Insulin Resistance And Pcos Biology Essay

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Polycystic ovary syndrome has to be considered as a serious issue because of its implication on long term health regardless of the age. PCOS and insulin resistance are interlinked; approximately 40% of women with PCOS are insulin resistant. However, the detailed molecular basis for insulin resistance that coupled with PCOS remains poorly understood.

Objective: To review the published evidence that polymorphisms in genes that involved in insulin secretion and action are associated with an increased risk of PCOS.

Methods: We reviewed articles published up until November 2012, on polymorphisms of genes related to insulin signaling and glucose homeostasis and their associations with PCOS. Articles were indentified via Medline searches.

Conclusions: No consistent evidence emerged of a strong association between risk of PCOS and any known gene related to insulin signaling and glucose homeostasis. Further, recent genome-wide association studies are not consistent in identifying the associations between PCOS and insulin metabolism genes. Many of the studies reviewed were limited by heterogeneity in the PCOS diagnosis as well as small numbers of study participants. Further studies are warranted to determine predisposing risk factors that modify environmental factors to knock out the risk. Large genome-wide association studies devoted solely to PCOS will be necessary to identify new candidate genes and proteins that are involved in PCOS risk.

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Polycystic ovary syndrome has to be considered as a serious issue because of its implication on long term health regardless of the age. It needs to be seen as a lifelong condition, not just a concern tied to pregnancy. Polycystic ovary syndrome (PCOS) is a very common and a complex female endocrine disorder. It affects women in their reproductive years with an estimated prevalence of 4-8% (1). A consensus conference that held in Rotterdam ESHRE/ASRM in 2003, defined the syndrome as two of the following three conditions to be diagnosed as PCOS: oligo-ovulation, clinical or biochemical evidence of androgen excess and multi-cystic ovaries. The diagnostic criteria for defining the PCOS are as heterogeneous as the disease itself and underwent amendments during recent years. During the first international conference on PCOS at the National Institutes of Health (NIH) in the USA in 1990, three key features of PCOS were generally agreed on: chronic anovulation, hyperandrogenism (clinical or laboratory evidence) and the absence of other endocrine disorders (e.g. congenital adrenal hyperplasia, hyperprolactinaemia or thyroid abnormalities) (2). Women of all races and nationalities have polycystic ovary syndrome. This heterogeneous condition affects 7-10% of women worldwide (3, 4), irrespective of ethnic background (5). Polycystic ovaries showed an estimated prevalence of 20% of the normal female population (6). PCOS is the most common cause of oligoanovulatory infertility characterized by insulin resistance (IR) and hyperinsulinemia in 50-70% of PCOS women. Women with PCOS are at increased risk of diabetes, dyslipidemia, atherosclerosis (7-9) and endometrial carcinoma (10, 11). It is also suggested that women with PCOS have an increased risk of miscarriage, gestational diabetes, preeclampsia and preterm labour (12). Due to the clinical and biochemical heterogeneity of PCOS, several studies have focused on the aspects of hormonal, genetic and environmental factors involved in the development of the syndrome. A study on PCOS subjects belongs to three different ethnic groups revealed obesity and hirsutism varied with genetic and environmental factors, where as the prevalence of adrenal androgen excess and insulin resistance appeared fairly uniform (13). Later, DeUgarte (14) observed that the ethnicity and PCOS were associated with independent and additive defects of insulin action in Caribbean-Hispanic PCOS women. However, women with PCOS have several interrelated features including ovarian hyperandrogenism, chronic anovulation, polycystic ovaries and are coupled with anomalous androgen and insulin-related parameters irrespective of other regular reproductive factors (15). The genetic basis of the disease is not clearly known because of the difficulties in determining the inheritance of the disease. . Genes that regulate insulin secretion and action, ovarian and adrenal Steroidogenesis and energy regulation act as candidate genes that determine the expression of several integral phenotypes of PCOS. The present review is concentrating on the polymorphisms in the genes that involved in insulin secretion and action.

Insulin resistance and PCOS

PCOS and insulin resistance are interlinked; approximately 40% of women with PCOS are insulin resistant (16-18). Insulin resistance is a common feature in both polycystic ovary syndrome (PCOS) and non-insulin-dependent diabetes mellitus (NIDDM)  but persistent reproductive disturbances were limited to the PCOS, suggesting that insulin resistance in the ovary itself may confer this susceptibility (19). Insulin resistance refers to a state in which circulating insulin does not bind to the insulin receptors on the cell, or it binds but its effects are deficient hence there is a less than normal reduction of glucose to a given amount of insulin(20). The pancreas then continues to secrete more insulin, leading to higher levels in the blood, and ensure normal glucose tolerance (21). The association between insulin resistance and PCOS has provided significant insight into the pathogenesis of PCOS (22). Several studies showed an altered insulin levels which can directly stimulate ovarian androgen production in PCOS (23, 24). Hyperinsulinemia leads to hyperandrogenemia by stimulating ovarian androgen production (25, 26), Insulin can also stimulate adrenal steroidogenesis by enhancing sensitivity to adrenocorticotrophic hormone (ACTH) and can increase pituitary LH release (27, 28). Increased androgen levels lead to menstrual disturbances, development of ovarian cysts, hirsutism and other related disorders (7-9). Important physiological processes like cellular glucose uptake (29, 30), metabolism (30, 31) and gene expression(32) are been regulated by insulin. Specific abnormalities of insulin metabolism has been identified in PCOS which include reduction in secretion, reduced hepatic extraction(33), impaired suppression of hepatic gluconeogenesis (34) and abnormalities in insulin receptor signaling (35).

Insulin signaling pathway:

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Insulin regulates both metabolism and gene expression. The insulin signal passes from the plasma membrane receptor to insulin sensitive metabolic enzymes and then reaches the nucleus where it stimulates transcription of certain genes. The insulin receptor is a heterodimeric complex consisting of 2 extracellular α-subunits and 2 transmembrane β-subunits. The α-subunit contains the insulin binding domain. The binding of insulin to the α subunit activates the tyrosine kinase activity of β subunit to transphosphorylate one another. This allows association of insulin receptor substrates, such as IRS-1 and IRS-2 a cascade of intracellular signaling proteins to the regulatory subunit of P13k kinase. The activated P13k further phosphorylates the membrane phospholipids and produces the phosphatidylinositol-3, 4, 5 triphosphate (PIP3). This PIP3 activates the enzyme protein kinase B (PKB: also called Akt) which helps in the translocation of GLUT4 to the cell surface and results in increased glucose uptake of the cells (36). Defects in the insulin signaling system may result in insulin resistance, obesity and type II diabetes (37-39). Nevertheless, the detailed molecular basis for insulin resistance that coupled with PCOS remains poorly understood.

Genes involved in insulin resistance

The majority of the evidence supports that most women with PCOS have insulin resistance and also compensatory hyperinsulinemia. Insulin resistance in PCOS predisposes the individual to type 2 diabetes. Heritability of beta-cell dysfunction observed in families of women with PCOS demonstrated beta-cell dysfunction, a significant factor that predisposes to type 2 diabetes (40). Therefore, several candidate genes involving signaling pathways (insulin secretion and action) are examined for PCOS.

Insulin gene (INS)

Insulin consists of 2 dissimilar polypeptide chains, A and B, which are linked by 2 disulfide bonds. The gene coding for insulin is localized to 11p15.5 (41) and is located between genes for tyrosine hydroxylase and insulin-like growth factor-II (IGF-II) (42). The human insulin gene contains 3 exons; exon 2 encodes the signal peptide, the B chain, and part of the C peptide, while exon 3 encodes the remainder of the C peptide and the A chain (43). Insulin hormone is not synthesized as active protein, initially insulin mRNA is translated into a single chain precursor called preproinsulin. The preproinsulin is 110 amino acids long and made up of A, B and C chains and a signal peptide. The preproinsulin enters the endoplasmic reticulum and loses its signal peptide and converts into proinsulin. Proinsulin is 86 amino acids long, containing the A, B, and C chains. Later the proinsulin is exposed to several specific endopeptidases and further looses the C chain and left with A and B chains, which is considered the insulin hormone.

The transcription factor Pur1 initiates transcription after binding to the promoter element that is located 596 bp upstream of the insulin gene translation initiation site. This promoter element known to have variable number of tandem repeat (VNTR) region with varying repeats, 26-63 repeats (Class I), 80 repeats (Class II), and 140-200repeats (Class III) (44). Class I and class III alleles are common in Caucasians and the class II alleles are very rare in Caucasians but common in Africans (45) as the HphI T/A SNP at the locus -23 (rs689) polymorphism of the insulin promoter region is in strong linkage disequilibrium and acts as surrogate marker to INS-VNTR (46). Hence Class I and III alleles of INS-VNTR were determined by -23 HphI A and T alleles, respectively. Class III alleles are associated with reduced expression of INS and IGF2 in the pancreas and placenta (47).

The first evidence for linkage and an association between VNTR and PCOS subjects revealed that the class III alleles were associated with only in women who were anovulatory and hyperinsulinaemic (48). Another study on 74 UK women with PCOS reported an association between the class III allele and lower insulin sensitivity (49). In Slovene PCOS subjects Class III INS VNTR alleles were found to be more frequent and its interaction with body mass index was a significant predictor of serum insulin level (50). In contrast to this no association between INS VNTR polymorphism and PCOS was reported in Czech women (51), Spanish women (52). Subsequently, in a large-scale study using 255 nuclear families and 3000 subjects from Irish and Finland populations showed that INS-VNTR was not a key factor in the pathogenesis and progress of PCOS (53). Comparison of INS VNTR between PCOS and tubal infertility groups revealed that INS VNTR genotypes are not associated with PCOS but could have a certain influence on the phenotypic spectrum of the syndrome (54). No association between PCOS and INS-VNTR polymorphism was observed in the Han Chinese population (55) and Korean populations (56). 

Insulin receptor gene (INSR)

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The Insulin Receptor is a heterotetrameric glycoprotein with two alpha and beta units. Its gene is located at chromosome 19p13.2, spanning 120Kb with 22 exons (57). The tyrosine kinase domain of the receptor which is necessary for insulin signal transduction is encoded by exon 17-21. Alpha and beta subunits of the insulin receptor were derived by proteolytic processing of a common 1382 amino acid preproreceptor (58).

Two compound heterozygote mutations in the insulin-receptor gene have been identified in a patient with leprechaunism, both acts in a cis-dominant fashion to decrease mRNA transcription levels. But in only one allele there is a nonsense mutation at codon 897 and the other allele have a normal sequence at all 22 exons indicating that the mutation in this allele appears to map outside the coding sequence of the gene (59). Later direct sequencing of all 22 exons of INSR gene in three women with PCOS did not reveal any mutations (60). Screening of 22 hyperinsulinemic patients for mutations involving the tyrosine kinase domain of the insulin receptor gene revealed that these mutations are not involved in causing insulin resistance in UK subjects with PCOS (61). Furthermore, screening of 24 severe insulin resistance patients revealed several mutations, but none of the missense or nonsense mutations contributed to insulin resistance in UK subjects with PCOS (62). A His1058 C/T SNP at exon 17 of INSR is not associated with decreased insulin resistance in Chinese (63, 64) Korean (65) and Turkish women with PCOS (66). But this polymorphism showed significant association with the lean rather than obese American (67) and Indian PCOS women (68). A novel SNP in intron 21 (176477 C>T) of INSR showed strong association with the pathogenesis of PCOS in the Korean population (60). A meta-analysis of eight studies comprising 795 cases and 576 controls found no significant evidence for association with PCOS and INSR His1058 C/T polymorphism (69). Linkage analysis using STRs encompassing INSR region of chromosome 19 showed evidence for association with D19S884 locus on INSR (70-72). Furthermore, DNA sequence surrounding D19S884 conferred in vitro promoter activity in lymphoblastoid cell lines (73). A recent study using pathway-based tagging SNP identify new INSR SNPs associated with PCOS and a large replication cohort confirmed association of PCOS with rs2252673 (74). A family based association study using 260 trios of Han Chinese origin did not reveal significant evidence of association or linkage of the INSR gene to PCOS (75). A novel T/C SNP at codon Cys1008 of INSR is associated with decreased insulin sensitivity in Chinese women with PCOS and that the association is not by the change of synthesis or secretion of INSR beta-subunit, but most possibly by the effects of this novel SNP on the function of INSR beta-subunit (76). +176477 C>T, a novel SNP in the INSR gene, was associated with the pathogenesis of PCOS in a Korean population (77). The study shows significant association of C/T polymorphism at His1058 of INSR with PCOS in the lean rather than obese Indian women (78).

Insulin Receptor Substrates (IRS)

Insulin binding to its receptor results in the tyrosine phosphorylation, this in turn leads to phosphorylation of several protein substrates, of insulin receptor substrates (IRS), primarily IRS-1 and IRS-2 to initiate and coordinate multiple downstream pathways (79, 80). Series of Gene knockout experiment demonstrates the critical role of both IRS-1 and IRS-2 where both aid in activating multiple signalling pathways for the regulation of glucose homeostasis by insulin (81, 82). The human IRS-1 gene contains the entire 5'-untranslated region and protein coding region in a single exon and was localized on chromosome 2 q36-37 by in situ hybridization (83). The IRS-2 gene is mapped on chromosome 13q34 (84). The open reading frames of IRS-1 and IRS-2 predicts a molecular weight of 131 and 136 kD. Arg972Gly, a common variant of IRS-1, lies between two potential sites of tyrosine phosphorylation involves in binding the p85 subunit of PI-3 kinase. The G972R variant is not associated with abnormal expression of IRS-1 protein (85) but impairs signaling (86). Asp1057Gly, a common IRS-2 variant, has not been associated with changes in insulin sensitivity in lean or obese adults (87).

Although the first study did not reveal any association of PCOS with IRS-1 gene (88), because of the complementary role of IRS-1 and IRS-2 in insulin signaling many studies have been concentrating on Arg972Gly and Asp1057Gly polymorphisms in PCOS. Higher frequency of IRS-1 variant was observed in adolescent girls with hyperandrogenism (89), but the G972R variant acted as a modifier locus among women who are heterozygous carriers of CYP21 indicating its limited role in the development of PCOS (90). Recently, attention has also been focused on Insulin receptor substrates and the association of SNPs at the IRS-1 and IRS-2 loci with PCOS. However, the results are contradictory. Slightly higher frequency of Arg972 was observed in PCOS women of Chilean (91, 92) and Turkish population(93). The  IRS-1 Gly972Arg polymorphism significantly associated with PCOS in the Japanese (94) and Greek populations (95). The IRS-1 Gly972Arg has the highest frequency reported world-wide and is associated with insulin resistance and higher fasting insulin in Southern Italian women (96). Furthermore, IRS-1 genotype also influenced the fasting insulin levels and HOMA indices in PCOS women on metformin therapy (97). No significant association between Insulin receptor substrate genes and PCOS was reported in French (98) Spainsh (99), German (100), Taiwanese  (101), Chilean (102), Slovak  (103), Greek (104), Indian (105) and Iranian populations (106). Very few studies reported association between IRS-2 Gly1057Asp and PCOS. The Gly1057Asp polymorphism influenced blood glucose levels in nondiabetic white and African-American women with PCOS (107). Analysis of Caucasian American women revealed three additional IRS2 SNPs that associated with PCOS (rs7997595, rs7987237, rs1865434) (108). A recent genome-wide association (GWA) study of PCOS in Han Chinese failed to detect associations between the polymorphism of IRS gene and PCOS (109). However, two independent meta-analyses suggested that IRS-1 Gly972Arg polymorphism causes is significant risk for PCOS, but IRS-2 Gly1057Asp polymorphism has not shown such risk (110, 111).

Insulin-like growth factors (IGFs)

The IGFs are peptide hormones secreted from many different cells and exhibit high sequence similarity to insulin. There are two principle IGFs referred to as IGF-1 and IGF-2. Their functions include mediation of growth hormone action, stimulation of growth of cultured cells, stimulation of the action of insulin, and involvement in development and growth. Each of these has a number of variant forms, resulting from use of alternative gene promoters and alternative splicing. The gene, IGF2, is located on chromosome 11p15.5 (112). A single nucleotide polymorphism (SNP) in the 3′ untranslated region of the IGF2 gene (ApaI; rs:680) is known to increase IGF2 mRNA in leukocytes, and possibly result in increased liver IGF2 expression and secretion. Together with IGF1 and IGF-binding proteins, IGF2 stimulates adrenal and ovarian androgen secretion. The association between PCOS and G alleles of the ApaI polymorphism (IGF2 3'UTR GA; rs:680) was first established in Spanish women (113). A subsequent study showed that the ApaI polymorphism in the IGF2 cluster in combination with the -108 polymorphism (rs705379) in PON1 increased the risk of PCOS in German women (114). A recent study showed a predominance of ApaI GA+AA genotypes in younger Brazil women with PCOS (115).

Peroxisome Proliferator-Activated Receptor γ (PPARG)

peroxisome proliferator- activated receptors are members of the nuclear receptor super family of ligand-activated transcription factors (116). The PPARγ 2 is formed by an alternative mRNA splicing pathway and it regulates the transcription and expression of numerous target genes, which have been shown to be involved in adipocyte differentiation, lipid and glucose metabolism and atherosclerosis (117). The gene coding for PPAR-γ has been mapped to chromosome 3q25 (118). The human PPAR-γ gene is composed of 9 exons and it spans more than 100 kb of genomic DNA (119). A common C to G base Exchange leads to the substitution of proline with alanine at codon 12, was associated with reductions in both DNA binding and transcriptional activity in vitro. Recent studies have indicated that the Ala12 allele involved in increased insulin sensitivity by enhanced suppression of lipid oxidation, which permits more efficient glucose disposal.

Several studies found similar genotype and allele frequencies of the PPAR-γPro12Ala polymorphism in PCOS women and healthy controls of Italy (120, 121), Spain (113), China (122), Turkey (123), Chile (124), Korea (125), Greek (126-128), Los angeles (129), German (100, 130), Poland (131) and Solvenia

(132). Although PPARγ-Pro12Ala polymorphism is equally distributed in PCOS women and healthy controls, it showed modifier effect on insulin resistance in German (133) and multi ethnic populations (134). On contrary to this some studies have shown that the Pro12Ala polymorphism is significantly more frequent in control subjects compared with PCOS women, indicating a protective effect of the Ala allele against the development of PCOS in Finland (135) , Turkey (136), India (105), Korea (137). PCOS subjects carrying Pro12Ala showed higher leptin levels than the pro12pro and Ala12ala genotypes indicating that single Ala allele may have a protective role as for as hyperleptinemia (138). Although protective trend of G allele existed, a recent meta-analysis did not show significant association between pro12Ala and PCOS (139). A meta-analysis using 17 case control studies from Europe and Asia supported that the PPARγ pro12ala polymorphism was capable of reducing the PCOS in Europeans but not in Asians (140). Another meta-analysis using 17 studies reported that Ala variant would decrease the risk of PCOS and result in lower BMI and fast insulin levels in Europeans but had no impact on HOMA-IR in PCOS patients (141).

Calpain-10 (CAPN10)

Calpains are calcium-dependent intracellular nonlysosomal proteases that are capable of hydrolyzing specific substrates involved in calcium regulated signaling pathways (142). Calpain-10 is an atypical member of the calpain family and is expressed at the mRNA and protein levels by several tissue types, with different mRNA isoforms reported, in particular those involved in the regulation of glucose homeostasis, such as pancreatic β islet cells, liver, skeletal muscle, and adipocytes (143, 144). The gene encoding calpain-10 (CAPN10) consists of 15 exons and it is located on chromosome 2q37.3. It was shown to be related to proinsulin processing, insulin secretion and insulin resistance (145, 146). CAPN10 variants are known to influence the cholesterol levels and blood pressure values and also is associated with insulin resistance phenotypes in the Spanish population (147). Several SNPs in CAPN 10 (UCSNP-63, -44, -43, -19) were the focus of PCOS researches but the results are contradictory.

CAPN10 UCSNPs associated with PCOS varies in different populations. CAPN10 UCSNP-44 allele showed significant association in Spanish population (148, 149), Turkish (150) and Indian populations (151). Significant association between UCSNP-43 polymorphism and PCOS metabolic phenotype was in southern Brazilian hirsute patients (152) and Chilean PCOS women (153). The UCSNP45 C allele is associated with idiopathic hirsutism in Spanish PCOS women (154). The UCSNP-56 and ins/del-19 are in strong linkage disequilibrium and showed significant association with PCOS in German women. The TGG3AGCA and TGA2AGCA haplotypes showed decreased and increased risk for PCOS (155). The more common allele of UCSNP-63 showed evidence for excess transmission in single-locus transmission disequilibrium analysis of European trios. But this association was not replicated in the case-control study from that region (156). In contrast to these associations, none of the CAPN10 polymorphisms were associated with PCOS in German Caucasians (100), Turkish adolescent girls. (66). Although there is no significant association between individual polymorphisms of CAPN10 and PCOS, haplotype or diplotypes of this gene showed significant associations with PCOS in both African-American (157), Korean (158) and Indian populations (151). A recent meta analysis using 11 case control studies demonstrated that the CAPN10 UCSNP-63 homozygous allele and UCSNP-19 insert allele are protective factors for PCOS (159).

Metformin and PCOS

Several studies have been postulated that the use of metformin in women with PCOS may reduce the endocrine and metabolic features of PCOS. The first and foremost study of metformin in obese women with PCOS demonstrated restoration of normal menses and reduced hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure (160). Ensuing studies have reported that metformin can alter sex hormone binding globulin (SHBG) and free T levels (161), increase rate of ovulation (162, 163) and improve efficacy of ovulation induction medications such as clomiphene citrate (164) and exogenous gonadotropins (165). A meta-analysis using 13 randomized trials involving 543 women with PCOS reported that the metformin significantly increased ovulation frequency compared to placebo. Furthermore, this meta-analysis confirmed that the metformin in combination with clomiphene citrate showed superior ovulation than the clomiphene alone (166). Although metformin's actions are mediated by activation of AMP-activated protein kinase (AMPK) (167), its exact molecular mode of action remains unclear.

Several lines of evidence indicate that metformin treatment in women with PCOS results in a decline of insulin as well as total bioavailable T (168), leading to significant reduction in hyperinsulinemia and hyperandrogenism (169). It has been shown that luteinizing hormone (LH) and insulin reduction with metformin increases progesterone (170), serum glycodelin and insulin-like growth factor-binding protein 1 concentrations (171) during luteal phases indicating an improved endometrial milieu for the establishment and maintenance of pregnancy in PCOS women. A meta-analysis of eight randomized controlled studies investigating metformin in PCOS women showed significant reduction in the risk of ovarian hyperstimulation syndrome but not the improved pregnancy rates after metformin treatment (172). However, metformin is listed as a "Category B" drug, because its safety in pregnancy has not been established at the same time significant teratogenicity is also not evident.

Environmental factors and PCOS

Many studies have concentrated on possible environmental factors that contribute to the development or progression of PCOS. Several environmental factors are known to unveil genetically programmed susceptibility to PCOS and contribute to its phenotypic expression. These environmental factors mainly interact with early stages of human development and convert a predisposed genotype to the phenotypic expression of PCOS. Low-birth-weight infants showed increased incidence of precocious puberty, hyperinsulinemia, and hyperandrogenism than the normal-weight infants (173). The foetus or infant with retarded growth will develop PCOS when exposed to nutritional surplus later in life (174). Nutritional surplus with consumption of high-calorie diets leads to obesity and induce the development or progression of the clinical spectrum of PCOS (175, 176). Furthermore, environmental determinants may influence the clinical severity of PCOS, ranging from a less severe phenotype to the mature phenotype of classic PCOS. Exposure of pregnant non-human primates and sheep to excess androgens developed a syndrome similar to polycystic ovary syndrome, indicating that the exposure to androgen-like chemicals absorbed by the body can lead to PCOS (177, 178).  A retrospective study demonstrated that disposable plastic cup for drinking, cooking oil fume and indoor decoration increased the PCOS risk, indicating environmental endocrine-disrupting chemicals are associated with the risk of PCOS (179). Bisphenol A, a known hormone disrupter, present in our environment, food, and consumer products is elevated and associated with higher levels of male hormones in the blood of women  and resulting in a deviation from normal homeostasis or reproduction. Studies using experimental animals have demonstrated that neonatal exposure to BPA leads to PCOS development (180). Moreover, serum BPA levels were positively associated with serum androgen levels and insulin resistance indices in lean and obese PCOS women (181).

Conclusions:

Future research should focus on early detection of predisposing risk factors in PCOS development and long-term studies that modify environmental factors to knock out the risk. Large genome-wide association studies devoted solely to PCOS should conduct to identify new candidate genes and proteins that are involved in PCOS risk. Experiments related to pathophysiological perturbances and interventions that normalize signal transduction of these pathways to be conducted in a number of cell culture models and animal models to shed more light on our understanding of the patho-physiology of PCOS. The use of Systems Biology approaches in analyzing biochemical networks will help in better understanding of multi-system cross-talk underlying PCOS etiology.

Acknowledgements:

Dr. LVKSB and Dr. GUR acknowledge funding from the Department of Biotechnology (DBT), Government of India (Project Ref. No. BT/PR14090/GBD/27/275/2010).

Variants studied

Population

Study design

Samples

Association

Reference

INS

INS-VNTR

United Kingdom

Family based

17 Families

Yes

(48)

INS-VNTR

European

family based

150 Families

No

(88)

INS-VNTR

UK

family based

74 families

Yes

(49)

INS-VNTR

Czechoslovakia

case-control

38 cases, 22 controls

No

(51)

INS-VNTR

Spanish

case-control

96 cases, 38 controls

No

(52)

INS-VNTR

Irish

case-control

185 cases, 1062 controls

No

(53)

INS-VNTR

United Kingdom

family based association trios

255 parent-offspring trios

No

(53)

INS-VNTR

Finnish

Cohort

1599

No

(53)

INS-VNTR

Estonian women

case-control

30 cases, 75 controls

No

(54)

INS-VNTR

Slovene

case-control

117 cases, 108 controls

Yes

(50)

INS-VNTR

Han chinese

case-control

216 cases, 192 controls

No

(55)

INS-VNTR

Korean

case-control

218 cases,141 controls

No

(56)

INSR

His1058C/T

United Kingdom

case-control

22 cases, 8 controls

No

(61)

Mutation scanning

United Kingdom

case-control

108cases, 5 control

No

(62)

D19S884 & other loci

European

family based

150

Yes

(88)

D19S884 & other loci

Caucasian

case-control

85 cases, 87 controls

Yes

(72)

C/T -C10923T

US

case-control

99 cases, 136 controls

Yes

(67)

His1058 C/T

Chinese

No

(64)

His1058 C/T

Korean

case-control

9 cases, 9 controls

No

(65)

His1058C/T

Chinese

case-control

120 cases, 40 controls

Yes

(63)

Cys1008

Chinese

case-control

109 cases, 107 controls

Yes

(76)

176447C>T

Korean

case-control

134cases, 100 controls

Yes

(77)

His1058C/T

Indian

case-control

180 cases, 144 controls

Yes

(78)

INSR exon17 C/T

Turkish

case-control

44 cases, 50 controls

No

(66)

IRS

IRS1-Gly972Arg,IRS2-Gly1057Asp

France

case-control

53 cases, 102 controls

Yes

(98)

IRS1-Gly972Arg

Caucasians

case-control

69 cases, 15 controls

Yes

(89)

IRS1-Gly972Arg

Chile

case-control

82 cases, 70 controls

Yes

(91)

IRS1-Gly972Arg,IRS2-Gly1057Asp

African-American

case-control

227 cases, 175 controls

No

(107)

IRS1-Gly972Arg

Chile

case-control

143 cases, 97 controls

Yes

(92)

IRS1-Gly972Arg

Turkish

case-control

60 cases, 60 controls

Yes

(93)

IRS1-Gly972Arg

USA

case-control

114 cases, 95 controls

No

(90)

IRS1-Gly972Arg,IRS2-Gly1057Asp

Spanish

case-control

103 cases, 48 controls

No

(99)

IRS1-Gly972Arg,IRS2-Gly1057Asp

Germany

case-control

57 cases, 567 controls

No

(100)

IRS1-Gly972Arg

Taiwanese

case-control

47 cases, 45 controls

No

(101)

IRS1-Gly972Arg

Japanese

case-control

123 cases, 380 controls

Yes

(94)

IRS1-Gly972Arg

Chile

case-control

50 cases, 75 controls

No

(102)

IRS1-Gly972Arg,

IRS2-Gly1057Asp

Greece

case-control

183 cases, 88 controls

Yes, No

(95)

IRS1-Gly972Arg

Italian

case-control

65 cases, 27 controls

Yes

(96)

IRS1-Gly972Arg

Slovak

case-control

53 cases, 21 controls

No

(103)

IRS1-Gly972Arg

Greece

case-control

162 cases, 122 controls

No

(104)

IRS2-rs7997595, rs7987237, rs1865434

Caucasians

discovery cohort

273 cases, 173 controls

Yes

(108)

replication cohort

526 cases, 3585 controls

IRS1-Gly972Arg,IRS2-Gly1057Asp

Iranian

case-control

48 cases, 52 controls

No

(106)

IRS1-Gly972Arg and G2323A

Indian

case-control

250 cases, 299 controls

yes

(105)

IGFs

IGF1,IGF2 Apa1,IGF1 RECEPTOR,IGF2 RECEPTOR

Spanish

case-control

72 cases, 42 controls

Yes

(113)

IGF2 Apa1

case-control

153 cases, 178 controls

No

(114)

IGF2-3'UTR GA rs680

case-control

117 cases, 105 controls

No

(115)

PPARG

Pro12Ala

USA

case-control

124 cases, N/A

Yes

(134)

Pro12Ala

Finnish

case-control

135 cases, 115 controls

Yes

(135)

CAC ⁴⁷⁸CAT, Pro12Ala

Italy

case-control

120 cases, 120 control

Yes

(121)

Pro12Ala

Spanish

case-control

72 cases, 42 controls

No

(113)

Pro12Ala

Turkey

case-control

60 cases, 60 controls

No

(123)

Pro12Ala

Turkish

case-control

100 cases, 100 controls

No

(136)

Pro12Ala, Gly482Ser

Han Chinese

case-control

201 cases, 147 controls

No

(122)

His 447 His in exon6, Pro12Ala

Los angeles

case-control

285 cases, 187 controls

No

(129)

Pro12Ala

Greek

case-control

156 cases, 56 controls

No

(126)

Pro12Ala, 1431C/T

Korean

meta-analysis

238 cases, 125 controls

Yes

(137)

Pro12Ala

Greek

case-control

180 cases, 140 controls

No

(127)

D3S1263

European

family based

150 Families

No

(88)

Pro12Ala and His447His

Indian

Case-control

250 cases, 299 controls

yes

(105)

CAPN10

UCSNP 44,43,19,63

Spanish

case-control

55 cases, 93 controls

Yes

(148)

UCSNP 43,19,63

White of European ancestry

only Cases

124

No

(157)

African-American

57

Hispanic

13

Asian-American

13

Middle Eastern

5

UCSNP 44,43,19,63

Europid

case-control

185 cases, 525 controls

Yes

(156)

UCSNP 43,44,45

Caucasians

case-control

81 cases, 37 controls

Yes

(154)

UCSNP 44,43,19,63

Spanish

case-control

146 cases, 93 controls

No

(149)

UCSNP 44,43,45

Caucasians

case-control

57 cases, 567 controls

No

(100)

UCSNP 43,19,63

Brazil

case-control

59 cases, 29 controls

Yes

(152)

UCSNP 43,44,58,19,56,63,22

Europid

case-control

146 cases, 606 controls

No

(155)

UCSNP 43,19,63

chile

case-control

50 cases, 70 controls

Yes

(153)

UCSNP 43,19,63

Spanish

population based

899

Yes

(147)

UCSNP 43,19,63

Korean

case-control

188 cases, 439 controls

Yes

(158)

UCSNP 44,43,19,63

Turkish

case-control

107 cases, 114 controls

Yes

(150)

UCSNP 44,43,19,63

Turkish

case-control

44 cases, 50 controls

Yes

(66)

UCSNP 44,43,56,19,63

Indian

case-control

250 cases, 299 controls

Yes

(151)