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1.
Int J Endocrinol ; 2021: 7752526, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34721574

RESUMO

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.

2.
Diabetes Care ; 2021 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-34620611

RESUMO

OBJECTIVE: Type 1 and type 2 diabetes are associated with gut dysbiosis. However, the relationship between the gut microbiota and latent autoimmune diabetes in adults (LADA), sharing clinical and metabolic features with classic type 1 and type 2 diabetes, remains unclear. Here, we used a multiomics approach to identify the characteristics of the gut microbiota and metabolic profiles in patients with LADA. RESEARCH DESIGN AND METHODS: This age- and sex-matched case-control study included 30 patients with LADA, 31 patients with classic type 1 diabetes, 30 patients with type 2 diabetes, and 29 healthy individuals. The gut microbiota profiles were identified through the 16S rRNA gene, and fecal and serum metabolites were measured through untargeted liquid chromatography-mass spectrometry. RESULTS: Patients with LADA had a significantly different structure and composition of the gut microbiota and their metabolites as well as a severe deficiency of short-chain fatty acid-producing bacteria. The gut microbiota structure of the patients with LADA was more similar to that of patients with type 1 diabetes who were positive for GAD antibody. We identified seven serum metabolite modules and eight fecal metabolite modules that differed between the LADA group and the other groups. CONCLUSIONS: The characteristic gut microbiota and related metabolites of patients with LADA are associated with autoantibodies, glucose metabolism, islet function, and inflammatory factors, which may contribute to the pathogenesis of LADA. Future longitudinal studies should explore whether modulating the gut microbiota and related metabolites can alter the natural course of autoimmune diabetes in the quest for new therapeutics.

3.
Mol Genet Genomic Med ; 9(11): e1816, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34636164

RESUMO

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.

4.
Metabolism ; 120: 154779, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33895182

RESUMO

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.


Assuntos
Aterosclerose/etiologia , Doenças Metabólicas/patologia , Hepatopatia Gordurosa não Alcoólica/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Índice Tornozelo-Braço , Aterosclerose/diagnóstico , Aterosclerose/epidemiologia , Aterosclerose/patologia , Espessura Intima-Media Carotídea , China/epidemiologia , Estudos de Coortes , Progressão da Doença , Feminino , Seguimentos , Humanos , Masculino , Doenças Metabólicas/complicações , Doenças Metabólicas/diagnóstico , Doenças Metabólicas/epidemiologia , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Hepatopatia Gordurosa não Alcoólica/etiologia , Remissão Espontânea , Fatores de Risco
5.
Aging (Albany NY) ; 13(7): 10075-10086, 2021 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-33818417

RESUMO

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.


Assuntos
Pressão Sanguínea/fisiologia , Hipertensão/fisiopatologia , Rigidez Vascular/fisiologia , Adulto , Idoso , American Heart Association , Índice Tornozelo-Braço , Índice de Massa Corporal , Colesterol/sangue , Feminino , Humanos , Hipertensão/sangue , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco , Estados Unidos
6.
Int J Cardiol ; 332: 209-215, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33667580

RESUMO

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.


Assuntos
Doenças Cardiovasculares , Adulto , Índice de Massa Corporal , Peso Corporal , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , China/epidemiologia , Humanos , Fatores de Risco
7.
J Clin Endocrinol Metab ; 106(7): e2775-e2788, 2021 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-33570562

RESUMO

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.


Assuntos
Grupo com Ancestrais do Continente Asiático/estatística & dados numéricos , Distribuição da Gordura Corporal/estatística & dados numéricos , Grupos de Populações Continentais/estatística & dados numéricos , Grupos Étnicos/estatística & dados numéricos , Obesidade/etnologia , Adulto , Grupo com Ancestrais do Continente Africano/estatística & dados numéricos , Pressão Sanguínea , Índice de Massa Corporal , Fatores de Risco Cardiometabólico , China/etnologia , Suscetibilidade a Doenças/etnologia , Grupo com Ancestrais do Continente Europeu/estatística & dados numéricos , Feminino , Humanos , Masculino , Americanos Mexicanos/estatística & dados numéricos , Pessoa de Meia-Idade , Inquéritos Nutricionais , Obesidade/fisiopatologia , Análise de Regressão , Triglicerídeos/sangue , Circunferência da Cintura/etnologia
8.
J Med Genet ; 58(1): 66-72, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32389901

RESUMO

BACKGROUND: FGF8-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. METHODS: A 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. RESULTS: Four 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. CONCLUSION: Our 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.


Assuntos
Fosfatase 6 de Especificidade Dupla/genética , Hipogonadismo/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas do Tecido Nervoso/genética , Receptores de Interleucina/genética , Adolescente , Adulto , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Hipogonadismo/epidemiologia , Hipogonadismo/patologia , Masculino , Mutação/genética , Sequenciamento Completo do Exoma , Adulto Jovem
9.
Diabetes Care ; 44(2): 499-510, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33355246

RESUMO

OBJECTIVE: Comprehensive assessment of serum bile acids (BAs) aberrations before diabetes onset remains inconclusive. We examined the association of serum BA profile and coregulation with the risk of developing type 2 diabetes mellitus (T2DM) among normoglycemic Chinese adults. RESEARCH DESIGN AND METHODS: We tested 23 serum BA species in subjects with incident diabetes (n = 1,707) and control subjects (n = 1,707) matched by propensity score (including age, sex, BMI, and fasting glucose) from the China Cardiometabolic Disease and Cancer Cohort (4C) Study, which was composed of 54,807 normoglycemic Chinese adults with a median follow-up of 3.03 years. Multivariable-adjusted odds ratios (ORs) for associations of BAs with T2DM were estimated using conditional logistic regression. RESULTS: In multivariable-adjusted logistic regression analysis, per SD increment of unconjugated primary and secondary BAs were inversely associated with incident diabetes, with an OR (95% CI) of 0.89 (0.83-0.96) for cholic acid, 0.90 (0.84-0.97) for chenodeoxycholic acid, and 0.90 (0.83-0.96) for deoxycholic acid (P < 0.05 and false discovery rate <0.05). On the other hand, conjugated primary BAs (glycocholic acid, taurocholic acid, glycochenodeoxycholic acid, taurochenodeoxycholic acid, and sulfated glycochenodeoxycholic acid) and secondary BA (tauroursodeoxycholic acid) were positively related with incident diabetes, with ORs ranging from 1.11 to 1.19 (95% CIs ranging between 1.05 and 1.28). In a fully adjusted model additionally adjusted for liver enzymes, HDL cholesterol, diet, 2-h postload glucose, HOMA-insulin resistance, and waist circumference, the risk estimates were similar. Differential correlation network analysis revealed that perturbations in intraclass (i.e., primary and secondary) and interclass (i.e., unconjugated and conjugated) BA coregulation preexisted before diabetes onset. CONCLUSIONS: These findings reveal novel changes in BAs exist before incident T2DM and support a potential role of BA metabolism in the pathogenesis of diabetes.


Assuntos
Diabetes Mellitus Tipo 2 , Resistência à Insulina , Adulto , Ácidos e Sais Biliares , China/epidemiologia , Diabetes Mellitus Tipo 2/epidemiologia , Jejum , Humanos , Pessoa de Meia-Idade
11.
Glob Heart ; 15(1): 59, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32923352

RESUMO

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 <10%. Conclusions: ECG screening might provide a marginal improvement in CVD risk prediction in adults at high risk. However, ECG should not be recommended in adults at low risk.


Assuntos
Doenças Cardiovasculares/diagnóstico , Eletrocardiografia/métodos , Frequência Cardíaca/fisiologia , Programas de Rastreamento , Medição de Risco/métodos , Doenças Cardiovasculares/mortalidade , Doenças Cardiovasculares/fisiopatologia , China/epidemiologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco , Taxa de Sobrevida/tendências , Fatores de Tempo
12.
Eur J Endocrinol ; 183(3): 245-254, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32520725

RESUMO

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.


Assuntos
Hipogonadismo/genética , Hipogonadismo/patologia , Proteínas do Tecido Nervoso/genética , China , Estudos de Coortes , Feminino , Genótipo , Humanos , Masculino , Mutação/genética , Linhagem , Fenótipo , Sequenciamento Completo do Exoma/métodos
13.
Int J Biometeorol ; 64(9): 1509-1517, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32415619

RESUMO

Previous studies have examined the associations of meteorological factors with blood pressure; however, these associations have not fully elucidated, especially lacking of evidence from cohort study, little information about the associations of cold pressor sensitivity with blood pressure and its fluctuation. The objective of this study was to investigate the outdoor and indoor temperature, barometric pressure, humidity, and cold pressor sensitivity with blood pressure and its fluctuation. Forty-eight healthy subjects were recruited, and response of blood pressure to cold exposure was measured with cold pressor test (CPT). Then, all the subjects were followed up, and blood pressure was measured every half a month in a period of consecutive 12 months. Multiple panel analysis with random-effects generalized least squares (GLS) regression was used to analyze the effect of the outdoor and indoor temperature, barometric pressure, humidity, and response to cold pressor exposure on blood pressure. Outdoor and indoor temperature and humidity were found to be independently associated with blood pressure (all the P values < 0.05). The response to cold exposure positively associated with blood pressure and its fluctuation (P < 0.05). The subjects with higher cold pressor sensitivity had about 4.7 mmHg higher maximum difference of SBP in 1 year than the subjects with lower sensitivity. Outdoor and indoor temperature, humidity, and response to cold exposure are associated with blood pressure and its fluctuation. These findings provided extending evidence on blood pressure management in clinic and preventive practice.


Assuntos
Temperatura Baixa , Pressão Sanguínea , Estudos de Coortes , Umidade , Temperatura
14.
J Am Heart Assoc ; 9(7): e014175, 2020 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-32233751

RESUMO

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.


Assuntos
Experiências Adversas da Infância , Doenças Cardiovasculares/epidemiologia , Transtornos da Nutrição Infantil/epidemiologia , Fome Epidêmica , Transtornos da Nutrição do Lactente/epidemiologia , Desnutrição/epidemiologia , Adolescente , Adulto , Fatores Etários , Idoso , Doenças Cardiovasculares/diagnóstico , Criança , Transtornos da Nutrição Infantil/diagnóstico , Pré-Escolar , China/epidemiologia , Estudos Transversais , Feminino , Fatores de Risco de Doenças Cardíacas , Humanos , Lactente , Transtornos da Nutrição do Lactente/diagnóstico , Recém-Nascido , Masculino , Desnutrição/diagnóstico , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Medição de Risco , Fatores de Tempo
15.
J Diabetes ; 12(8): 573-582, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32119184

RESUMO

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.


Assuntos
Diabetes Mellitus/diagnóstico , Técnicas de Diagnóstico Endócrino , Hemoglobina A Glicada/análise , Estado Pré-Diabético/diagnóstico , Adulto , Idoso , Glicemia/análise , Glicemia/metabolismo , China/epidemiologia , Cidades/epidemiologia , Diabetes Mellitus/sangue , Diabetes Mellitus/epidemiologia , Técnicas de Diagnóstico Endócrino/normas , Feminino , Teste de Tolerância a Glucose/métodos , Teste de Tolerância a Glucose/normas , Hemoglobina A Glicada/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Estado Pré-Diabético/sangue , Estado Pré-Diabético/epidemiologia , Valor Preditivo dos Testes , Estudos Prospectivos , Valores de Referência , Sensibilidade e Especificidade , População Urbana/estatística & dados numéricos
17.
Clin Genet ; 97(5): 696-703, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32060892

RESUMO

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.


Assuntos
Hipogonadismo/genética , Infertilidade/genética , Síndrome de Kallmann/genética , Semaforina-3A/genética , Adulto , Movimento Celular/genética , Feminino , Quinase 1 de Adesão Focal/genética , Hormônio Liberador de Gonadotropina/genética , Células HEK293 , Heterozigoto , Humanos , Hipogonadismo/patologia , Infertilidade/patologia , Síndrome de Kallmann/patologia , Masculino , Mutação/genética , Linhagem , Fenótipo , Sequenciamento Completo do Exoma
18.
Fertil Steril ; 113(1): 158-166, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31748124

RESUMO

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.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Fator 8 de Crescimento de Fibroblasto/genética , Fatores de Crescimento de Fibroblastos/genética , Hipogonadismo/genética , Mutação/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Adolescente , Adulto , Estudos de Coortes , Feminino , Genótipo , Humanos , Hipogonadismo/diagnóstico , Hipogonadismo/terapia , Masculino , Linhagem , Fenótipo , Estudos Retrospectivos , Sequenciamento Completo do Exoma/métodos , Adulto Jovem
19.
J Clin Endocrinol Metab ; 105(5)2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31689711

RESUMO

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.


Assuntos
DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Hipogonadismo/genética , Hipogonadismo/patologia , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Grupo com Ancestrais do Continente Asiático/genética , China , Estudos de Coortes , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Masculino , Mutação de Sentido Incorreto , Fenótipo , Adulto Jovem
20.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(9): 877-881, 2019 Sep 10.
Artigo em Chinês | MEDLINE | ID: mdl-31515780

RESUMO

OBJECTIVE: To identify pathogenic variants in 5 sporadic patients and two Chinese pedigrees affected with 17-hydroxylase deficiency (17-OHD). METHODS: Peripheral blood samples were collected with informed consent. Variants of CYP17A1 gene were screened by PCR and Sanger sequencing. Suspected mutations were validated in other members of the pedigrees. RESULTS: Gene sequencing has identified a homozygous c.985_987delTACinsAA (Y329Kfs) mutation in exon 6 of the CYP17A1 gene in 4 patients and the sister of case 3. Case 1 was found to harbor compound heterozygous mutations c.1459_1467del9 (p.D487_F489del) and c.1244-3C>A. The parents and brother of cases 2 and 5 were heterozygous carriers of a c.985_987delTACinsAA(Y329Kfs) mutation. CONCLUSION: Mutations of the CYP17A1 gene probably underlie the pathogenesis of 17-OHD, for which c.985_987delTACinsAA(Y329Kfs) is the most common. The c.1244-3C>A is a novel mutation. Above results have facilitated genetic counseling for the affected families.


Assuntos
Hiperplasia Suprarrenal Congênita/genética , Esteroide 17-alfa-Hidroxilase/genética , Éxons , Feminino , Humanos , Masculino , Mutação , Linhagem
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