic), WHR, leptin insulin and glucagon and lower value of GH. In β₂-AR (-47) T/C and IRS-1 Gly972Arg gene polymorphisms we did not found significant differences in genotype or allele frequencies. Moreover, none of the studied hormonal or metabolic parameters showed any association with the gene polymorphisms.

CONCLUSIONS:

Study reveals no significant association of β₂-AR (-47 and -20, T to C) and IRS-1 Gly 972 Arg polymorphisms with obesity in northern Indians.     

ENPP1/PC-1 K121Q polymorphism and genetic susceptibility to type 2 diabetes in North Indians

Genetic susceptibility may be responsible for high prevalence of type 2 diabetes worldwide. A common missense single nucleotide polymorphism, K121Q in the ectoenzyme nucleotide pyrophosphate phosphodiesterase (ENPP1) gene, has recently been associated with type 2 diabetes in Italian, South Indian, and American populations. The objective of this study was to investigate the possible role of K121Q polymorphism in ENPP1 gene with type 2 diabetes in North Indians. The genotype of the ENPP1/PC-1 K121Q polymorphism was determined using polymerase chain reaction-restriction fragment length polymorphism analysis for 328 T2DM patients and 326 non-diabetic participants. Anthropometric and clinical characteristics (Body mass index (BMI), glucose, total cholesterol, triglyceride, high-density lipoprotein cholesterol (HDL), Creatinine, HbA1c, and insulin levels) were measured using standard protocols. Their Chi-square analyses were used to test the significance differences in genotypic and allelic frequencies. Association studies were undertaken using the t test and logistic regression analyses. Our results revealed there was no significant difference in the genotypic distribution between T2DM patients and control subjects. The KK and KQ genotype frequencies were similar in T2DM cases and controls (60.7 and 39.3% in T2DM and 59.8 and 40.2% in controls). No subjects with the QQ genotype were found. Binary logistic regression analysis of data did not show any association of K121Q polymorphism with type 2 diabetes (OR; 0.97, 95% CI; 0.7–1.32, P = 0.82). No significant correlation among the BMI, WHR, BP, TG, TC, HDL-C, LDL-C, Glucose, HbA1c, Creatinine, and insulin indices (HOMA-IR) was observed in the individuals carrying KK and KQ genotypes. In conclusion, our results showed that ENPP1/PC-1 K121Q polymorphism is not associated with type 2 diabetes and related quantitative metabolic traits in North Indian Punjabi population.     

Androgen levels and metabolic parameters are associated with a genetic variant of F13A1 in women with polycystic ovary syndrome

The polycystic ovary syndrome (PCOS), characterized by hyperandrogenism, is one of the most common hormonal disorders among premenopausal women and is associated with infertility, obesity, and insulin resistance. Accumulating evidence suggests a role of the blood coagulation factor gene F13A1 in obesity (GeneBank ID: NM_000129.3). The aim of this study was to investigate the association of intronic allelic variants of the F13A1 gene with PCOS susceptibility and metabolic parameters in lean and obese PCOS women. In a case-control study, we determined an intronic F13A1 single nucleotide polymorphism (SNP) (dbSNP ID: rs7766109) in 585 PCOS and 171 control women and tested for PCOS susceptibility and associations with anthropometric, metabolic and hormonal parameters. Genotype frequencies of the F13A1 SNP rs7766109 were equivalent in PCOS and control women. In PCOS women, F13A1 gene variants were significantly associated with body mass index (BMI) (p=0.013), systolic blood pressure (p=0.042), insulin response (AUCins) (p=0.015), triglycerides (TG) (p=0.001), and high density lipoprotein cholesterol (HDL) (p=0.012). In the subgroup of obese PCOS women free androgen index (FAI), free testosterone and sex hormone binding globulin (SHBG) as well as glucose measurements showed a significantly different pattern across F13A1 gene variants (p=0.043; p=0.039 and p=0.013, respectively). We report for the first time an association of the F13A1 SNP rs7766109 with BMI, androgens, and insulin resistance in PCOS women. Further studies are needed to confirm our findings and to evaluate whether F13A1 is causally involved in the pathogenesis of PCOS related metabolic and hormonal disturbances.     

Genetic polymorphisms of glutathione S-transferase Z1 (GSTZ1) and susceptibility to preeclampsia

Preeclampsia (PE) is a complex disorder affected by genetic and environmental factors. Although the exact genes involved in development of PE are still not fully discovered, an important role for oxidative stress in its pathogenesis is accepted. In the present study, the association between the functional genetic polymorphisms in codons 32, 42 and nucleotide -1002 of glutathione S-transferases Z1 (GSTZ1) and susceptibility to PE was investigated. The present case-control study was performed on 151 preeclapmtic patients, and a total of 200 normal pregnant women, as a control group. The healthy control group was frequency matched with the age of the preeclamptic patients. Control subjects had no history of previous pregnancies with PE. Genotypes were determined by PCR-RFLP assay. There was no significant association between G-1002A and Glu32Lys polymorphisms of GSTZ1 with PE risk. The variant allele of Gly42Arg polymorphism decreased the risk of PE (OR = 0.24, 95 % CI 0.08-0.73, P = 0.012). The haplotype of "-1002A, 32Lys, 42Arg" (having three variant alleles) versus to the other haplotypes significantly decreased among PE patients compared to the control group (5.0 vs. 0.9 percent among control and PE patient groups, respectively; χ(2) = 9.328, df = 1, P = 0.002). The present results indicate that the haplotype of "-1002A, 32Lys, 42Arg" (containing three variant alleles) of GSTZ1 have protective effect compared to the other haplotypes.     

DNA polymorphism analysis of candidate genes for type 2 diabetes mellitus in a Mexican ethnic group

Type 2 diabetes mellitus is a complex metabolic disorder resulting from the action and interaction of many genetic and environmental factors. It has been reported that polymorphisms in genes involved in the metabolism of glucose are associated with the susceptibility to develop type 2 diabetes mellitus. Although the risk of developing type 2 diabetes mellitus increases with age, as well as with obesity and hypertension, its prevalence and incidence are different among geographical regions and ethnic groups. In Mexico, a higher prevalence and incidence has been described in the south of the country, and differences between urban and rural communities have been observed.We studied 73 individuals from Santiago Jamiltepec, a small indigenous community from Oaxaca State, Mexico. This population has shown a high prevalence of type 2 diabetes mellitus, and the aim of this study was to analyze the relationship between the Pst I (insulin gene), Nsi I (insulin receptor gene) and Gly972Arg (insulin receptor substrate 1 gene) polymorphisms and type 2 diabetes mellitus, obesity and hypertension in this population. Clinical evaluation consisted of BMI and blood pressure measurements, and biochemical assays consisted of determination of fasting plasma insulin and glucose levels. PCR and restriction enzyme digestion analysis were applied to genomic DNA to identify the three polymorphisms. From statistical analysis carried out here, individually, the Pst I, Nsi I and Gly972Arg polymorphisms were not associated with the type 2 diabetes, obese or hypertensive phenotypes in this population. Nevertheless, there was an association between the Nsi I and Pst I polymorphisms and increased serum insulin levels.     

Influence of b2 adrenergic receptor polymorphism (rs1042713 and rs1042714) on anthropometric,hormonal and lipid profiles in polycystic ovarian syndrome

BackgroundPolycystic ovarian syndrome (PCOS) is a frequently encountered disorder. This study aimed to identify polymorphisms in ADRB2 in Saudi PCOS development and to study its influence on lipids, hormones, and anthropometric parameters.MethodsSaudi females (100) suffering from PCOS and healthy controls (100) were investigated. The estimation of cholesterol, triglycerides, high-density lipoprotein (HDL-C), low-density lipoprotein (LDL-C), plasma glucose, leptin Insulin, and ghrelin were carried out. The DNA was extracted, and ADRB2 fragment carrying the exon 1 was amplified and sequenced.ResultsThe waist, W/H ratio, lipids, glucose, and insulin were significantly higher in the obese PCOS compared to the normal weight group. The leptin and ghrelin were not different. Two single nucleotide polymorphisms (SNPs): rs1042713 (Arg16Gly; A>G) and rs1042714 (Gln27Glu; C>G) were identified. The genotype and allele frequency of rs1042713 did not differ in the total PCOS and normal weight, and obese PCOS compare to the controls. However, rs1042714 was significantly associated with PCOS development, where the minor G allele was protective against PCOS development.ConclusionsThe rs1042714 polymorphism of the ADRB associates with PCOS development in Saudis, while rs1042713 does not. However, the GG genotype of rs1042713 associates significantly with elevated BMI, waist, hip, W/H, and leptin, and decreased ghrelin. On the other hand, rs1042714 genotypes do not associate with any abnormality except the homozygous GG have higher triglycerides and lower HDL-C. Interestingly, glucose showed different correlation patterns in individuals carrying different genotypes of the two studied SNP, indicating clearly that the metabolic responses to a normal nutrient are significantly influenced by the genotypes of the SNPs in ADRB2.     

Genetic aspects of polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is a common heterogenous endocrine disorder associated with amenorrhoea (or oligomenorrhoea), hyperandrogenism, hirsutism, obesity, insulin resistance, and an approximately 7-fold increased risk of type 2 diabetes mellitus (NIDDM - non-insulin dependent diabetes mellitus). It is a leading cause of female infertility. The prevalence of PCOS among reproductive-age women has been estimated at 4%-12%. Familial aggregation of this syndrome is well established. There are also ethnic and racial variations in the prevalence of the syndrome and its symptoms. Multiple biochemical pathways have been implicated in the pathogenesis of PCOS. Several genes from these pathways have been tested include genes involved in steroid hormone biosynthesis and metabolism (StAR, CYP11, CYP17, CYP19 HSD17B1-3, HSD3B1-2), gonadotropin and gonadal hormones action (ACTR1, ACTR2A-B, FS, INHA, INHBA-B, INHC, SHBG, LHCGR, FSHR, MADH4, AR), obesity and energy regulation (MC4R, OB, OBR, POMC, UCP2-3), insulin secretion and action (IGF1, IGF1R, IGFBPI1-3, INS VNTR, IR, INSL, IRS1-2, PPARG) and many others. Most women with PCOS, both obese and lean, have a degree of insulin resistance. The minisatellite of insulin gene (INS VNTR), especially class III alleles and III/III genotypes might not only determine the predisposition to anovulatory PCOS but also the concomitant risk for development of type 2 diabetes. The function of the insulin receptor (IR) is probably normal in woman with PCOS. However abnormal serine phosphorylation in the receptor may impair signal transduction accounting for a post-binding defect in insulin action. Serine phosphorylation is also involved in the postranslational regulation of 17,20-lyase activity (CYP17). There may be a common aetiology for both insulin resistance and hyperandrogenism. Polymorphic alleles of both IRS-1 and IRS-2 (insulin receptor substrate 1 - 2), alone or in combination, may have a functional impact on the insulin-resistant component of PCOS. There is no evidence to suggest that follistatin gene polymorphisms play a role in the pathogenesis of insulin resistance in PCOS women. PCOS appears to be associated with the absence of the four-repeat-units allele in a polymorphic region of pentanucleotide (TTTTA)n repeats within CYP11A gene, which encodes cytochrome P450scc. It has been hypothesized that up-regulation of this enzyme could lead to increased androgen production. There is no evidence of any association of alleles of CYP19 gene (encoding cytochrome P450arom) with PCOS. Association exists between androgen receptor gene (AR) polymorphisms an androgens action in PCOS. Increased hirustism and decreased CAG repeat length within AR gene has been also demonstrated in women with normal testosterone levels. Expression of estrogen receptor (ERs) as well as 5-alpha-reeducates (SRD5A1-2 genes) activity was analysed in granulosa (GC) and theca cells (TC). The results of this study demonstrate that there are significant alterations in the expression of ERalpha and ERbeta in PCOS that may be related to abnormal follicular development. On the other hand elevated SRD5A activity in polycystic ovaries supported the hypothesis that 5-alpha-reduced androgens may play a role in the pathogenesis of the syndrome. The genetic aetiology of PCOS remains unknown. There are a number of interlinking factors that affects expression of PCOS. Single cause of PCOS is unlikely. Other possible mechanisms in pathogenesis of PCOS are discussed.     

A polymorphism in the beta1 adrenergic receptor is associated with resting heart rate

Resting heart rate is significantly associated with cardiovascular morbidity and mortality. However, the extent to which resting heart rate is genetically determined is poorly understood, and no genes have been found that contribute to variation in resting heart rate. Because signaling through the beta1 adrenergic receptor is a key determinant of cardiac function, we tested whether polymorphisms in this receptor are associated with resting heart rate. A cohort of >1,000 individuals of Chinese and Japanese descent, from nuclear families, was genotyped for two polymorphisms, resulting in a serine/glycine substitution at amino acid 49 (Ser49Gly) and an arginine/glycine substitution at residue 389 (Arg389Gly), in the beta1 adrenergic receptor. For comparison, polymorphisms in the beta2 and beta3 adrenergic receptors were also evaluated. The Ser49Gly polymorphism was significantly associated (P=.0004) with resting heart rate, independent of other variables, such as body-mass index, age, sex, ethnicity, exercise, smoking, alcohol intake, hypertension status, and treatment with beta blockers. The data support an additive model in which individuals heterozygous for the Ser49Gly polymorphism had mean heart rates intermediate to those of either type of homozygote, with Ser homozygotes having the highest mean heart rate and with Gly homozygotes having the lowest. Neither the Arg389Gly polymorphism in the beta1 adrenergic receptor nor polymorphisms in the beta2 and beta3 adrenergic receptors were associated with resting heart rate. The heritability of heart rate was 39.7% +/- 7.1% (P<10-7).     

The importance of ERα and ERβ gene polymorphisms in PCOS

Estrogens act through binding to estrogen receptor α (ERα) and β (ERβ). Studies in knockout mice have shown that the absence of ERα leads to the polycystic ovary syndrome (PCOS) phenotype. Furthermore, the expression of ERβ gene is lower in follicles derived from women with PCOS compared with healthy women. The aim of this study was to investigate the importance of ERα and ERβ gene polymorphisms in PCOS. A cohort of 180 women with PCOS and 140 healthy controls were recruited, and the PvuII and XbaI polymorphisms of ERα, as well as, the AluI and RsaI polymorphisms of ERβ were genotyped. No difference was found in the distribution of these polymorphisms between patients and healthy controls. However, in PCOS women, carriers of TC and TT genotypes of PvuII polymorphism had lower fasting glucose to insulin ratio compared with carriers of CC genotype (p = 0.029). In addition, the presence of AA genotype of XbaI polymorphism was associated with lower levels of follicle-stimulating hormone (FSH) compared with the presence of AG and GG genotypes (p = 0.03). The association of ERα polymorphisms with insulin resistance indices and FSH levels emphasizes the importance of ERα as a genetic modifier of the PCOS phenotype.     

Insulin resistance in the skeletal muscle of women with PCOS involves intrinsic and acquired defects in insulin signaling

Insulin resistance in polycystic ovary syndrome (PCOS) is due to a postbinding defect in signaling that persists in cultured skin fibroblasts and is associated with constitutive serine phosphorylation of the insulin receptor (IR). Cultured skeletal muscle from obese women with PCOS and age- and body mass index-matched control women (n = 10/group) was studied to determine whether signaling defects observed in this tissue in vivo were intrinsic or acquired. Basal and insulin-stimulated glucose transport and GLUT1 abundance were significantly increased in cultured myotubes from women with PCOS. Neither IR beta-subunit abundance and tyrosine autophosphorylation nor insulin receptor substrate (IRS)-1-associated phosphatidylinositol (PI) 3-kinase activity differed in the two groups. However, IRS-1 protein abundance was significantly increased in PCOS, resulting in significantly decreased PI 3-kinase activity when normalized for IRS-1. Phosphorylation of IRS-1 on Ser312, a key regulatory site, was significantly increased in PCOS, which may have contributed to this signaling defect. Insulin signaling via IRS-2 was also decreased in myotubes from women with PCOS. In summary, decreased insulin-stimulated glucose uptake in PCOS skeletal muscle in vivo is an acquired defect. Nevertheless, there are intrinsic abnormalities in glucose transport and insulin signaling in myotubes from affected women, including increased phosphorylation of IRS-1 Ser312, that may confer increased susceptibility to insulin resistance-inducing factors in the in vivo environment. These abnormalities differ from those reported in other insulin resistant states consistent with the hypothesis that PCOS is a genetically unique disorder conferring an increased risk for type 2 diabetes.