A genetic risk score is associated with polycystic ovary syndrome-related traits.

STUDY QUESTION: Is a genetic risk score (GRS) associated with polycystic ovary syndrome (PCOS) and its related clinical features? SUMMARY ANSWER: The GRS calculated by genome-wide association studies (GWASs) was significantly associated with PCOS status and its related clinical features. WHAT IS KNOWN ALREADY: PCOS is a heterogeneous disorder and is characterized by oligomenorrhea, hyperandrogenism and polycystic ovary morphology. Although recent GWASs have identified multiple genes associated with PCOS, a comprehensive genetic risk study of these loci with PCOS and related traits (e.g. free testosterone, menstruation number/year and ovarian morphology) has not been performed. STUDY DESIGN, SIZE, DURATION: This study was designed as a cross-sectional case-control study. We recruited 862 women with PCOS and 860 controls. Women with PCOS were divided into four subgroups: (1) oligomenorrhea + hyperandrogenism + polycystic ovary, (2) oligomenorrhea + hyperandrogenism, (3) oligomenorrhea + polycystic ovary and (4) hyperandrogenism + polycystic ovary. PARTICIPANTS/MATERIALS, SETTINGS, METHODS: Genomic DNA was genotyped for the PCOS susceptibility loci using the HumanOmni1-Quad v1 array. Venous blood was drawn in the early follicular phase to measure baseline metabolic and hormonal parameters. A GRS was calculated by summing the number of risk alleles from 11 single-nucleotide polymorphisms (SNPs) that were identified in previous GWASs on PCOS. A weighted GRS (wGRS) was calculated by multiplying the number of risk alleles for each SNP by its estimated effect (beta) obtained from the association analysis. MAIN RESULTS AND THE ROLE OF CHANCE: The GRS was higher in women with PCOS than in controls (8.8 versus 8.2, P < 0.01) and was significantly associated with PCOS after adjusting for age and BMI. An analysis of GRS quartiles (Q1 = 3-5, Q2 = 6-8, Q3 = 9-11, Q4 = 12-15) revealed that the subjects in the highest quartile showed a remarkable increased risk of PCOS compared with those in the lowest quartile (odds ratio = 6.28, P < 0.001). Free testosterone level, menstruation number per year, ovarian volume and ovarian follicle numbers were significantly associated with the GRS (in all cases, P < 0.01). The wGRS yielded similar results. LIMITATIONS, REASONS FOR CAUTION: We used 11 loci for the calculation of GRS, but a higher number of PCOS risk alleles was reported in previous studies. Therefore, further studies should assess the value of GRS including the additional SNPs related to PCOS. Although a GRS of ≥12 was significantly associated with PCOS, the GRS showed a poor predictive value; therefore, the use of genetic information based on current GWAS data only may present problems. WIDER IMPLICATIONS OF THE FINDINGS: The GRS could be used to identify asymptomatic individuals among people at risk and stratify them into accurate risk categories for the purpose of individualizing treatment approaches, which could potentially improve health outcomes. STUDY FUNDING/COMPETING INTERESTS: None of the authors have any conflicts of interest to declare. No funding was obtained for the study.

Genome-wide association study identified new susceptibility loci for polycystic ovary syndrome.

STUDY QUESTION: Are there any novel genetic markers of susceptibility to polycystic ovary syndrome (PCOS)? SUMMARY ANSWER: We identified a novel susceptibility locus on chromosome 8q24.2 and several moderately associated loci for PCOS in Korean women. WHAT IS KNOWN ALREADY: PCOS is a highly complex disorder with significant contributions from both genetic and environmental factors. Previous genome-wide association studies (GWAS) in the Han Chinese population identified several risk loci for PCOS. However, GWAS studies on PCOS remain very few. The aim of this study was to identify novel markers of susceptibility to PCOS through GWAS. STUDY DESIGN, SIZE, DURATION: A two-stage GWAS was conducted. The initial discovery set for GWAS consisted of 976 PCOS cases and 946 controls. The second stage (replication study) included 249 PCOS cases and 778 controls. PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients were diagnosed according to the Rotterdam criteria. Genomic DNAs were genotyped using the HumanOmni1-Quad v1 array. In the replication stage, the 21 most promising signals selected from the discovery stage were tested for their association with PCOS. MAIN RESULTS AND THE ROLE OF CHANCE: One novel locus with genome-wide significance and seven moderately associated loci for PCOS were identified. The strongest association was on chromosome 8q24.2 (rs10505648, OR = 0.52, P = 5.46 × 10(-8)), and other association signals were located at 4q35.2, 16p13.3, 4p12, 3q26.33, 9q21.32, 11p13 and 1p22 (P = 5.72 × 10(-6)-6.43 × 10(-5)). The strongest signal was located upstream of KHDRBS3, which is associated with telomerase activity, and could drive PCOS and related phenotypes. LIMITATIONS, REASONS FOR CAUTION: The limitation of our study is the modest sample size used in the replication cohort. The limited sample size may contribute to a lack of statistical power to detect an association or show a trend in severity. WIDER IMPLICATIONS OF THE FINDINGS: Our findings provide new insight into the genetics and biological pathways of PCOS and could contribute to the early diagnosis and prevention of metabolic and reproductive morbidities. STUDY FUNDING/COMPETING INTERESTS: This work was supported in part by the grant from the Korea Centers for Disease Control and Prevention (2009-E00591-00). The work was also supported by the Ewha Global Top5 Grant 2013 of Ewha Womans University. None of the authors has any conflict of interest to declare.

Clinical implications of menstrual cycle length in oligomenorrhoeic young women.

OBJECTIVE: Although menstrual irregularity is associated with insulin resistance and hyperandrogenism, the relationship between the severity of menstrual infrequency and clinical phenotypes in young women with oligomenorrhoea (OM) is unclear. We evaluated whether a longer menstrual cycle length is associated with less favourable metabolic features. DESIGN/PATIENTS/MEASUREMENTS: A total of 1174 young women (aged 19-39 years) with a menstrual cycle length over 40 days and 1430 women with regular menstrual cycles participated voluntarily. Metabolic parameters, insulin sensitivity index (ISI) and testosterone were measured. Oligomenorrhoeic women were divided into three groups: (i) polycystic ovary syndrome (PCOS) by National Institute of Health criteria, (ii) severe OM (menstrual cycle length >60 days), and (iii) mild OM (menstrual cycle length 40-60 days). RESULTS: In normal-weight women (BMI < 23 kg/m(2)), the degrees of insulin resistance and hyperandrogenaemia are the highest in PCOS and higher in severe OM compared with mild OM. In overweight or obese women, PCOS was more insulin resistant and hyperandrogenaemic, but there was no difference between severe and mild OM. After excluding PCOS, women with severe OM showed a twofold increased risk of metabolic syndrome compared with regular cycling women (odds ratio 2·4, 95% confidence interval 1·1-5·6). By linear regression analysis, a longer menstrual cycle length was associated with ISI after adjustment for age, BMI, metabolic risk factors and testosterone. CONCLUSIONS: Women with a menstrual cycle length over 60 days should be more closely monitored for the metabolic syndrome than women with a menstrual cycle length of 40-60 days, even if they have no PCOS.

Phenotypic characteristics according to insulin sensitivity in non-obese Korean women with polycystic ovary syndrome.

Over 50% of women with polycystic ovary syndrome (PCOS) have been reported to have varying degree of insulin resistance and it may contribute to hyperandrogenism. The aim of the study is to identify whether the insulin resistance is present in non-obese Korean women with PCOS and whether the phenotype is different according to insulin sensitivity. Seventy-three non-obese (BMI<23 kg/m(2)) women with PCOS and 34 age and BMI comparable control women with regular menstrual cycles were examined. Standard 75 g OGTT was performed to determine the status of glucose tolerance. Insulin sensitivity was measured by euglycemic hyperinsulinemic clamp technique. The fasting plasma glucose (p<0.01) and post-glucose load plasma insulin (p<0.01) of women with PCOS were higher than those of controls. Glucose disposal rate (M-value) was lower in women with PCOS compared to controls (p<0.05). Insulin resistant (IR) and insulin sensitive (IS) PCOS were divided by the M-value of 25-percentile (5.5mg/kg min) in controls. Between IR and IS groups, DHEAS (p<0.01), post-glucose load plasma insulin (p<0.05) showed differences after the adjustment for BMI. Our non-obese women with PCOS showed significant insulin resistance compared to their age and BMI comparable control subjects and their insulin resistance may contribute to hyperandrogenism especially via adrenal androgen overproduction.

The metabolic syndrome in young Korean women with polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is characterized by insulin resistance and consequent hyperinsulinemia. Insulin resistance also plays an important role in the metabolic syndrome (MS). We conducted a cross-sectional study to determine the prevalence of the MS in young Korean women with PCOS and whether it is associated insulin resistance. One hundred and seventeen young women with PCOS (age: 26+/-5, 16-39 years) were evaluated for the frequency of MS according to the modified Adult Treatment Panel III. Total testosterone (T), free T, androstenedione, dehydroepiandrosterone sulfate (DHEAS) and sex hormone binding globulin (SHBG) were measured, and insulin sensitivity was evaluated by euglycemic hyperinsulinemic clamp technique. The prevalence of MS in women with PCOS was 14.5%, nearly 3.5-fold higher than in age-matched women in Korean urban population (4.3%) [J.-Y. Oh, Y.-A. Sung, Y.S. Hong, E. Barrett-Conner, Prevalence and factor analysis of metabolic syndrome in an urban Korean population, Diabetes Care 27 (2004) 2027-2032]. The most frequently occurring component of MS was low HDL cholesterol (45%), and the least frequent was high fasting serum glucose level (0.9%). PCOS women with MS had significantly higher free T, and lower SHBG compared with those without MS. And women with MS showed significantly lower M-value and higher fasting/post-glucose load insulin levels. M-value was still significantly lower in women with MS even after the adjustment for BMI. MS is frequent in young Korean women with PCOS and it reflects more severe insulin resistance. These results suggest the importance of early and regular screening of metabolic disturbance in even young women with PCOS.

Different impacts of hypertension and diabetes mellitus on all-cause and cardiovascular mortality in community-dwelling older adults: the Rancho Bernardo Study.

OBJECTIVES: Although the prevalence rates of hypertension (HTN) and diabetes mellitus are slowing in some high-income countries, HTN and diabetes mellitus remain as the two major risk factors for atherosclerotic cardiovascular disease (CVD), the leading cause of death in the United States and worldwide. We aimed to observe the association of HTN and diabetes mellitus with all-cause and CVD mortality in older white adults. METHODS: All community-dwelling Rancho Bernardo Study participants who were at least 55 years old and had carefully measured blood pressure and plasma glucose from 75-g oral glucose tolerance test at the baseline visit (1984-1987, n = 2186) were followed up until death or the last clinic visit in 2013 (median 14.3 years, interquartile range 8.4-21.3). RESULTS: In unadjusted analyses, diabetes mellitus was associated with all-cause mortality [hazard ratio 1.40, 95% confidence interval (CI) 1.23-1.60] and CVD mortality (hazard ratio 1.67, 95% CI 1.39-2.00); HTN with all-cause mortality [hazard ratio 1.93 (1.73-2.15)] and CVD mortality [hazard ratio 2.45 (2.10-2.93)]. After adjustment for cardiovascular risk factors, including age, BMI, triglycerides, HDL-cholesterol, smoking, exercise, and alcohol consumption, diabetes mellitus was associated with CVD mortality only (hazard ratio 1.25, P = 0.0213). Conversely, HTN was associated with both all-cause (hazard ratio 1.34, P < 0.0001) and CVD mortality (hazard ratio 1.40, P = 0.0003). Having both diabetes mellitus and HTN was associated with all-cause (hazard ratio 1.38, P = 0.0002) and CVD mortality (hazard ratio 1.70, P < 0.0001). CONCLUSION: We report the novel finding that HTN is more strongly associated with all-cause and CVD mortality than diabetes mellitus. Having both confers a modest increase in the hazards for these types of mortality.

Differentiation between polycystic ovary syndrome and polycystic ovarian morphology by means of an anti-Müllerian hormone cutoff value.

BACKGROUND/AIMS: Although increased serum anti-Müllerian hormone (AMH) level has been suggested to be a surrogate marker of polycystic ovarian morphology (PCOM), its association with polycystic ovary syndrome (PCOS) is controversial, and its diagnostic value has not been determined. We aimed to observe the relationship between the AMH level and PCOS phenotypes and to determine the optimal cutoff value of AMH for the diagnosis of PCOS in young Korean women. METHODS: We recruited 207 women with PCOS (120 with PCOM and 87 without PCOM) and 220 regular cycling women with normoandrogenemia (100 with PCOM and 120 without PCOM). Subjects underwent testing at a single outpatient visit. Serum AMH level was measured. RESULTS: Women with PCOS had higher serum AMH levels than did regular cycling women with normoandrogenemia (p < 0.05). Women with PCOM had higher serum AMH levels than women without PCOM, regardless of PCOS status (p < 0.05). The optimal AMH cutoff value for the diagnosis of PCOS was 10.0 ng/mL (71% sensitivity, 93% specificity). Serum AMH was an independent determinant of total testosterone after adjustment for age, body mass index, and the number of menses/year (ß = 0.31, p < 0.01). An association between AMH and hyperandrogenism was only observed in women with PCOS, and it was independent of the presence of PCOM. CONCLUSION: The serum AMH level can be useful for the diagnosis of PCOS at any age less than 40 years, and the optimal cutoff value for the diagnosis of PCOS identified in this study of young Korean women was 10.0 ng/mL.

Triglycerides to High-Density Lipoprotein Cholesterol Ratio Can Predict Impaired Glucose Tolerance in Young Women with Polycystic Ovary Syndrome.

PURPOSE: The triglycerides to high-density lipoprotein cholesterol (TG/HDL-C) ratio could be related to insulin resistance (IR). We previously reported that Korean women with polycystic ovary syndrome (PCOS) had a high prevalence of impaired glucose tolerance (IGT). We aimed to determine the cutoff value of the TG/HDL-C ratio for predicting IR and to examine whether the TG/HDL-C ratio is useful for identifying individuals at risk of IGT in young Korean women with PCOS. MATERIALS AND METHODS: We recruited 450 women with PCOS (24±5 yrs) and performed a 75-g oral glucose tolerance test (OGTT). IR was assessed by a homeostasis model assessment index over that of the 95th percentile of regular-cycling women who served as the controls (n=450, 24±4 yrs). RESULTS: The cutoff value of the TG/HDL-C ratio for predicting IR was 2.5 in women with PCOS. Among the women with PCOS who had normal fasting glucose (NFG), the prevalence of IGT was significantly higher in the women with PCOS who had a high TG/HDL-C ratio compared with those with a low TG/HDL-C ratio (15.6% vs. 5.6%, p<0.05). CONCLUSION: The cutoff value of the TG/HDL-C ratio for predicting IR was 2.5 in young Korean women with PCOS, and women with NFG and a high TG/HDL-C ratio had a higher prevalence of IGT. Therefore, Korean women with PCOS with a TG/HDL-C ratio >2.5 are recommended to be administered an OGTT to detect IGT even if they have NFG.

Sex differences in the association between proinsulin and intact insulin with coronary heart disease in nondiabetic older adults: the Rancho Bernardo Study.

BACKGROUND: Insulin or insulin resistance is considered a coronary heart disease (CHD) risk factor, but proinsulin may have a stronger association with CHD than insulin. The role of sex differences in this association is unclear. We examined the cross-sectional association of proinsulin and insulin with CHD in older men and women without diabetes. METHODS AND RESULTS: A cross-sectional study of community-dwelling men (n=554) and women (n=902), 50 to 97 years of age, without diabetes by history or oral glucose tolerance test, was done between 1992 and 1996; plasma levels of intact insulin, proinsulin, and C-peptide were measured by radioimmunoassay. Based on questionnaire, medical history, or ECG abnormalities, 25% of men (n=136) and 24% of women (n=214) had prevalent CHD. All insulin variables were positively correlated with CHD risk factors. Compared with those without CHD, men and women with CHD had significantly higher levels of proinsulin. Women but not men with CHD also had higher levels of C-peptide and fasting and postchallenge insulin. Only proinsulin was significantly and independently associated with prevalent CHD in both men (OR=2.41, 1.42 to 4.11) and women (OR=1.80, 1.22 to 2.64) (adjusted for age, body mass index, systolic blood pressure, and HDL cholesterol). Similar analyses for fasting and postchallenge intact insulin and for C-peptide showed that among these three variables, only postchallenge insulin was significantly associated with CHD, and only in women. CONCLUSIONS: In older nondiabetic men and women, proinsulin was more strongly and consistently associated with CHD than was intact insulin.

Endogenous sex hormones and the development of type 2 diabetes in older men and women: the Rancho Bernardo study.

OBJECTIVE: To determine the prospective association between endogenous sex hormones and the development of type 2 diabetes in older men and women. RESEARCH DESIGN AND METHODS: A standardized medical history was obtained, an oral glucose tolerance test was performed, and plasma samples for sex hormones and covariates were collected from ambulatory, community-dwelling men and women at baseline from 1984 to 1987. Approximately 8 years later (1992-1996), another medical history was obtained, an oral glucose tolerance test was performed, fasting and 2-h insulin levels were measured, and the homeostasis model assessment for insulin resistance (HOMA-IR) was evaluated. This report is based on the 294 men and 233 women, aged 55-89 years, who completed both visits and who did not have diabetes as determined by history or glucose tolerance test at baseline, as well as women who were postmenopausal and not taking replacement estrogen. RESULTS: In age-adjusted correlation analyses, total testosterone was inversely and significantly related to subsequent levels of fasting and postchallenge glucose and insulin in men, whereas bioavailable testosterone and bioavailable estradiol were positively and significantly related to fasting and postchallenge glucose and insulin in women (all P <0.05). There was similar significant association with insulin resistance (HOMA-IR) in unadjusted and multiply adjusted analyses (P <0.05). There were 26 men and 17 women with new (incident) diabetes. The odds for new diabetes were 2.7 (95% CI 1.1-6.6) for men in the lowest quartile of total testosterone and 2.9 (1.1-8.4) for women in the highest quartile of bioavailable testosterone. CONCLUSIONS: Low testosterone levels in men and high testosterone levels in women predict insulin resistance and incident type 2 diabetes in older adults.

Prevalence and factor analysis of metabolic syndrome in an urban Korean population.

OBJECTIVE: The aim of this study was to explore the prevalence and pattern of the metabolic syndrome and its association with hyperinsulinemia in an urban Korean population of 269 men and 505 women. RESEARCH DESIGN AND METHODS: The National Cholesterol Education Program Adult Treatment Panel (ATP) III guidelines were used to calculate the sex-specific prevalence of the metabolic syndrome. After excluding individuals taking medication for hypertension, diabetes, or dyslipidemia, we used factor analysis to examine the pattern of the metabolic syndrome in 206 men and 449 women. RESULTS: The prevalence of metabolic syndrome was 16.0% in men and 10.7% in women aged 30-80 years. However, ATP III criteria for central obesity are not optimal for an Asian-Pacific population; when waist circumference is reduced from 102 to 90 cm in men and 88 to 80 cm in women, the prevalence of the metabolic syndrome increased to 29.0 and 16.8%, respectively. Sex-specific factor analysis showed four factors in men (obesity, glucose intolerance, hypertension, and dyslipidemia) and three in women (obesity-hypertension, glucose intolerance, and obesity-dyslipidemia). Insulin resistance estimated from fasting insulin levels clustered with three of the four factors in men and two of the three factors in women. By ATP III or Asian-Pacific waist circumference criteria, the prevalence of the metabolic syndrome increased with increasing tertiles of insulin resistance, which was estimated by a homeostasis model assessment. CONCLUSIONS: The metabolic syndrome is common in an urban Korean population when using Asian-Pacific waist criteria. The prevalence of the metabolic syndrome increased with increasing tertiles of insulin resistance.

Increased Epicardial Adipose Tissue Thickness in Type 2 Diabetes Mellitus and Obesity.

BACKGROUND: Epicardial adipose tissue (EAT) is suggested to play an important role in the progression of metabolic syndrome. We aimed to establish a simple method to measure EAT and examine the differences in EAT thickness according to the presence of type 2 diabetes mellitus or obesity. METHODS: A total of 94 patients (42.6% type 2 diabetes mellitus, 53.2% obese, mean age 61±13) who underwent multidetector computed tomography were enrolled. Thickness of EAT was measured on the parasternal short and horizontal long axis view. Epicardial fat area (EFA) was measured at the level of left main coronary artery (LMCA). RESULTS: All EAT thicknesses were correlated with EFA at the LMCA level (r=0.235 to 0.613, all Ps<0.05), and EAT thickness in the left atrioventricular groove (LAVG) had the highest correlation coefficient (r=0.613). EFA, and EAT thicknesses in the LAVG and the left ventricular apex were higher in the group with type 2 diabetes mellitus than in the group without type 2 diabetes mellitus when adjusted only for body mass index. When adjusted only for type 2 diabetes mellitus, EFA, and EAT thicknesses in the LAVG and the right atrioventricular groove were higher in obese group than in nonobese group. CONCLUSION: In conclusion, EAT thickness can be easily measured and represent EFA. EAT thickness, especially in LAVG, was higher in groups with type 2 diabetes mellitus and obesity independently. These findings implicate that EAT thickness may be a useful indicator for type 2 diabetes mellitus and obesity.

Metabolic effects of polycystic ovary syndrome in adolescents.

PURPOSE: Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenic anovulation in women of reproductive age. We investigated the metabolic effects of lean and overweight adolescents with PCOS. METHODS: Anthropometric measurements and biochemical parameters were evaluated in 49 adolescents with PCOS and 40 age- and body mass index (BMI)-matched controls. We further divided both PCOS and control groups into those having BMI within the normal range of less than 85(th) percentile and those being overweight and obese with a BMI greater than 85(th) percentile. RESULTS: Hemoglobin, gamma-glutamyl transferase (r-GT), total cholesterol, low-density lipoprotein-cholesterol and 2-hour postglucose load plasma insulin levels were significantly elevated in the lean PCOS group than in the lean control group. In the overweight/obese PCOS group, hemoglobin and r-GT levels were significantly elevated than in the overweight/obese control group. In the normal weight group, none of the subjects had metabolic syndrome according to the Adult Treatment Panel III criteria, but the incidence of metabolic syndrome in the overweight/obese PCOS group was 8.3% and that in the overweight/obese control group was 6.7%. CONCLUSION: PCOS in adolescents causes metabolic abnormalities, underscoring the importance of early diagnosis of PCOS in oligomenorrheic adolescents.

Pathway Analysis Based on a Genome-Wide Association Study of Polycystic Ovary Syndrome.

BACKGROUND: Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women of reproductive age, and it is affected by both environmental and genetic factors. Although the genetic component of PCOS is evident, studies aiming to identify susceptibility genes have shown controversial results. This study conducted a pathway-based analysis using a dataset obtained through a genome-wide association study (GWAS) to elucidate the biological pathways that contribute to PCOS susceptibility and the associated genes. METHODS: We used GWAS data on 636,797 autosomal single nucleotide polymorphisms (SNPs) from 1,221 individuals (432 PCOS patients and 789 controls) for analysis. A pathway analysis was conducted using meta-analysis gene-set enrichment of variant associations (MAGENTA). Top-ranking pathways or gene sets associated with PCOS were identified, and significant genes within the pathways were analyzed. RESULTS: The pathway analysis of the GWAS dataset identified significant pathways related to oocyte meiosis and the regulation of insulin secretion by acetylcholine and free fatty acids (all nominal gene-set enrichment analysis (GSEA) P-values < 0.05). In addition, INS, GNAQ, STXBP1, PLCB3, PLCB2, SMC3 and PLCZ1 were significant genes observed within the biological pathways (all gene P-values < 0.05). CONCLUSIONS: By applying MAGENTA pathway analysis to PCOS GWAS data, we identified significant pathways and candidate genes involved in PCOS. Our findings may provide new leads for understanding the mechanisms underlying the development of PCOS.

Association between vitamin D receptor polymorphism and type 2 diabetes or metabolic syndrome in community-dwelling older adults: the Rancho Bernardo Study.

Vitamin D receptor (VDR) polymorphism influences susceptibility to type 1 diabetes, but the association with type 2 diabetes is not clear. We investigated the association between VDR polymorphism and type 2 diabetes and metabolic syndrome in a community-based study of unrelated older adults without known diabetes. Oral glucose tolerance test (75 g), plasma glucose and insulin measurement, homeostasis model assessment (HOMA), and VDR genotyping were performed. The distributions of genotype frequencies of ApaI, BsmI, and TaqI polymorphism did not differ between persons with and without diabetes, but the frequency of aa genotype of ApaI polymorphism was marginally higher in persons with type 2 diabetes (P =.058). Fasting plasma glucose (P <.05) and prevalence of glucose intolerance (P <.05) were significantly higher in nondiabetic persons with aa genotype compared with those with AA genotype. The bb genotype of BsmI polymorphism was associated with insulin resistance as assessed by HOMA after adjustment for age, sex, body mass index (BMI), and calcium and vitamin D use in persons without diabetes (P <.05). Our research suggests that ApaI polymorphism may be associated with glucose intolerance independent of defective insulin secretion and BsmI polymorphism with insulin resistance in a nondiabetic Caucasian population.

Comparison of the body adiposity index to body mass index in Korean women.

PURPOSE: Obesity is a major public health issue and is associated with many metabolic abnormalities. Consequently, the assessment of obesity is very important. A new measurement, the body adiposity index (BAI), has recently been proposed to provide valid estimates of body fat percentages. The objective of this study was to compare the BAI and body mass index (BMI) as measurements of body adiposity and metabolic risk. MATERIALS AND METHODS: This was a cross-sectional analysis performed on Korean women. The weight, height, and hip circumferences of 2950 women (mean age 25±5 years old, 18-39 years) were measured, and their BMI and BAI [hip circumference (cm)/height (m)1.5-18] values were calculated. Bioelectric impedance analysis was used to evaluate body fat content. Glucose tolerance status was assessed with a 75-g oral glucose tolerance test, and insulin sensitivity was estimated with the insulin sensitivity index. RESULTS: BMI was more significantly correlated with fat mass and fat percentage. Additionally, BMI was also more significantly associated with metabolic parameters, including fasting glucose, post-load 2-h glucose, fasting insulin, post-load 2-h insulin, triglycerides, and high density lipoprotein cholesterol than BAI. Receiver operating characteristic curve analysis revealed that BMI was a better tool for predicting body fat percentage than BAI. Insulin sensitivity and metabolic syndrome were more significantly associated with BMI than with BAI. CONCLUSION: In Korean women, the current BMI-based classifications for obesity might be superior to BAI-based measurements for determining obesity and predicting metabolic risk.

Hyperandrogenemia is implicated in both the metabolic and reproductive morbidities of polycystic ovary syndrome.

OBJECTIVE: To determine the features of polycystic ovary syndrome (PCOS) that are implicated in the associated reproductive and metabolic morbidities. DESIGN: Cross-sectional case-control study. SETTING: Academic medical setting. PATIENT(S): A total of 1,062 women with PCOS and 1,887 women without PCOS. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Physical examination including hirsutism scoring, biochemical and hormone measurements, ovarian ultrasound, and a 75-g oral glucose tolerance test to measure glucose and insulin levels. RESULT(S): A factor analysis identified four dominant factors in women with PCOS. These factors were interpreted as follows: [1] metabolic and hyperandrogenemia factor, [2] oligomenorrhea and hyperandrogenemia factor, [3] blood pressure factor, and [4] ovarian morphology factor. In women with PCOS, hyperandrogenemia was a significant predictor of metabolic syndrome after adjusting for age, body mass index, and insulin resistance in the regression analysis. CONCLUSION(S): A factor analysis identified multiple factors that are responsible for the abnormalities associated with PCOS. Hyperandrogenemia was a common underlying feature of the metabolic and reproductive abnormalities in women with PCOS but not in women without PCOS.

FTO Gene Variants Are Associated with PCOS Susceptibility and Hyperandrogenemia in Young Korean Women.

BACKGROUND: The fat mass and obesity-associated (FTO) gene is associated with obesity and type 2 diabetes mellitus. Obesity and insulin resistance are also common features of polycystic ovary syndrome (PCOS). Therefore, the FTO gene might be a candidate gene for PCOS susceptibility. The aim of the present study was to evaluate the effects of FTO gene variants on PCOS susceptibility and metabolic and reproductive hormonal parameters. METHODS: We recruited 432 women with PCOS (24±5 years) and 927 healthy women with regular menstrual cycles (27±5 years) and performed a case-control association study. We genotyped the single nucleotide polymorphisms rs1421085, rs17817449, and rs8050136 in the FTO gene and collected metabolic and hormonal measurements. RESULTS: Logistic regression revealed that the G/G genotype (rs1421085, 1.6%), the C/C genotype (rs17817449, 1.6%), and the A/A genotype (rs8050136, 1.6%) were strongly associated with an increased risk of PCOS (odds ratio, 2.551 to 2.559; all P<0.05). The strengths of these associations were attenuated after adjusting for age and BMI. The women with these genotypes were more obese and exhibited higher free androgen indices (P<0.05) and higher free testosterone levels (P=0.053 to 0.063) compared to the other genotypes. However the significant differences disappeared after adjusting for body mass index (BMI). When we analyzed the women with PCOS and the control groups separately, there were no significant differences in the metabolic and reproductive hormonal parameters according to the FTO gene variants. CONCLUSION: The rs1421085, rs17817449, and rs8050136 variants of the FTO gene were associated with PCOS susceptibility and hyperandrogenemia in young Korean women. These associations may be mediated through an effect of BMI.

Association between extraversion personality and abnormal glucose regulation in young Korean women.

Depression and psychological distress are known to be associated with diabetes development as well as the disease progression including glycemic control and chronic complication, but relationship of personality with diabetes is controversial. We examined whether personality trait and the presence of abnormal glucose regulation (AGR; diabetes and pre-diabetes) are associated in young women. A total of 1,617 young women aged 19-39 years without previously diagnosed diabetes were participated voluntarily. Personality trait was assessed by self-reported questionnaire using the five-factor model (neuroticism, extraversion, openness to experience, agreeableness and conscientiousness) consisting of five-point scale ranging from 'strongly disagreeable' to 'strongly agreeable.' Glucose tolerance status was assessed by standard 75-g oral glucose tolerance test. One hundred and eleven women were newly diagnosed with AGR (6.9 %). Among five factors, only extraversion trait was significantly associated with AGR. Multiple linear regression analysis showed significant negative association between extraversion trait and 2-h post-load glucose after adjustment for age, BMI, systolic blood pressure, triglycerides, HDL cholesterol and family history of diabetes (ß = -0.16, P = 0.026). Multiple logistic regression showed extraversion trait having a significant association with the presence of AGR after adjustment for the same covariates (OR 0.97, 95 % CI 0.95-0.99, P = 0.011). The frequency of AGR was significantly increased according to the decrease in extraversion score (P for trend with exact test = 0.047). In conclusion, extraversion may be an important personality trait having a beneficial effect on decreasing the risk of AGR.

Plasma glucose regulation and mortality in Korea: a pooled analysis of three community-based cohort studies.

BACKGROUND: Although diabetes is a well-known risk factor for death, its impact on cancer death is not clearly understood. Furthermore, it remains controversial whether impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) are associated with increased risk of mortality. We investigated the impact of diabetes or glucose tolerance categories on all cause and cause-specific mortality. METHODS: Mortality analysis was conducted in three population-based cohort studies of 3,801 participants, divided according to fasting plasma glucose (FPG) (normal; stage 1 IFG [5.6≤FPG<6.1 mmol/L]; stage 2 IFG [6.1≤FPG<7.0 mmol/L]; diabetes mellitus [DM]-FPG); or 2-hour glucose after 75 g glucose loading (2hPG) (normal; IGT; DM-2hPG), or a combination of FPG and 2hPG criteria. RESULTS: During a median follow-up of 11.0 years, 474 subjects died from all causes. Hazard ratios (HRs) for all cause death were higher in those with diabetes as defined by either FPG or 2hPG criteria than their normal counterparts (HR, 2.2, 95% confidence interval [CI], 1.6 to 2.9 for DM-FPG; HR, 2.0, 95% CI, 1.5 to 2.7 for DM-2hPG). Similarly, diabetes defined by either FPG or 2hPG was associated with cancer death (HR, 2.9, 95% CI, 1.7 to 5.0; and HR, 2.1, 95% CI, 1.2 to 3.9, respectively). Although neither IFG nor IGT conferred higher risk for death, when combining stage 2 IFG and/or IGT, the risk of all cause death was higher than in subjects with normal glucose regulation (HR, 1.3; 95% CI, 1.0 to 1.6). CONCLUSION: Diabetes is associated with higher risk of death from all causes and cancer. In subjects without diabetes, stage 2 IFG and/or IGT confers increased risk for mortality.