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Background Excessive adiposity in adulthood is positively associated with the risk of cardiovascular disease (CVD). However, it is less studied how the risk is separately explained by early adulthood weight and later weight change, especially in Asian ancestries. Methods This study included 121160 participants in a large population-based cohort in China. Body weight at 20 and 40 years of age wase self-reported. Information on CVD history was obtained through standard questionnaires. Results The odds ratios (ORs) were 1.20 (95% CI, 1.10–1.31) for coronary heart disease (CHD), 1.74 (95% CI, 1.36–2.22) for myocardial infarction (MI), 1.14 (95% CI, 0.99–1.32) for stroke and 1.21 (95% CI, 1.12–1.31) for total CVD among individuals with early overweight, and became more prominent for early obesity. Meanwhile, A moderate weight gain of 2.5 kg between early adulthood and midlife significantly increased the risk of CHD (OR: 1.18, 95% CI: 1.05–1.32), stroke (OR: 1.19, 95% CI: 1.03–1.38) and total CVD (OR: 1.15, 95% CI: 1.04–1.27), and the risk escalated with higher amounts of weight gain. Conversely, a weight loss of 2.5 kg conferred lower risk of CVD compared with a stable weight. In further cross-analysis, participants with early adulthood overweight or obesity and significant weight gain afterwards exhibited the greatest risk of CVD. Conclusions High early adulthood BMI and subsequent weight gain had both independent and combined effect on the risk of CVD after midlife. Therefore, weight management should start before early adulthood, and emphasized throughout adulthood for CVD prevention.

Objective To examine the association between stage 1 hypertension defined by the 2017 American College of Cardiology and American Heart Association (ACC/AHA) guideline and risk of developing arterial stiffness. Methods During 2010-2015, 4595 adults aged ≥40 years without cardiovascular disease were followed up for a median of 4.3 years. BP levels at baseline were categorized into normal, elevated, stage 1 hypertension, and stage 2 hypertension. The development of arterial stiffness was defined as a normal brachial-ankle pulse wave velocity (ba-PWV) at baseline and an increased ba-PWV at follow-up. Results Compared with participants with normal BP, participants with stage 1 hypertension had a 1.48-fold increased risk of developing arterial stiffness [odds ratio (OR) =2.48; 95% confidence interval (CI) =1.59-3.85] after adjustment for cardiovascular risk factors. The association was more evident in adults aged 40-59 years (OR =4.08; 95% CI =2.06-8.08) than that in those aged ≥60 years (OR =1.47; 95% CI =0.81-2.67). A systolic BP 130~139 mmHg was significantly associated with arterial stiffness independent of diastolic BP (OR =2.90; 95% CI =1.86-4.52). Stage 1 hypertension either at baseline or at follow-up was associated with increased risks compared with normal BP at both baseline and follow-up. Conclusions The 2017 ACC/AHA stage 1 hypertension was significantly associated with higher risks of arterial stiffness.

Context The body mass index (BMI) and waist circumference (WC) as diagnostic tools of obesity do not reflect the same level of fat mass and whether obesity leads to various effects on cardiometabolic risk factors among different racial/ethnic population is unknown. Objective The study aims to address the multicollinearity between BMI and WC by using the residual model approach and to assess and compare the effects of obesity metrics on cardiometabolic risk factors among different races/ethnicities. Design, setting, and participants Data from a nationally representative sample of mainland Chinese adults collected in 2010 and data from the National Health and Nutrition Evaluation Survey 2005-2016 were used. By conducting a regression analysis between WC and BMI, the variation of BMI was removed from WC measures and residual of WC was obtained. The associations between obesity metrics and cardiometabolic risk factors were compared among different races/ethnicities by sex. Results The residual WC was significantly associated with all the cardiometabolic risk factors in mainland Chinese, and most of the factors in non-Hispanic white and non-Hispanic black adults, but not in the other races/ethnicities. The standardized regression coefficients of the associations between obesity metrics and cardiometabolic factors showed that the obesity metrics had greater impact on systolic blood pressure, diastolic blood pressure, and triglyceride in Chinese adults than those of other racial/ethnic groups. Conclusions Chinese adults are more susceptible to the effects of overall obesity and fat distribution on cardiometabolic risk factors than the other racial/ethnic population.

BackgroundFGF8-FGFR1 signalling is involved in multiple biological processes, while impairment of this signalling is one of the main reasons for isolated hypogonadotropic hypogonadism (IHH). Recently, several negative modulators of FGF8-FGFR1 signalling were also found to be involved in IHH, including DUSP6, IL17RD, SPRY2 and SPRY4. The aim of this study was to investigate the genotypic and phenotypic spectra of these genes in a large cohort of Chinese patients with IHH.MethodsA total of 196 patients with IHH were enrolled in this study. Whole-exome sequencing was performed to identify variants, which was verified by PCR and Sanger sequencing.ResultsFour heterozygous DUSP6 variants (p.S157I, p.R83Q, p.P188L and p.N355I) were found in six patients. Cryptorchidism, dental agenesis, syndactyly and blue colour blindness were commonly observed in patients with DUSP6 mutations. Six heterozygous IL17RD variants (p.P191L, p.G35V, p.S671L, p.A221T, p.I329M and p.I329V) were found in seven patients. Segregation analysis indicated that 100% (5/5) of probands inherited the IL17RD variants from their unaffected parents, and oligogenicity was found in 4/7 patients. One rare SPRY4 variant (p.T68S) was found in a female patient with Kallmann syndrome who also carried a PLXNA1 mutation.ConclusionOur study greatly enriched the genotypic and phenotypic spectra of DUSP6, IL17RD and SPRY4 in IHH. Mutations in DUSP6 alone seem sufficient to cause IHH in an autosomal dominant manner, whereas IL17RD or SPRY4 mutations may cause IHH phenotypes in synergy with variants in other IHH-associated genes.

This study aimed to evaluate the discriminative abilities of glycosylated hemoglobin (HbA1c) and to examine the optimal HbA1c cutoff values for diabetes and prediabetes in Chinese adults.Data of a population-based cohort of Chinese adults aged ≥40 years living in Jiading District in Shanghai were used. At baseline, 9389 and 7241 participants were included to identify the optimal HbA1c cutoff values for diabetes and prediabetes, respectively using the 1999 World Health Organization criteria as reference. In addition, the follow-up data on incident diabetes of 4538 participants were used to determine the HbA1c cutoff value for prediabetes using the development of diabetes as reference. The discriminative abilities of HbA1c were evaluated using receiver operating characteristic (ROC) curves, and the optimal cutoff values were determined by Youden's index.The areas under the ROC curves were 0.849 for diabetes, 0.614 for prediabetes using baseline data, and 0.648 for prediabetes using follow-up data. An HbA1c cutoff value of 6.0% had the largest Youden's index to diagnose diabetes with a sensitivity of 70.2% and a specificity of 87.4%. An HbA1c cutoff value of 5.6% was indicated for prediabetes using both baseline and follow-up data. However, the sensitivity and specificity were both low (55.4% and 61.1% using an oral glucose tolerance test as reference, 64.6% and 57.1% using incident diabetes as reference).An HbA1c value ≥6.0% could be used to detect diabetes in Chinese adults aged ≥40 years. However, although an HbA1c value of 5.6% to 5.9% was indicated in this study, the overall discrimination of HbA1c for prediabetes was poor.背景: 本研究旨在中国成年人群中, 评估糖化血红蛋白 (HbA1c) 诊断糖尿病和糖尿病前期的表现并寻找诊断的最佳HbA1c切点。 方法: 研究人群来自上海市嘉定区年龄≥40岁的社区居民。采用基线调查横断面数据, 以1999年世界卫生组织 (WHO) 糖尿病和糖尿病前期定义为参照标准, 分别纳入9389名和7241名研究对象来确定诊断糖尿病和糖尿病前期的最佳HbA1c切点。另外采用随访数据, 以糖尿病发病为参照标准, 纳入4538名研究对象来确定诊断糖尿病前期的最佳HbA1c切点。使用受试者工作特征曲线 (ROC) 评估HbA1c的诊断表现, 并根据约登指数确定最佳诊断切点。 结果: 采用基线数据, HbA1c诊断糖尿病的ROC曲线下面积(AUC)为0.849, HbA1c诊断糖尿病前期的AUC为0.614。采用随访数据, HbA1c诊断糖尿病前期的AUC为0.648。HbA1c切点取6.0%时, 诊断糖尿病的约登指数最大, 其敏感性为70.2%, 特异性为87.4%。基线和随访数据均显示, 诊断糖尿病前期的最佳HbA1c切点为5.6%, 但其敏感性和特异性均较低 (采用口服葡萄糖耐量试验为参照标准时,敏感性和特异性分别为55.4%和61.1%；采用随访过程中糖尿病发病作为参照标准时, 敏感性和特异性分别为64.6%和57.1%)。 结论: 在年龄≥40岁的中国成年人中, HbA1c≥6.0%可用于诊断糖尿病。然而, 尽管本研究得出糖尿病前期的HbA1c范围为5.6%-5.9%, 但HbA1c对诊断糖尿病前期的效果较差。.

Isolated hypogonadotropic hypogonadism (IHH) is a rare disorder characterized by impaired sexual development and infertility, caused by the deficiency of hypothalamic gonadotropin-releasing hormone neurons. IHH is named Kallmann's syndrome (KS) or normosmic IHH (nIHH) when associated with a defective or normal sense of smell. Variants in SEMA3A have been recently identified in patients with KS. In this study, we screened SEMA3A variants in a cohort of Chinese patients with IHH by whole exome sequencing. Three novel heterozygous SEMA3A variants (R197Q, R617Q and V458I) were identified in two nIHH and one KS patients, respectively. Functional studies indicated that R197Q and R617Q variants were ineffective in activating the phosphorylation of FAK (focal adhesion kinase) in GN11 cells, despite normal production and secretion in HEK293T cells. The V458I SEMA3A had defect in secretion as it was not detected in the conditioned medium from HEK293T cells. Compared with wild type SEMA3A protein, all three SEMA3A mutant proteins were ineffective in inducing the migration of GN11 cells. Our study further showed the contribution of SEMA3A loss-of-function variants to the pathogenesis of IHH.

Background Isolated hypogonadotropic hypogonadism (IHH) is a clinical syndrome described by failure of gonadal function secondary to defects on the synthesis, secretion, or action of the gonadotropin‐releasing hormone (GnRH). The secreted glycoprotein SEMA3A binds its receptors NRP1 or NRP2 and PLXNA to participate in axonal projection, dendritic branching, synaptic formation, and neuronal migration. Deficiency in SEMA3A, NRP1, NRP2, and PLXNA1 have been related to abnormal GnRH neuron development in mice and IHH in humans. Methods The aim of this study was to examine the genotypic and phenotypic spectra of the NRP1, NRP2, and PLXNA1 genes in a large cohort of IHH probands from China. We screened NRP1, NRP2, and PLXNA1 variants in Chinese IHH patients by whole exome sequencing and pedigree analysis. Results We identified 10 heterozygous missense variants in PLXNA1, five heterozygous missense variants in NRP1, and two heterozygous missense variants in NRP2. NRP1 variants were found only in IHH patients with defective olfaction (i.e., Kallmann syndrome, KS). In addition, 85% (17/20) of patients harbored variants in other IHH‐associated genes. Conclusion Our study greatly enriched the genotypic and phenotypic spectra of PLXNA1, NRP1, and NRP2 in IHH. It may be conducive to the genetic counseling, diagnosis, and treatment of IHH with mutations in the PLXNA1, NRP1, and NRP2 genes. Furthermore, our results indicated that NRP1 were strongly linked to hearing loss., Our study greatly enriched the genotypic and phenotypic spectra of PLXNA1, NRP1, and NRP2 in IHH. It may conducive to the genetic counseling, diagnosis, and treatment of IHH with mutations in the PLXNA1, NRP1, and NRP2 genes. Furthermore, our results indicated that NRP1 were strongly linked to hearing loss (2/8 individuals).

Kallmann syndrome (KS) is characterized by the association of anosmia and hypogonadotropic hypogonadism. The hypogonadotropic hypogonadism is due to deficient production, secretion or action of gonadotropin-releasing hormone (GnRH). Mutations in transcription factor SOX10 have been recently identified in patients with KS and hearing loss. In this study, we identified three novel SOX10 mutations in a cohort of Chinese KS patients by using exome sequencing. Two mutations (A44G and L80V) are in heterozygous state whereas the other one (G41V) is a homozygous mutation. The patient with a homozygous G41V mutation had impaired hearing in both ears, whereas the patient with a heterozygous L80V mutation showed subtle hearing impairment in the left ear. Functional studies indicated that all three SOX10 mutations showed reduced capacity to transactivate the MITF promoter alone or in synergy with PAX3, although they showed similar subcellular localization, and DNA binding ability. Our study further highlighted the significance of SOX10 haploinsufficiency as a genetic cause of KS with hearing problem.

Background Metabolic dysfunction-associated fatty liver disease (MAFLD) has been proposed and diagnosed based on modified criteria. However, evidence for the risks of developing subclinical atherosclerosis with MAFLD transitions according to its new definition has never been reported. Methods Using data from a community-based cohort, 6232 participants aged 40 years or older were included and were followed up for a median of 4.3 years during 2010–2015. Participants were categorized into four groups (stable non-MAFLD, MAFLD regressed to non-MAFLD, non-MAFLD progressed to MAFLD, and stable MAFLD). Subclinical atherosclerosis was defined as elevated carotid intima-media thickness (CIMT), elevated brachial-ankle pulse wave velocity (ba-PWV), or microalbuminuria. Results Compared with the stable non-MAFLD category, participants who progressed to MAFLD at follow-up visit had a 1.356-fold increased risk of developing elevated CIMT [odds ratio (OR) = 1.356; 95% confidence interval (CI) = 1.134–1.620], and a 1.458-fold increased risk of incident microalbuminuria (OR = 1.458; 95% CI = 1.034–2.056) after adjustment for confounders, respectively. In addition, participants with stable MAFLD showed 17.6%, 32.4%, and 35.4% increased risks of developing elevated CIMT, elevated ba-PWV and microalbuminuria, respectively. Compared with the stable MAFLD category, participants with MAFLD and low probability of fibrosis at baseline who regressed to non-MAFLD at follow-up visit had a 29.4% decreased risk of developing elevated CIMT (OR = 0.706; 95% CI = 0.507–0.984), a 43.1% decreased risk of developing elevated ba-PWV (OR = 0.569; 95% CI = 0.340–0.950), but was not significantly associated with incident microalbuminuria (OR = 0.709; 95% CI = 0.386–1.301). The decreased risks attributed to MAFLD regression were more evident in participants without diabetes or dyslipidemia, as well as in those with 0–1 metabolic risk abnormalities, respectively. Conclusions MAFLD was significantly associated with higher risks of developing subclinical atherosclerosis. Moreover, the regression of MAFLD might modify the risks of developing subclinical atherosclerosis, especially among those with low probability of fibrosis or less metabolic risk abnormalities. Since 40% of baseline participants with missing data on MAFLD measurement at follow-up were excluded, the conclusions should be speculated with caution.

Semaphorin (SEMA) has an important role in nerve development, organ formation, immune response, angiogenesis, and tumor growth. SEMA can regulate the growth and branching of axons, the morphology of dendrites, and the migration of neurons. The loss-of-function in SEMA and its receptors PLXNs and NRP affect the migration of GnRH neurons, leading to idiopathic hypogonadotropic hypogonadism (IHH). As a member of the SEMA family, SEMA3A has an important role in axonal rejection, dendritic branching, synaptic formation, and neuronal migration. There are more and more SEMA3A variants identified in IHH patients. In this study, we identified a novel SEMA3A variant (c.1369A > G (p.T457A)) in a male nIHH patient. Functional studies indicated that the T457A SEMA3A variant led to the defect of FAK phosphorylation and GN11 cell migration, which strongly argued in favor of its pathogenic effect in the nIHH patient. Our findings substantiated that the 435–457 position of SEMA3A might be very important for the secretion of SEMA3A. Haploin-sufficiency of SEMA3A in humans was sufficient to cause the IHH phenotype. SEMA3A variants might have a role in modifying the IHH phenotype, according to the variants at different positions of SEMA3A. SEMAs and its receptors formed a complex network, and other members of the SEMA-signaling pathway might also be involved in the pathogenesis of IHH.

Aims: To examine whether electrocardiography (ECG) could provide additional values to the traditional risk factors for cardiovascular disease (CVD) risk prediction among different cardiovascular risk subgroups. Methods: A total of 7,872 community residents aged ≥40 years were followed up for a median of 4.5 years. A 12-lead resting ECG was examined for participants at baseline. CVD events including myocardial infarction, stroke and cardiovascular mortality were collected. Cox proportional hazards models were used and models of traditional risk factors with and without ECG were compared. Results: At baseline, 2,470 participants (31.3%) had ECG abnormalities. During follow-up, 464 participants developed CVD events. ECG abnormalities were associated with an increased risk of CVD after adjustment for the traditional risk factors in participants with a 10-year atherosclerotic CVD (ASCVD) risk ≥10% (hazard ratio, HR: 1.45; 95% confidence interval, CI: 1.11, 1.91). Adding ECG abnormalities to the traditional CVD risk factors improved reclassification for those who did not experience events [net reclassification index: 8.0% (95% CI: 2%, 19.5%)], discrimination (integrated discrimination improvement: 0.7% (95% CI: 0.1%, 1.9%), and calibration (goodness of fit P value from 0.600 to 0.873) in participants with a 10-year ASCVD risk ≥10%. However, no significant association and improvement were found in participants with a 10-year ASCVD risk

Background Previous studies reported that early‐life exposure to undernutrition is associated with the risk of diabetes mellitus and metabolic syndrome in adulthood, but the association with risk of cardiovascular disease ( CVD ) later in life remains unclear. The current study aimed to investigate whether exposure to Chinese famine in early life is associated with risk of CVD . Methods and Results We used data from REACTION (Risk Evaluation of Cancers in Chinese Diabetic Individuals: A Longitudinal Study), which recruited a total of 259 657 community‐dwelling adults aged 40 years or older from 25 centers across mainland China between 2011 and 2012. Compared with the nonexposed participants, those who had been exposed to famine in early life had a significantly increased risk of total CVD , myocardial infarction, stroke, and coronary heart disease. In the multivariable‐adjusted logistic regression model, the odds ratios (95% CI) for total CVD , myocardial infarction, stroke, and coronary heart disease in fetal famine exposure were 1.35 (1.20–1.52), 1.59 (1.08–2.35), 1.40 (1.11–1.78), and 1.44 (1.26–1.65), respectively; those odds ratios in childhood famine exposure were 1.59 (1.40–1.81), 2.20 (1.52–3.20), 1.82 (1.45–2.28), and 1.80 (1.56–2.09), respectively; and those in adolescent famine exposure were 1.52 (1.27–1.81), 2.07 (1.28–3.35), 1.92 (1.42–2.58), and 1.83 (1.50–2.24), respectively. The main finding of our study is that, compared with those who lived in the less severely affected famine area, individuals in the severely affected famine area had significantly increased risk of total CVD in all 3 exposed groups. Conclusions Early‐life exposure to undernutrition is associated with significantly increased risk of CVD in later life, especially among those who were in the severely affected famine area.

Aim: To construct a model discriminating colorectal cancer (CRC) based on differential DNA methylation. Materials & methods: The CRC-related methylation-modulated genes were retrieved from literature. The methylation levels of CpG sites in the promoter regions and the first exons of candidate genes were verified in The Cancer Genome Atlas data. A model for discriminating CRC based on methylation levels was established using least absolute shrinkage and selection operator regression. Results: Five new differentially methylated CpG sites were identified and further validated in 94 Chinese CRC patients. A five-CpG-based panel was constructed, with the area under the curve values of 0.999 in The Cancer Genome Atlas data and 0.943 in Chinese patients, respectively. Conclusion: This five-CpG-based panel is a practical and reliable tool for CRC discrimination.

Objectives Homocysteine is a modifiable, independent risk factor for cardiovascular disease. The association between hyperhomocysteinemia and metabolic syndrome with the presence of early carotid artery atherosclerosis remains unknown in middle-aged Chinese adults. Methods Chinese adults (n = 1607) of Han ethnicity, age 35 to 65 y, and living in their communities >2 y were surveyed. Hyperhomocysteinemia was defined as homocysteine concentrations >15 µmol/L. Carotid intima-media thickness and carotid plaque were examined by ultrasonography. All participants were classified into four groups by hyperhomocysteinemia and metabolic syndrome status. Results Participants with both hyperhomocysteinemia and metabolic syndrome had the highest levels of waist circumference and systolic blood pressure compared with the three other groups. The highest proportion of increased carotid intima-media thickness (61.3%) was in the subgroup of both hyperhomocysteinemia and metabolic syndrome. After adjustments for the covariates, the risk of increased carotid intima-media thickness was only significantly higher in the group with metabolic syndrome but without hyperhomocysteinemia (odds ratio: 1.47; 95% confidence interval, 1.13–1.93) compared with people without hyperhomocysteinemia and metabolic syndrome. Furthermore, statistically significant variances of prevalence of plaque among the four subgroups were not discovered. Conclusions Our study demonstrated that metabolic syndrome had a strong effect on carotid intima-media thickness However, the increased homocysteine levels were not significantly associated with early carotid artery atherosclerosis in middle-aged Chinese people.

Objective: To identify CCDC141 variants in a large Chinese cohort with congenital hypogonadotropic hypogonadism (CHH) and to assess the contribution of CCDC141 to CHH. Design: Detailed phenotyping was conducted in CHH patients with CCDC141 variants and co-segregation analysis was performed, when possible. Methods: Whole-exome sequencing was performed in 177 CHH patients and 450 unrelated, ethnically matched controls from China. Results: Seven novel CCDC141 rare sequencing variants (RSVs) were identified in 12 CHH pedigrees. Four of the variants were private mutations; however, p.Q409X, p.Q871X and p.G1488S were identified in more than one patient. Up to 75% (9/12) of patients had mutations in other CHH-associated genes, which is significantly higher than CHH patients without CCDC141 RSVs. The co-segregation analysis for eight CHH families showed that 75% (6/8) CCDC141 RSVs were inherited from their fertile parents. Over half (58.3%, 8/18) of the patients exhibited other clinical deformities in addition to hypogonadism. One patient harbouring a CCDC141 RSV showed a reversal of CHH after sex-steroid replacement. Conclusions: Our results broaden the genotypic spectrum of CCDC141 in CHH, as CCDC141 RSVs alone do not appear sufficient to cause CHH. The phenotypic spectrum in patients with CCDC141 RSVs is much wider than originally believed.

Kallmann syndrome (KS) is characterized by isolated hypogonadotropic hypogonadism (IHH) with anosmia. Fibroblast growth factor receptor 1 (FGFR1) is one of KS-associated genes, accounts for approximately 10% of total patients. FGFR1 mutations have also been identified in more severe craniosynostosis syndromes, and a subset of craniosynostosis syndromes-associated FGFR1 mutations show dominant negative effect. In this study, we identified a novel FGFR1 mutation (c.867G>A; p.W289X) in a KS patient. The p.W289X mutation leads premature termination, producing a truncated FGFR1 without the transmembrane and intracellular domains. Indeed, the W289X FGFR1 was secreted into culture medium. Further, W289X FGFR1 interfered with the function of wild type receptor to induce ERK1/2 phosphorylation. We therefore identified a dominant negative FGFR1 mutation in the KS patient, and this mutant FGFR1 may be used to decipher the physiological function of FGFR1.

Purpose Idiopathic hypogonadotropic hypogonadism (IHH) and CHARGE (C, coloboma; H, heart abnormalities; A, choanal atresia, R, retardation of growth and/or development; G, gonadal defects; E, ear deformities and deafness) syndrome are 2 distinct developmental disorders sharing features of hypogonadism and/or impaired olfaction. CHD7 variants contribute to >60% CHARGE syndrome and ~10% IHH patients. A variety of extended CHARGE-like features are frequently reported in CHARGE patients harboring CHD7 variants. In this study, we aimed to systematically analyze the diagnostic CHARGE features and the extended CHARGE-like features in patients with IHH with CHD7 variants. Methods Rare sequencing variants (RSVs) in CHD7 were identified through exome sequencing in 177 IHH probands. Detailed phenotyping was performed in the IHH patients harboring CHD7 variants and their available family members. Results CHD7 RSVs were identified in 10.2% (18/177) of the IHH probands. Two diagnostic CHARGE features, hearing loss and ear deformities, were significantly enriched in patients with CHD7 variants. Furthermore, CHD7 variants were significantly associated with a panel of extended CHARGE-like phenotypes, including mild ocular defects, dyspepsia/gastroesophageal reflux disease and skeletal defects. We also developed a predictive model for prioritizing CHD7 genetic testing in IHH patients. Conclusion CHD7 variants rarely cause isolated IHH. Surveillance of symptoms in CHARGE syndrome-affected organs will facilitate the proper treatment for these patients. Certain clinical features can be useful for prioritizing CHD7 genetic screening.

Objective To analyze the prevalence of FGFR1, FGF8, and FGF17 mutations in a Chinese cohort with idiopathic hypogonadotropic hypogonadism (IHH) and to characterize the clinical presentations and therapeutic outcomes of IHH patients with FGFR1, FGF8, and FGF17 mutations. Design Retrospective cohort. Setting University hospital. Patient(s) A total of 145 IHH probands (125 men and 20 women) were recruited for this study. Interventions(s) Hormone assays. Main Outcome Measure(s) Whole-exome sequencing, polymerase chain reaction–Sanger sequencing, in silico functional prediction. Result(s) Six novel mutations (p.154_158del, p.E496Rfs*12, p.W190X, p.S134D, p.W10X, and c.1552 + 3insT) in FGFR1, two novel mutations (p.E176K and p.R184C) in FGF8, three novel mutations (p.48_52del, p.P120L, and p.K191R) in FGF17, and five reported mutations (p.W289X, p.G237S, p.V102I, p.R250Q, and p.T340M) in FGFR1 were identified in 18 IHH patients. The functional consequences of all mutations were analyzed in silico. In addition to hypogonadotropic hypogonadism, 44.4% (8/18) patients exhibited other clinical deformities, including dental agenesis (3/18, 16.7%), hearing loss (3/18, 16.7%), and hand malformation (2/18, 11.1%). hCG/hMG therapy was effective in promoting sexual development in IHH patients with FGFR1, FGF8, and FGF17 mutations. Conclusion(s) We extended the mutational spectrum of FGFR1, FGF8, and FGF17 in IHH patients. The prevalence of FGFR1, FGF8, and FGF17 mutations in IHH was 12.4%. hCG/hMG therapy was effective to acquire fertility for patients with FGFR1, FGF8, and FGF17 mutations but has a risk of transmitting the mutations and IHH to the next generation.

Idiopathic hypogonadotropic hypogonadism (IHH) is a rare disorder caused by the deficient production, secretion, or action of gonadotropin-releasing hormone. Prokineticin (PROK) receptor 2 ( PROKR2), a causative gene for IHH, encodes a GPCR PROKR2. When PROKR2 binds to its ligands PROKs, it may activate several signaling pathways, including IP3/Ca2+, MAPK, and cAMP pathways. However, the mutational spectrum of PROKR2 in Chinese patients with IHH has not been established. In the present study, we found that up to 13.3% (18/135) of patients with IHH in China carried mutations in PROKR2. Most of the variants in this study were private; however, a PROKR2 (c.533G > C; p.W178S) mutation was identified in 10 independent patients, implying a possible founder mutation. Functional studies indicated that 6 novel PROKR2 mutations led to decreased signaling to various extents. Two IHH-associated mutations (L218P and R270H) disrupted Gαq-dependent signaling but maintained normal Gαs and ERK1/2 signaling. A glutathione S-transferase pull-down experiment demonstrated that R270H mutation disrupted the interaction of intracellular loop 3 of PROKR2 to Gαq protein but not Gαs protein. Our results indicated that selective disruption of the interaction with a specific Gα-protein might underlie the biased signaling for certain IHH-associated PROKR2 mutations.-Zhao, Y., Wu, J., Jia, H., Wang, X., Zheng, R., Jiang, F., Chen, D.-N., Chen, Z., Li, J.-D. PROKR2 mutations in idiopathic hypogonadotropic hypogonadism: selective disruption of the binding to a Gα-protein leads to biased signaling.

Background Metabolically healthy obese phenotype (MHO) refers to obese individuals with absence of metabolic abnormalities such as dyslipidaemia, insulin resistance and hypertension. Many studies reported the long-term prognosis of MHO on diseases and mortality with inconsistent results. Methods We performed a meta-analysis to assess the risks of cardiovascular (CV) events and all-cause mortality for MHO individuals. Original prospective observational studies were searched in Medline, EMBASE, Web of Science and Cochrane library up to 30 September 2015. In this meta-analysis, the relative risk (RR) calculated on the basis of the incident number of disease events and deaths in participants and the corresponding multivariable-adjusted HR were both extracted to calculate pooled risk estimates. A random-effects model was used if there was heterogeneity among studies; otherwise, the fixed-effects model was used. Results 22 prospective studies, involving 584 799 participants, were archived in the analyses. With metabolically healthy normal weight as the reference, the MHO phenotype was associated with a higher risk of CV events (RR 1.50, 95% CI 1.27 to 1.77; HR 1.60, 95% CI 1.38 to 1.84). However, MHO individuals were not associated with increased risk of all-cause mortality (RR 1.18, 95% CI 0.83 to 1.66; HR 1.07, 95% CI 0.92 to 1.25). Conclusions The meta-analysis confirms a positive association between a metabolically healthy obese phenotype and the risk of CV events. However, higher risk for all-cause mortality is not evident in metabolically healthy obese individuals.

Background: The study was to investigate the prevalence of metabolic health in subjects with obesity in the Chinese population and to identify the determinants related to metabolic abnormality in obese individuals. Methods: 5013 subjects were recruited from seven provincial capitals in China. The obesity and metabolic status were classified based on body mass index (BMI) and the number of abnormalities in common components of metabolic syndrome. Results: 27.9% of individuals with obesity were metabolically healthy. The prevalence of the metabolically healthy obese (MHO) phenotype was significantly decreased with age in women (p trend &lt, 0.001), but not significantly in men (p trend = 0.349). Central obesity (odds ratio [OR] = 4.07, 95% confidence interval [CI] = 1.93–8.59), longer sedentary time (OR = 1.97, 95%CI = 1.27–3.06), and with a family history of obesity related diseases (hypertension, diabetes, dyslipidemia) (OR = 1.85, 95%CI = 1.26–2.71) were significantly associated with having metabolic abnormality in obese individuals. Higher levels of physical activity and more fruit/vegetable intake had decreased ORs of 0.67 (95%CI = 0.45–0.98) and 0.44 (95%CI = 0.28–0.70), respectively. Conclusion: 27.9% of obese participants are in metabolic health. Central obesity, physical activity, sedentary time, fruits/vegetables intake and family history of diseases are the determinants associated with metabolic status in obesity.

Objective According to World Health Organization, for every committed suicide there were 20 suicide attempts at least. In the last decade, despite the increasing awareness on suicide attempts among adolescents in China, there has been no comprehensive system reporting vital statistics. Consequently, the prevalence of suicide attempts reported in some studies ranged variedly. Therefore, the purpose of this study was to provide the first meta-analysis of cross-sectional studies of suicide attempts to fill this gap. Methods Two reviewers independently screened potentially relevant cross-sectional studies of suicide attempts through PubMed-Medline, Embase, Wanfang Data, Chongqing VIP and Chinese National Knowledge Infrastructure databases using the core terms ‘suicid*'/‘suicide attempt*' / ‘attempted suicide' and ‘adolescen*'/‘youth'/‘child*' / ‘student*' and ‘China'/‘Chinese' in the article titles, abstracts and keywords. Chi-square based Q test and I 2 statistic assessed the heterogeneity. Forest plot was used to display results graphically. Potential publication bias was assessed by the funnel plot, Begg's and Egger's test. Results In total, 43 studies with 200,124 participants met the eligibility criteria. The pooled prevalence of suicide attempts among Chinese adolescents was 2.94% (95% CI: 2.53%–3.41%). Substantial heterogeneity in prevalence estimates was revealed. Subgroup analyses showed that the prevalence for males was 2.50% (95% CI: 2.08%–3.01%), and for females was 3.17% (95% CI: 2.56%–3.91%). Conclusions In sum, abstracting across the literatures, the prevalence of suicide attempts among Chinese adolescents was moderate compared with other countries around the world. Necessary measures should be set out prevent them in the future.

Objective This study aimed to estimate the pooled prevalence of suicidal ideation among Chinese elderly aged ≥60years. Methods Two reviewers independently searched the potentially relevant studies through electronic database (PubMed-Medline, Embase, Wanfang Data, Chinese National Knowledge Infrastructure and Chongqing VIP) using key terms ‘suicid*', ‘suicidal ideation' combined with ‘aged', ‘elderly' and ‘old people'. All selected studies should meet the eligibility criteria in this study. Chi-square based Q test and I 2 statistic assessed the heterogeneity. Forest plots were used to display results graphically. Potential publication bias was assessed by the funnel plot and Begg's test. Prevalence rate was meta-analysed. Results In total, 11 studies were included with 11,526 subjects. The prevalence of suicidal ideation among Chinese elderly ranged from 2.2% to 21.5%. The pooled prevalence of all 11 studies was 11.5% (95% CI: 8.3%–14.8%). Subgroup analyses showed the prevalence for males was 11.0%, and for the females was 15.6%. In three subgroups for age, 60–69, 70–79 and ≥80, the prevalence was 9.1%, 12.1% and 18.9% respectively. A slightly higher prevalence in rural areas was calculated than in urban (14.7% vs. 11.8%). In mainland China, the prevalence was 12.6%. And in Taiwan and Hongkong, the pooled prevalence was 9.2%. Conclusions The prevalence of suicidal ideation was relatively high among elderly in China, and it should attract enough attention.

Few studies have described the characteristics of metabolically healthy individuals with excess fat in the Chinese population. This study aimed to prospectively investigate the natural course of metabolically healthy overweight/obese (MH-OW/OB) adults, and to assess the impact of weight change on developing metabolic abnormalities. During 2009–2010, 525 subjects without any metabolic abnormalities or other obesity-related diseases were evaluated and reevaluated after 5 years. The subjects were categorized into two groups of overweight/obese and normal weight based on the criteria of BMI by 24.0 at baseline. At follow-up, the MH-OW/OB subjects had a significantly increased risk of developing metabolically abnormalities compared with metabolically healthy normal-weight (MH-NW) individuals (risk ratio: 1.35, 95% confidence interval: 1.17–1.49, p value < 0.001). In the groups of weight gain and weight maintenance, the MH-OW/OB subjects was associated with a larger increase in fasting glucose, triglycerides, systolic blood pressure, diastolic blood pressure and decrease in high-density lipoprotein cholesterol comparing with MH-NW subjects. In the weight loss group, no significant difference of changes of metabolic parameters was observed between MH-OW/OB and MH-NW adults. This study verifies that MH-OW/OB are different from MH-NW subjects. Weight management is needed for all individuals since weight change has a significant effect on metabolic health without considering the impact of weight change according to weight status.

Supplemental Digital Content is available in the text, Background: We conducted a systematic review and meta-analysis to firstly obtain a reliable estimation of the prevalence of metabolically healthy obese (MHO) individuals in obesity, then assessed the risk of developing metabolic abnormalities (MA) among MHO individuals. At last, we evaluated the effects of traditional lifestyle interventions on metabolic level for MHO subjects. Methods: A systematic review and meta-analysis (PRISMA) guideline were conducted, and original studies were searched up to December 31, 2016. The prevalence of MHO in obesity from each study was pooled using random effects models. The relative risks (RRs) were pooled to determine the risk of developing MA for MHO compared with metabolically healthy normal-weight (MHNW) subjects. For the meta-analysis of intervention studies, the mean difference and standardized mean differences were both estimated for each metabolic parameter within each study, and then pooled using a random-effects model. Results: Overall, 40 population-based studies reported the prevalence of MHO in obesity, 12 cohort studies and 7 intervention studies were included in the meta-analysis. About 35.0% obese individuals were metabolically healthy in the obese subjects. There were dramatic differences in the prevalence among different areas. However, 0.49 (95% confidence intervals [CI]: 0.38 to 0.60) of the MHO individuals would develop one or more MA within 10 years. Compared with MHNW subjects, the MHO subjects presented higher risk of incident MA (pooled RR = 1.80, 95%CI: 1.53–2.11). Following intervention, there was certain and significant improvement of metabolic state for metabolically abnormal obesity (MAO) subjects. Only diastolic blood pressure had reduced for MHO individuals after intervention. Conclusions: Almost one-third of the obese individuals are in metabolic health. However, they are still at higher risk of advancing to unhealthy state. Therefore, it is still needed to advise MHO individuals to maintain or adopt a healthy lifestyle, so as to counterbalance the adverse effects of obesity.

Background: The effect of low serum vitamin E levels on the risk of colorectal cancer (CRC) remains inconclusive. This meta-analysis aims to synthesize relevant studies to evaluate the association between serum vitamin E and the risk of CRC based on case–control studies. Methods: Potentially relevant studies were selected by searching PubMed, EMBASE, and China National Knowledge Infrastructure databases according to inclusion and exclusion criteria. The association between serum vitamin E levels and CRC was estimated by the weighted mean difference (WMD) and 95% confidence interval (CI) using a random-effects model. Heterogeneity was evaluated using Q test and I2 statistic. Subgroup analysis was conducted to explore sources of heterogeneity. Sensitivity analysis was performed to reveal stability and reliability. Results: A total of 10 papers with 11 studies, including 6431 subjects with 520 CRC patients and 5981 controls, were included in this present meta-analysis. The results indicated that compared with healthy controls, patients with CRC showed lower concentrations of serum vitamin E (WMD = −2.994 μmol/L, 95% CI = −4.395 to −1.593). Ethnicity subgroup analysis indicated that the serum vitamin E levels were lower in European (WMD = −1.82 μmol/L, 95% CI = −3.00 to −0.65), but not in Asian. Control-source subgroup analysis revealed that a significant association was observed in subgroup with hospital-based controls (WMD = −3.43 μmol/L, 95% CI = −6.27 to −0.59), but not in those with population-based controls. Sensitivity analysis suggested no significant difference in the pooled estimates, indicating stable results. Conclusions: CRC is associated with a lower concentration of serum vitamin E. However, necessary prospective cohort studies should be conducted to assess the effect of serum vitamin E on the risk of CRC in the future.