Association of serum creatinine levels and risk of type 2 diabetes mellitus in Korea: a case control study.

BACKGROUND: Reduced skeletal muscle has been suggested as a potential risk factor for type 2 diabetes mellitus (T2DM). Serum creatinine is the primary metabolite of creatine in skeletal muscle. Therefore, low serum creatinine levels may be associated with an increased risk of T2DM. We aimed to evaluate the association between serum creatinine levels and the risk of T2DM in Korea. METHODS: We analyzed a total of 264,832 nondiabetic adults older than 40 years of age who had undergone a national health examination at least once from 2009 to 2015 in the Korean National Health Insurance Service Cohort. Hazard ratios for T2DM were calculated. RESULTS: In men, serum creatinine levels and the risk for T2DM showed an inverse J-shaped association. This association was confirmed after adjustment for age, body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), and fasting plasma glucose. In women, there was a trend that serum creatinine levels were inversely associated with the risk of T2DM among those with serum creatinine below 1.1 mg/dl. However, serum creatinine levels were not significantly associated with the risk of T2DM after adjustment for age, BMI, SBP, DBP, and fasting plasma glucose. CONCLUSIONS: Reduced levels of serum creatinine were significantly associated with an increased risk of T2DM in men with creatinine below 1.20 mg/dl. There was a trend that decreased levels of serum creatinine were associated with an increased risk of T2DM among women with serum creatinine below 1.1 mg/dl, although this result was not statistically significant.

The Association of Ovarian Reserve with Exposure to Bisphenol A and Phthalate in Reproductive-aged Women.

BACKGROUND: Exposure to endocrine disrupting chemicals (EDCs) that influence the hormonal and homeostatic systems is known to be associated with gynecologic health risks in many countries. In this study, we evaluated exposure to EDCs associated with diminished ovarian reserve (DOR) and gynecologic health risks. METHODS: This cross-sectional study was performed from September 2014 to November 2014 and included 307 Korean reproductive-aged women. Anthropometric measurements, laboratory tests with urine and blood sampling and pelvic ultrasound examinations were performed. RESULTS: Urinary bisphenol A (BLA) level was significantly higher in the DOR group with anti-Müllerian hormone lower than 25 percentile (1.89 ± 2.17 ug/g and 1.58 ± 1.08 ug/g, P < 0.05). Urinary mono-(2-ethyl-5-hydroxyhexyl) phthalate, mono-(2-ethyl-5-oxohexyl) phthalate and mono-N-butyl phthalate, and substrates of phthalate were evaluated and no significant difference was observed between the DOR group and non-DOR group. Logistic regression analysis suggested an increase in infertility in high BPA exposure group and the odds ratio (OR, 4.248) was statistically significant after adjustment for age, birth control pills, and the age of menarche, parity, and waist circumference. High phthalate exposure was associated with endometrial polyp after adjustment (OR, 2.742). CONCLUSION: BPA exposure might be associated with DOR and infertility. Meanwhile, endometrial polyp is increased in women with high phthalate exposure. Therefore, the risk of exposures to EDCs for reproduction should be a matter of concern in reproductive-aged women.

Insulin resistance is associated with hirsutism in unselected reproductive-aged women.

OBJECTIVE: Hirsutism affects 5%-10% of reproductive-aged women worldwide and exhibits clinical importance as a cutaneous manifestation of underlying hyperandrogenism. Racial and genetic factors play roles in manifestation of hirsutism, and the prevalence of hirsutism seems to be low in East Asians. However, the reference value of the modified Ferriman-Gallwey (mFG) score to diagnose hirsutism and the prevalence of hirsutism have not been determined in Korean populations to date. We aimed to investigate the distribution of the mFG score and establish its reference value for defining hirsutism and to examine its relationship with metabolic and reproductive traits in reproductive-aged Korean women. DESIGN, PATIENTS AND MEASUREMENTS: We enrolled 2139 female volunteers of reproductive age (15-39 years). We recorded mFG scores from 0 to 4 on 9 different body locations (upper lip, chin, chest, arm, upper abdomen, lower abdomen, upper back, lower back and thighs). Hirsutism was defined as >95th percentile of mFG score. In addition, a 75-g oral glucose tolerance test was performed, and the homoeostasis model assessment of insulin resistance (HOMA-IR) was calculated. RESULTS: The mFG values of the 50th, 75th, 90th and 95th percentiles were 0, 1, 4 and 6, respectively. Therefore, the mFG score was indicative of hirsutism when the score was 6 or greater, which represents the 95th percentile. In the correlation analysis, total testosterone, free testosterone, fasting plasma insulin and HOMA-IR were positively correlated with mFG score (all Ps <0.05). Multiple linear regression analysis revealed that HOMA-IR (ß = 0.081) was positively associated with mFG score after adjustments for age, body mass index, total testosterone and the number of menses per year (P < 0.001). CONCLUSIONS: In conclusion, setting the 95th percentile of the mFG score as normal, the reference value to define hirsutism was 6 in reproductive-aged Korean women. HOMA-IR was positively associated with the mFG score even after adjustment for biochemical hyperandrogenism.

Vitamin D receptor and binding protein polymorphisms in women with polycystic ovary syndrome: a case control study.

BACKGROUND: Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women of reproductive age, characterized by hyperandrogenism, oligomenorrhea, polycystic ovary morphology, and insulin resistance. Vitamin D deficiency and vitamin D receptor (VDR)/vitamin D binding protein (VDBP) gene variants could play an important role in susceptibility to PCOS and contribute to metabolic disturbances and menstrual dysfunction. We aimed to investigate the associations of VDR gene and VDBP gene polymorphisms with PCOS susceptibility and to elucidate the impacts of these polymorphisms on the hormonal and metabolic parameters of PCOS. METHODS: We recruited 432 women with PCOS and 927 controls. Polymorphisms in the VDR gene (VDR Fok-I, Cdx2, Apa-I, and Bsm-I) and VDBP gene (VDBP rs4588, rs7041, and rs22822679) were genotyped. A 75-g oral glucose tolerance test was performed. RESULTS: The distributions of genotypes and allele frequencies in VDR and VDBP genes did not differ between PCOS and control. In women with PCOS, compared to the VDR Fok-I GG genotype, the VDR Fok-I AG genotype was significantly associated with increased levels of total testosterone (ß = 5.537, P = 0.005). Compared to the VDR Cdx2 AC genotype, the VDR Cdx2 CC genotype was associated with increased levels of fasting insulin and HOMA-IR in women with PCOS, however, the associations were not statistically significant. CONCLUSIONS: This finding indicates that genetic variations in VDR and VDBP were not associated with increased risk for PCOS. In contrast, the VDR Fok-I polymorphism was associated with testosterone level and the Cdx2 polymorphism with insulin sensitivity in PCOS. However, the Cdx2 polymorphism was not significantly associated with increased insulin and insulin sensitivity in women with PCOS after multiple linear regression.

Meta-analysis of genome-wide SNP- and pathway-based associations for facets of neuroticism.

Neuroticism is a heritable personality trait that is comprised of distinct sub-factors, or facets. Sub-factors of neuroticism are linked to different emotional states or psychiatric symptoms and studying the genetic variants associated with these facets may help reveal the biological mechanisms underlying psychiatric disorders. In the present study, a meta-analysis of genome-wide association studies for six facets of neuroticism was performed in 5584 participants from three cohorts. Additionally, a Gene Set Enrichment Analysis was conducted to find biological pathways associated with each facet. Six neuroticism facets (N1: anxiety, N2: angry hostility, N3: depression, N4: self-consciousness, N5: impulsivity and N6: vulnerability) were assessed using the Korean version of the Revised NEO Personality Inventory. In the single-nucleotide polymorphism-based analysis, results showed genome-wide significance for N2 within the MIR548H3 gene (rs1360001, P=4.14 × 10-9). Notable genes with suggestive associations (P<1.0 × 10-6) were ITPR1 for N1, WNT7A for N2, FGF10 and FHIT for N3, DDR1 for N4, VGLL4 for N5 and PTPRD for N6. In the pathway-based analysis, the axon guidance pathway was identified to be associated with multiple facets of neuroticism (N2, N4 and N6). The focal adhesion and extracellular matrix receptor interaction pathways were significantly associated with N2 and N3. Our findings revealed genetic influences and biological pathways that are associated with facets of neuroticism.

Polycystic ovary morphology is associated with insulin resistance in women with polycystic ovary syndrome.

BACKGROUND/OBJECTIVES: Polycystic ovary syndrome (PCOS) is a heterogeneous disorder characterized by chronic anovulation, hyperandrogenism, polycystic ovary morphology (PCOM) and metabolic disturbances including insulin resistance and type 2 diabetes mellitus. Although insulin resistance could be associated with PCOM, recent studies have shown controversial results. The aim of this study was to determine the relationship between PCOM and insulin resistance. SUBJECTS/METHODS: This was a cross-sectional clinical study. A total of 679 women with PCOS who were diagnosed using the National Institute of Child Health and Human Disease (NICHD) criteria and 272 control women were analysed. We measured fasting glucose and insulin levels, 75 g oral glucose tolerance test-derived glucose and insulin levels, testosterone levels, ovarian volume and follicle number. RESULTS: Polycystic ovary morphology was described in 543 women (80.0%) with PCOS. Women with PCOS had significantly higher 2 hours postload glucose, fasting and 2 hours postload insulin levels, ovarian volume, ovarian follicle numbers and lower insulin sensitivity compared with those of the controls (all P<.01). In women with PCOS, ovarian volume and ovarian follicle number were negatively associated with the quantitative insulin sensitivity check index after adjusting for age, body mass index and total testosterone; however, this association was not observed in the controls. In the logistic regression analysis, increased ovarian follicle number was associated with decreased insulin sensitivity in women with PCOS. CONCLUSIONS: In PCOS, enlarged ovarian volume and follicle excess were associated with insulin resistance, and the number of ovarian follicles could be a predictor of insulin resistance.

Urinary bisphenol A is associated with insulin resistance and obesity in reproductive-aged women.

BACKGROUND/OBJECTIVES: The prevalence of obesity has markedly increased and is closely related to insulin resistance. Although lifestyle and genetic predisposition are significant factors influencing the pathophysiology within the body, endocrine-disrupting chemicals (EDCs) are also important triggers of metabolic disturbance. We investigated the relationship between exposure to EDCs and insulin resistance and obesity in healthy, reproductive-aged women. SUBJECTS/METHODS: This cross-sectional analysis included 296 healthy, reproductive-aged women between 30 and 49 years. Metabolically healthy was defined as an absence of the components of metabolic syndrome. Urinary levels of bisphenol A (BPA), mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP) and mono-n-butyl phthalate (MnBP) were measured by high-performance liquid chromatography and tandem mass spectroscopy (LC-MS). Homoeostatic model analysis of insulin resistance (HOMA-IR) was utilized as an index of insulin resistance. RESULTS: Urinary BPA levels were positively correlated with BMI, waist circumference, fasting serum insulin and HOMA-IR. MEHHP, MEOHP and MnBP were not associated with any of the above parameters. In the multiple regression analysis, the BPA levels were significantly associated with BMI and waist circumference after adjusting for age, smoking and alcohol consumption status, triglycerides (TG), total cholesterol (TC) and high-density lipoprotein (HDL). Fasting insulin and HOMA-IR values were also significantly related to urinary BPA concentration after adjusting for confounding variables. Metabolically unhealthy women exhibited significantly higher levels of urinary BPA (P = 0·01) compared to metabolically healthy women. CONCLUSIONS: Higher urinary BPA levels are associated with obesity, insulin resistance and metabolic disruption in Korean reproductive-aged women. BPA could play an important role in the pathogenesis of metabolic abnormalities. Further studies are required to elucidate the relationship between EDCs and metabolic disturbances in various age and sex groups.

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.

GWA meta-analysis of personality in Korean cohorts.

Personality is a determinant of behavior and lifestyle that is associated with health and human diseases. Despite the heritability of personality traits is well established, the understanding of the genetic contribution to personality trait variation is extremely limited. To identify genetic variants associated with each of the five dimensions of personality, we performed a genome-wide association (GWA) meta-analysis of three cohorts, followed by comparison of a family cohort. Personality traits were measured with the Revised NEO Personality Inventory for the five-factor model (FFM) of personality. We investigated the top five single-nucleotide polymorphisms (SNPs) for each trait, and revealed the most highly association with neuroticism and TACC2 (rs1010657, P=8.79 × 10(-7)), extraversion and PTPN12 (rs12537271, P=1.47 × 10(-7)), openness and IMPAD1 (rs16921695, P=5 × 10(-8)), agreeableness and RPS29 (rs8015351, P=1.27 × 10(-6)) and conscientiousness and LMO4 (rs912765, P=2.91 × 10(-6)). It had no SNP reached the GWA study threshold (P<5 × 10(-8)). When expanded the SNPs up to top 100, the correlation of PTPRD (rs1029089) and agreeableness was confirmed in Healthy Twin cohort with other 13 SNPs. This GWA meta-analysis on FFM personality traits is meaningful as it was the first on a non-Caucasian population targeted to FFM of personality traits.

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.

A randomized, double-blind, placebo-controlled, phase II clinical trial to investigate the efficacy and safety of oral DA-1229 in patients with type 2 diabetes mellitus who have inadequate glycaemic control with diet and exercise.

BACKGROUND: DA-1229 is a novel, potent and selective dipeptidyl peptidase-4 (DPP-IV) inhibitor that is orally bioavailable. We aimed to evaluate the optimal dose, efficacy and safety of DA-1229, in Korean subjects with type 2 diabetes mellitus suboptimally controlled with diet and exercise. METHODS: We enrolled 158 patients (mean age, 53 years and a mean BMI, 25.6 kg/m(2) ). The mean baseline fasting plasma glucose level, HbA1c and duration of diabetes were 8.28 mmol/L, 7.6% (60 mmol/mol) and 3.9 years, respectively. After 2 or 6 weeks of an exercise and diet program followed by 2 weeks of a placebo period, the subjects were randomized into one of four groups for a 12-week active treatment period: placebo, 2.5, 5 or 10 mg of DA-1229. RESULTS: All three doses of DA-1229 significantly reduced HbA1c from baseline compared to the placebo group (-0.09 in the placebo group vs. -0.56, -0.66 and -0.61% in 2.5, 5 and 10-mg groups, respectively) but without any significant differences between the doses. Insulin secretory function, as assessed by homeostasis model assessment ß-cell, the insulinogenic index, 2-h oral glucose tolerance test (OGTT) C-peptide and post-OGTT C-peptide area under the curve (AUC)0-2h, significantly improved with DA-1229 treatment. The incidence of adverse events was similar between the treatment groups and DA-1229 did not affect body weight or induce hypoglycaemic events. CONCLUSIONS: DA-1229 monotherapy (5 mg for 12 weeks) improved HbA1c, fasting plasma glucose level, OGTT results and ß-cell function. This drug was well tolerated in Korean subjects with type 2 diabetes mellitus.

A prospective, randomized, multicenter trial comparing the efficacy and safety of the concurrent use of long-acting insulin with mitiglinide or voglibose in patients with type 2 diabetes.

This trial was conducted to compare the efficacy and safety of combination therapy with basal insulin glargine plus mitiglinide to that of basal insulin glargine plus voglibosein patients with type 2 diabetes. This was a 20-week, randomized, multicenter non-inferiority trial. Patients with HbA1c levels over 7.0% were randomly assigned to receive either mitiglinide (10 mg tid) or voglibose (0.2 mg tid) concurrent with insulin glargine for 16 weeks after a 4-week of basal insulin glargine monotherapy. The intention-to-treat population included 156 patients; 79 were placed in the mitiglinide group, and 77 were placed in the voglibose group. At 20 weeks, there was no significant difference between the mitiglinide group and the voglibose group in terms of the mean HbA1c level or the mean decrease of the HbAlc level from baseline (-0.9% [-7.5 mmol/mol] and -0.7%, [-5.3 mmol/mol] respectively). The mean fasting plasma glucose level and data of self-monitoring blood glucosewere significantly decreased from baseline to week 20 in both groups, but there was no significant difference between the two groups. The changes in the basal insulin requirements of each group were not significant. The prevalence of adverse events and the risk of hypoglycemia were similar for both groups. Combination therapy with mitiglinide plus basal insulin glargine was non-inferior to voglibose plus basal insulin glargine in terms of the effect on overall glycemic control.

A randomized, placebo-controlled, double-blind, phase 3 trial to evaluate the efficacy and safety of anagliptin in drug-naïve patients with type 2 diabetes.

The aim of this study was to evaluate the efficacy and safety of anagliptin in drug-naïve patients with type 2 diabetes in a double-blind randomized placebo-controlled study. A total of 109 patients were randomized to 100 mg (n=37) or 200 mg (n=33) anagliptin twice daily or placebo (n=39). The primary objective was to alter HbA1c levels from baseline at a 24-week endpoint. The overall baseline mean age and body mass index were 56.20 ± 9.77 years and 25.01 ± 2.97 kg/m(2), respectively, and the HbA1c level was of 7.14 ± 0.69 %. Anagliptin at 100 mg and 200 mg produced significant reductions in HbA1c (-0.50 ± 0.45 % and -0.51 ± 0.55%, respectively), and the placebo treatment resulted in an increase in HbA1c by 0.23 ± 0.62 %. Both doses of anagliptin produced significant decreases in fasting plasma glucose (-0.53 ± 1.25 mmol/L and -0.72 ± 1.25 mmol/L, respectively) and the proinsulin/insulin ratio (-0.04 ± 0.15 and -0.07 ± 0.18, respectively) compared with placebo. No meaningful body weight changes from baseline were observed in three groups. Plasma dipeptidyl peptidase (DPP)-4 activity was significantly inhibited after 24 weeks of anagliptin treatment, and >75% and >90% inhibitions were observed during the meal tolerance tests with 100 mg and 200 mg anagliptin, respectively. The incidences of adverse or serious adverse events were similar among the three study groups. Twice-daily anagliptin therapy effectively inhibited DPP-4 activity and improved glycemic control and was well-tolerated in patients with type 2 diabetes.

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.

Risk factor control and cardiovascular events in patients with type 2 diabetes mellitus.

BACKGROUND: Since patients with type 2 diabetes mellitus (T2DM) have an increased risk of cardiovascular events, interventions addressing risk factors reduce the incidence of cardiovascular disease (CVD) events. This study aimed to evaluate the difference in the incidence of CVD events according to risk factor control in patients with diabetes with and without cardio-renal disease. METHODS: We analyzed 113,909 patients with diabetes and 290,339 without diabetes using data released by the National Health Insurance Service (NHIS). RESULTS: Among patients with diabetes with four or five poorly controlled risk factors, hazard ratio for CVD events was 1.19 (95% confidence interval [CI], 1.06-1.34) in patients with cardio-renal disease and 2.31 (95% CI, 1.95-2.74) in patients without cardio-renal disease compared to patients with diabetes without risk factors. In subjects with diabetes and cardio-renal disease, patients with four or five poorly controlled risk factors had a higher risk of CVD mortality compared to subjects without risk factors (hazard ratio, 1.64; 95% CI, 1.18-2.30). CONCLUSION: Controlling cardiovascular risk factors reduced the incidence of CVD events in patients with diabetes, especially those without cardio-renal disease. The degree of risk control was strongly associated with CVD mortality in patients with diabetes with baseline cardio-renal disease.

Genome-wide association study of the five-factor model of personality in young Korean women.

Personality is a determinant of behavior and lifestyle associated with health and human diseases. Although personality is known to be a heritable trait, its polygenic nature has made the identification of genetic variants elusive. We performed a genome-wide association study on 1089 Korean women aged 18-40 years whose personality traits were measured with the Revised NEO Personality Inventory for the five-factor model of personality. To reduce environmental factors that may influence personality traits, this study was restricted to young adult women. In the discovery phase, we identified variants of PTPRD (protein tyrosine phosphatase, receptor type D) that associated this gene with the Openness domain. Other genes that were previously reported to be associated with neurological phenotypes were also associated with personality traits. In particular, DRD1 and OR1A2 were linked to Neuroticism, NKAIN2 with Extraversion, HTR5A with Openness and DRD3 with Agreeableness. Data from our replication study of 2090 subjects confirmed the association between OR1A2 and Neuroticism. We first identified and confirmed a novel region on OR1A2 associated with Neuroticism [corrected]. Candidate genes for psychiatric disorders were also enriched. These findings contribute to our understanding of the genetic architecture of personality traits and provide critical clues to the neurobiological mechanisms that influence them.

The effect of menopause on cardiovascular risk factors according to body mass index in middle-aged Korean women.

BACKGROUND: Menopausal status and obesity are associated with an increased risk for cardiovascular diseases. However, there are few studies on the effect of menopause on cardiovascular risk factors according to the degree of obesity during the menopausal transition. We aimed to evaluate the effect of menopause on cardiovascular risk factors according to body mass index (BMI) in middle-aged Korean women. METHODS: We analyzed 361 postmenopausal women and 758 premenopausal women (age: 45-55 years) without diabetes mellitus, hypertension, or dyslipidemia, using a cohort database released by the Korean National Health and Nutrition Examination Survey 2016-2018. Subjects were divided into two groups based on BMI. Women who underwent a hysterectomy or were pregnant were excluded from this study. Differences between groups adjusted for age and BMI were assessed. RESULTS: Postmenopausal women (52 ± 2 years) were older than premenopausal women (48 ± 2 years), and BMI did not differ between the two groups (22.8 ± 2.9 vs. 23.0 ± 3.1 kg/m2). After adjustment for age and BMI in total and non-obese subjects (not obese subjects), postmenopausal women exhibited higher hemoglobin A1c and total cholesterol levels than premenopausal women. Subgroup analysis for 138 postmenopausal and 138 age- and BMI-matched premenopausal women showed that postmenopausal women had higher total cholesterol levels than premenopausal women with marginal significance (201 ± 25 vs. 196 ± 27 mg/dL). CONCLUSION: Menopausal status was associated with increased glucose and cholesterol levels independent of age and BMI in middle-aged Korean women. Menopausal status showed a significant relationship with increased total cholesterol levels even after adjusting for age and BMI in non-obese women but not obese women. Therefore, intensive monitoring and treating of lipid status is necessary to prevent cardiovascular events during the menopausal transition, especially in non-obese subjects.

Relationship between age at menarche and metabolic diseases in Korean postmenopausal women: The Korea National Health and Nutrition Examination Survey 2016-2018.

BACKGROUND: Cardiovascular disease is the leading cause of morbidity and mortality in postmenopausal women. Early menarche may be associated with an increased risk of metabolic diseases such as diabetes and cardiovascular disease. This study aimed to investigate the effect of menarche age and the risk of diabetes and metabolic syndrome in Korean postmenopausal women. METHODS: We analyzed 4,933 postmenopausal women (mean age: 64.7 years) using the Korean National Health and Nutritional Examination Survey 2016-2018. Subjects were divided into three groups according to menarche age (early menarche: ≤ 12 years (n = 451), reference: 13-16 years (n = 3,421), and late menarche: ≥ 17 years (n = 1,061)). Logistic regression analysis was used to estimate the odds ratio (OR) for diabetes and metabolic syndrome. RESULTS: Women with an early menarche age were younger, more educated, and had higher income than the other groups (p-value < 0.001). There were no differences in body mass index, blood pressure, fasting glucose, HbA1c, and cholesterol levels among the three groups. After adjusting for potential confounding factors, early menarche age was significantly associated with the risk of diabetes (OR 1.435, 95% confidence interval (CI): 1.069-1.928). The prevalence of metabolic syndrome in all subjects was 41.1%. After adjusting for potential confounding factors, the OR of metabolic syndrome in the early menarche group was 1.213 (95% CI: 0.971-1.515). CONCLUSION: The risk of diabetes was 1.43 times higher in postmenopausal Korean women with early menarche. Although the risk of metabolic syndrome was not statistically significant, it showed a tendency to increase in the early menarche group. Our results suggest that age at menarche may be helpful in diabetes risk stratification and early interventions for postmenopausal women.

Non-alcoholic fatty liver disease is associated with hyperandrogenism in women with polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a highly complex reproductive metabolic disorder and women with PCOS have high prevalence of non-alcoholic fatty liver disease (NAFLD). Despite both hyperandrogenism and insulin resistance are common pathophysiologies in NAFLD and PCOS, this association is still controversial. Therefore, the aim of this study is to evaluate the relationship between hyperandrogenism and NAFLD in females diagnosed with PCOS. We recruited 667 women diagnosed with PCOS and 289 women with regular menstrual cycles as control. The PCOS diagnosis was made using National Institute of Child Health and Human Disease criteria. Total and free testosterone levels (TT and TF, respectively), and free androgen index (FAI) were used as measures of hyperandrogenism. Fatty liver index and liver fat score (FLI and LFS, respectively), and hepatic steatosis index (HSI) were used to assess NAFLD. The prevalence of NAFLD in PCOS women evaluated by LFS, FLI, and HIS were 19.9, 10.3, and 32.2%, respectively. In the control group, the incidence was 2.1, 0.7, and 4.2%, respectively. Both FT and FAI levels showed significant association with increased NAFLD-related indices, after adjusting for insulin resistance and other factors (LFS (OR 3.18 (95% CI 1.53-6.63) in FT; 1.12 (1.04-1.22) in FAI), FLI (OR 2.68 (95% CI 1.43-5.03) in FT; 1.13 (1.06-1.20) in FAI), and HSI (OR 3.29 (95% CI 2.08-5.21) in FT; 1.5 (1.09-1.21) in FAI). TT did not exhibit association with any NAFLD index. In women with PCOS, significantly higher rate of NAFLD was observed compared to the control women. The FT and FAI were independently associated with NAFLD in women with PCOS. The findings suggest the possibility of hyperandrogenism contributing to the progression and/or development of NAFLD in PCOS.

Genome-wide association study identifies GYS2 as a novel genetic factor for polycystic ovary syndrome through obesity-related condition.

To investigate the role of genetic predisposition in the pathogenesis of polycystic ovary syndrome (PCOS) in relation to obesity, we performed a genome-wide association study of PCOS in Koreans (n=1741). PCOS is a heterogeneous endocrinal disorder of uncertain etiology. Obesity is one of the well-known risk factors for PCOS. Genome-wide association study. Women with or without PCOS. A total of 1881 samples were genotyped using Illumina HumanOmni1 Quad v1 and processed by R packages. The PCOS patients were divided into two subgroups according to PCOS diagnostic criteria (Rotterdam and National Institutes of Health (NIH)). For PCOS-associated loci in the two definitions, we successfully confirmed significant associations of GYS2 for body mass index in the discovery stage. We further replicated pleiotropic associations of GYS2 in a childhood obesity study (n=482) and in a gestational diabetes study (n=1710), respectively. Our study provides a preliminary framework upon diverse genetic effects underlying PCOS in Korean women. A newly identified GYS2 gene as a predisposing factor of PCOS might expand understanding of the biological pathways in metabolic and endocrine regulation.