Hsin-Fang Chung

Early menarche, nulliparity and the risk for premature and early natural menopause

Abstract STUDY QUESTION Are parity and the timing of menarche associated with premature and early natural menopause? SUMMARY ANSWER Early menarche (≤11 years) is a risk factor for both premature menopause (final menstrual period, FMP <40 years) and early menopause (FMP 40–44 years), a risk that is amplified for nulliparous women. WHAT IS KNOWN ALREADY Women with either premature or early menopause face an increased risk of chronic conditions in later life and of early death. Findings from some studies suggest that early menarche and nulliparity are associated with early menopause, however overall the evidence is mixed. Much of the evidence for a direct relationship is hampered by a lack of comparability across studies, failure to adjust for confounding factors and inadequate statistical power. STUDY DESIGN, SIZE, DURATION This pooled study comprises 51 450 postmenopausal women from nine observational studies in the UK, Scandinavia, Australia and Japan that contribute to the International collaboration for a Life course Approach to reproductive health and Chronic disease Events (InterLACE). PARTICIPANTS/MATERIALS, SETTING, METHODS Age at menarche (categorized as ≤11, 12, 13, 14 and 15 or more years) and parity (categorized as no children, one child and two or more children) were exposures of interest. Age at FMP was confirmed by at least 12 months of cessation of menses where this was not the result of an intervention (such as surgical menopause due to bilateral oophorectomy or hysterectomy) and categorized as premature menopause (FMP before age 40), early menopause (FMP 40–44 years), 45–49 years, 50–51 years, 52–53 years and 54 or more years. We used multivariate multinomial logistic regression models to estimate relative risk ratio (RRR) and 95% CI for associations between menarche, parity and age at FMP adjusting for within-study correlation. MAIN RESULTS AND THE ROLE OF CHANCE The median age at FMP was 50 years (interquartile range 48–53 years), with 2% of the women experiencing premature menopause and 7.6% early menopause. Women with early menarche (≤11 years, compared with 12–13 years) were at higher risk of premature menopause (RRR 1.80, 95% CI 1.53–2.12) and early menopause (1.31, 1.19–1.44). Nulliparity was associated with increased risk of premature menopause (2.26, 1.84–2.77) and early menopause (1.32, 1.09–1.59). Women having early menarche and nulliparity were at over 5-fold increased risk of premature menopause (5.64, 4.04–7.87) and 2-fold increased risk of early menopause (2.16, 1.48–3.15) compared with women who had menarche at ≥12 years and two or more children. LIMITATIONS, REASONS FOR CAUTION Most of the studies (except the birth cohorts) relied on retrospectively reported age at menarche, which may have led to some degree of recall bias. WIDER IMPLICATIONS OF THE FINDINGS Our findings support early monitoring of women with early menarche, especially those who have no children, for preventive health interventions aimed at mitigating the risk of adverse health outcomes associated with early menopause. STUDY FUNDING/COMPETING INTEREST(S) InterLACE project is funded by the Australian National Health and Medical Research Council project grant (APP1027196). G.D.M. is supported by Australian Research Council Future Fellowship (FT120100812). There are no competing interests.

Increased Ferritin Concentrations Correlate with Insulin Resistance in Female Type 2 Diabetic Patients

Aims: Iron overload identified by elevated ferritin concentrations has been implicated in risks of altered glucose metabolism and diabetic complications. The relationship between ferritin and insulin resistance in different gender and ethnicities remains uncertain; this study aimed to investigate it using homeostasis model assessment (HOMA-IR), and to explore whether it is gender-specific. Methods: A total of 524 type 2 diabetic patients were selected cross-sectionally from a cohort participating in a diabetic control study in Taiwan. Result: Overall, tertiles of ferritin were significantly and dose-dependently associated with elevated fasting plasma glucose, hemoglobin A1c, high-sensitivity C-reactive protein, HOMA-IR levels as well as Western dietary pattern scores generated by factor analysis (all p trend <0.05). Stratified by gender, a 1-tertile ferritin increase significantly correlated with a 0.241-unit increase in HOMA-IR (beta = 0.241, p = 0.001) in female diabetes, but not in male diabetes (beta = 0.072, p = 0.232), after adjusting for demographic, dietary, clinical and inflammatory factors. Conclusion: Iron overload, which produces elevated levels of ferritin, may augment insulin resistance in female but not in male type 2 diabetes. Longitudinal studies are warranted to establish relationships between iron stores and diabetes development in men and women of different ethnicities.

Relationships between changes in leptin and insulin resistance levels in obese individuals following weight loss

Obesity can augment insulin resistance (IR), leading to increased risk of diabetes and heart disease. Leptin, ghrelin, and various fatty acids present in the cell membrane may modulate IR. In this study, we aimed to investigate the impact of weight loss on IR, serum leptin/ghrelin levels, and erythrocyte fatty acids, and studied the associations between changes in these variables. A total of 35 obese (body mass index ≥ 27) adults participated in a weight loss program for 3 months. IR was assessed using homeostasis model assessment for insulin resistance (HOMA‐IR). The obese participants had a mean weight loss of 5.6 ± 3.8 kg followed by a 16.7% and 23.3% reduction in HOMA‐IR and leptin (p < 0.001) levels, and an 11.3% increase in ghrelin levels (p = 0.005). The level of erythrocyte saturates decreased by 2.8%, while the level of n–3 polyunsaturates increased by 16.8% (all p < 0.05). The changes in leptin levels (−5.63 vs. −1.57 ng/mL) were significantly different (p = 0.004) in those with improved IR (changes in HOMA‐IR < 0) than those without improvement (changes in HOMA‐IR ≥ 0), though there were no differences in the changes of ghrelin (p = 0.120) and erythrocyte fatty acids (all p > 0.05) levels. After adjusting for age, gender, changes in ghrelin, and body fat, we found a significant correlation between decreases in leptin and less risk of no improvement in HOMA‐IR levels [odds ratio (OR) = 0.69, p = 0.039]. In conclusion, a moderate weight reduction in obese participants over a short period significantly improved IR. This weight reduction concomitantly decreased serum leptin, increased ghrelin, and elevated some erythrocyte unsaturates. Only leptin correlated independently with IR improvement upon multivariable logistic regression analysis, which indicates that leptin may play a role in the modulation of IR following weight loss.

Association of n-3 polyunsaturated fatty acids and inflammatory indicators with renal function decline in type 2 diabetes

BACKGROUND & AIMS The n-3 polyunsaturated fatty acids (PUFAs) and the inflammatory indicator, interleukin-6 (IL-6), have been implied in the development of renal dysfunction. This longitudinal study examined the effect of n-3 PUFAs and IL-6 on the risk of renal function decline and explored whether n-3 PUFAs modify the effect of inflammatory indicators on renal dysfunction risk in type 2 diabetes. METHODS Studying 676 type 2 diabetic patients, we analyzed erythrocyte fatty acids and inflammatory markers in 2008 and estimated glomerular filtration rate (eGFR) in 2008 and 2012. Renal function decline was defined as an eGFR decline of ≥25% over a 4-year period. RESULTS Multivariable logistic regression revealed erythrocyte total PUFAs, n-3 PUFAs, and n-3/n-6 PUFA ratio correlated negatively with risk of renal function decline (OR = 0.75, 0.78, and 0.61, respectively, all p < 0.01), while n-6 PUFAs did not. IL-6 independently predicted risk of renal dysfunction (OR = 1.18, p = 0.015). Stratifying erythrocyte PUFAs into low (<50(th) percentile) or high group (≥50(th) percentile), we found a positive association between IL-6 and risk of renal dysfunction only in the low n-3 PUFA (OR = 1.27, p = 0.035), low n-3/n-6 PUFA (OR = 1.27, p = 0.034), and low total PUFA groups (OR = 1.36, p = 0.005), but not in the high groups. CONCLUSIONS High PUFA concentrations, especially n-3 or higher n-3/n-6 PUFA ratio, may exert protective effects against renal function impairment in type 2 diabetic patients. Whether the effect is mediated via modification of inflammatory biomarker such as IL-6 by high n-3 PUFA status warrants further investigation.

The InterLACE study: Design, data harmonization and characteristics across 20 studies on women's health.

OBJECTIVES The International Collaboration for a Life Course Approach to Reproductive Health and Chronic Disease Events (InterLACE) project is a global research collaboration that aims to advance understanding of womens reproductive health in relation to chronic disease risk by pooling individual participant data from several cohort and cross-sectional studies. The aim of this paper is to describe the characteristics of contributing studies and to present the distribution of demographic and reproductive factors and chronic disease outcomes in InterLACE. STUDY DESIGN InterLACE is an individual-level pooled study of 20 observational studies (12 of which are longitudinal) from ten countries. Variables were harmonized across studies to create a new and systematic synthesis of life-course data. MAIN OUTCOME MEASURES Harmonized data were derived in three domains: 1) socio-demographic and lifestyle factors, 2) female reproductive characteristics, and 3) chronic disease outcomes (cardiovascular disease (CVD) and diabetes). RESULTS InterLACE pooled data from 229,054 mid-aged women. Overall, 76% of the women were Caucasian and 22% Japanese; other ethnicities (of 300 or more participants) included Hispanic/Latin American (0.2%), Chinese (0.2%), Middle Eastern (0.3%), African/black (0.5%), and Other (1.0%). The median age at baseline was 47 years (Inter-quartile range (IQR): 41-53), and that at the last follow-up was 56 years (IQR: 48-64). Regarding reproductive characteristics, half of the women (49.8%) had their first menstruation (menarche) at 12-13 years of age. The distribution of menopausal status and the prevalence of chronic disease varied considerably among studies. At baseline, most women (57%) were pre- or peri-menopausal, 20% reported a natural menopause (range 0.8-55.6%) and the remainder had surgery or were taking hormones. By the end of follow-up, the prevalence rates of CVD and diabetes were 7.2% (range 0.9-24.6%) and 5.1% (range 1.3-13.2%), respectively. CONCLUSIONS The scale and heterogeneity of InterLACE data provide an opportunity to strengthen evidence concerning the relationships between reproductive health through life and subsequent risks of chronic disease, including cross-cultural comparisons.

Adiponectin gene (ADIPOQ) polymorphisms correlate with the progression of nephropathy in Taiwanese male patients with type 2 diabetes

AIMS Polymorphisms of the ADIPOQ gene were associated with diabetic nephropathy (DN) in case-control studies predominantly among European populations. Gender may modify the ADIPOQ associated risk for DN. We investigated the association of 18 ADIPOQ polymorphisms with DN in a prospective Taiwanese cohort of type 2 diabetes (T2D) and explored whether gender plays a role in this genetic association. METHODS Selected single nucleotide polymorphisms (SNPs) of ADIPOQ were genotyped in 566 T2D patients with normoalbuminuria at baseline. DN was defined based on urinary albumin-to-creatinine ratio (ACR). The Cox proportional hazard model was used to explore the association of individual SNP to DN events under different genetic models over a 6-year follow-up period. Analyses were further stratified by gender. RESULTS In male patients, the adjusted hazard ratios under the recessive models were 1.81 for rs2241766 TT (vs. GT+GG, 95% CI=1.10-2.96, p=0.019) and 1.89 for rs1063537 CC (vs. CT+TT, 95% CI=1.15-3.11, p=0.013). In the Kaplan-Meier survival curve, males carrying rs2241766 TT (vs. GT+GG, p=0.050) and rs1063537 CC (vs. CT+TT, p=0.037) recessive homozygotes also had a reduced nephropathy-free survival rate. SNPs rs2241767 and rs2082940, both in strong correlation with tag SNP rs1063537 (r(2)≥ 0.96), were also associated with DN progression in males. In females, ADIPOQ polymorphisms were not associated with the progression of DN. CONCLUSIONS ADIPOQ genetic polymorphisms rs2241766 (+45T>G), rs1063537, rs2241767 and rs2082940 were correlated with the progression of DN in Taiwanese male patients with T2D. The role of gender in this ADIPOQ genetic association needs to be further investigated in other populations.

Interleukin-6 gene polymorphisms correlate with the progression of nephropathy in Chinese patients with type 2 diabetes: A prospective cohort study

AIMS Interleukin-6 (IL-6), an inflammatory cytokine, is considered a candidate gene possibly involved in susceptibility to nephropathy in diabetes. This study aimed to examine whether IL-6 polymorphisms predict the progression of nephropathy in a prospective Chinese cohort of patients with type 2 diabetes. METHODS A total of 568 type 2 diabetic patients with normoalbuminuria at baseline were followed up for a mean of 5.3±1.5years. Urinary albumin-to-creatinine ratio (ACR) ⩾30mg/g in two consecutive urine tests were defined as progression to diabetic nephropathy (n=143). Five polymorphisms of IL-6 gene, rs1800795, rs1800796, rs1524107, rs2069837, and rs2069840, were genotyped. Cox proportional hazard models were used to estimate hazard ratio (HR) and 95% CI of progression to diabetic nephropathy under different genetic models. RESULTS Almost all patients (99.6%) carried the rs1800795 GG homozygous genotypes. In the Cox proportional models adjusted for multiple covariates, the HR under recessive model was 2.02 for rs1800796 GG (vs. CC+CG, 95% CI: 1.08-3.75, p=0.027), 2.37 for rs2069837 GG (vs. AA+AG, 95% CI: 1.15-4.87, p=0.019), and 2.08 for rs1524107 CC (vs. TT+TC, 95% CI: 1.12-3.89, p=0.021). These associations remained significant for rs1800796 and rs1524107 after correction for multiple testing (α=0.017). Overall, our results suggest that rs1800796 GG and rs1524107 CC homozygous genotypes may confer a greater risk for development of nephropathy in type 2 diabetes. CONCLUSIONS IL-6 gene polymorphisms rs1800796 and rs1524107 may serve as predictors of progression of nephropathy in Chinese patients with type 2 diabetes.

Obesity, weight change, and chronic kidney disease in patients with type 2 diabetes mellitus: A longitudinal study in Taiwan

The aim of the present study was to investigate relationships between the risk of chronic kidney disease (CKD) and obesity and weight changes in Asian patients with type 2 diabetes.

FADS Gene Polymorphisms, Fatty Acid Desaturase Activities, and HDL-C in Type 2 Diabetes

Polyunsaturated fatty acids (PUFA) correlate with risk of dyslipidemia and cardiovascular diseases. Fatty acid desaturase (FADS) single nucleotide polymorphisms (SNPs) modulate circulating PUFA concentrations. This study examined influence of FADS1 and FADS2 genetic variants on desaturase activities and blood lipid concentrations in type 2 diabetes patients, and further assessed their interrelationships. Selected SNPs (FADS1: rs174547, rs174548, rs174550; FADS2: rs174575, rs174576, rs174583, rs498793 and rs2727270) were genotyped in 820 type 2 diabetes patients and compared with those reported in the HapMap. Patient subgroups (n = 176) without taking lipid-lowering medicine were studied to assess influence of tag SNPs including rs174547, rs174575, rs498793 and rs2727270 on delta-5 desaturase (D5D: 20:4 (n-6)/20:3 (n-6)) and delta-6 desaturase (D6D:18:3 (n-6)/18:2 (n-6)) activities, and blood lipids. FADS1 rs174547 TT/TC/CC and FADS2 rs2727270 CC/CT/TT were significantly (p for trend < 0.05) associated with reduced HDL-C, D5D and D6D activities. Upon adjustment for confounders, D5D (p = 0.006) correlated significantly and D6D marginally (p = 0.07) correlated with increased HDL-C levels, whereas rs174547 and rs2727270 polymorphisms were not associated. D6D andD5D activities may play a role in modulating HDL-C levels in type 2 diabetes. Future studies with larger sample sizes are needed to investigate how FADS genetic variations interact with desaturase activities or PUFAs in the metabolism of lipoproteins in diabetic patients.

Obesity, weight change, and chronic kidney disease in patients with type 2 diabetes mellitus: a longitudinal study in Taiwan

The aim of the present study was to investigate relationships between the risk of chronic kidney disease (CKD) and obesity and weight changes in Asian patients with type 2 diabetes.