Genfu Tang

Efficacy of Folic Acid Therapy in Primary Prevention of Stroke Among Adults With Hypertension in China: The CSPPT Randomized Clinical Trial

IMPORTANCE Uncertainty remains about the efficacy of folic acid therapy for the primary prevention of stroke because of limited and inconsistent data. OBJECTIVE To test the primary hypothesis that therapy with enalapril and folic acid is more effective in reducing first stroke than enalapril alone among Chinese adults with hypertension. DESIGN, SETTING, AND PARTICIPANTS The China Stroke Primary Prevention Trial, a randomized, double-blind clinical trial conducted from May 19, 2008, to August 24, 2013, in 32 communities in Jiangsu and Anhui provinces in China. A total of 20,702 adults with hypertension without history of stroke or myocardial infarction (MI) participated in the study. INTERVENTIONS Eligible participants, stratified by MTHFR C677T genotypes (CC, CT, and TT), were randomly assigned to receive double-blind daily treatment with a single-pill combination containing enalapril, 10 mg, and folic acid, 0.8 mg (n = 10,348) or a tablet containing enalapril, 10 mg, alone (n = 10,354). MAIN OUTCOMES AND MEASURES The primary outcome was first stroke. Secondary outcomes included first ischemic stroke; first hemorrhagic stroke; MI; a composite of cardiovascular events consisting of cardiovascular death, MI, and stroke; and all-cause death. RESULTS During a median treatment duration of 4.5 years, compared with the enalapril alone group, the enalapril-folic acid group had a significant risk reduction in first stroke (2.7% of participants in the enalapril-folic acid group vs 3.4% in the enalapril alone group; hazard ratio [HR], 0.79; 95% CI, 0.68-0.93), first ischemic stroke (2.2% with enalapril-folic acid vs 2.8% with enalapril alone; HR, 0.76; 95% CI, 0.64-0.91), and composite cardiovascular events consisting of cardiovascular death, MI, and stroke (3.1% with enalapril-folic acid vs 3.9% with enalapril alone; HR, 0.80; 95% CI, 0.69-0.92). The risks of hemorrhagic stroke (HR, 0.93; 95% CI, 0.65-1.34), MI (HR, 1.04; 95% CI, 0.60-1.82), and all-cause deaths (HR, 0.94; 95% CI, 0.81-1.10) did not differ significantly between the 2 treatment groups. There were no significant differences between the 2 treatment groups in the frequencies of adverse events. CONCLUSIONS AND RELEVANCE Among adults with hypertension in China without a history of stroke or MI, the combined use of enalapril and folic acid, compared with enalapril alone, significantly reduced the risk of first stroke. These findings are consistent with benefits from folate use among adults with hypertension and low baseline folate levels. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00794885.

Ser1369Ala Variant in Sulfonylurea Receptor Gene ABCC8 Is Associated With Antidiabetic Efficacy of Gliclazide in Chinese Type 2 Diabetic Patients

OBJECTIVE—The purpose of this study was to investigate whether genetic variants could influence the antidiabetic efficacy of gliclazide in type 2 diabetic patients. RESEARCH DESIGN AND METHODS—A total of 1,268 type 2 diabetic patients whose diabetes was diagnosed within the past 5 years and who had no recent hypoglycemic treatment were enrolled from 23 hospitals in China. All of the patients were treated with gliclazide for 8 weeks. Fasting and oral glucose tolerance test 2-h plasma glucose, fasting insulin, and A1C were measured at baseline and after 8 weeks of treatment. We used two independent cohorts to test the associations of 25 single nuclear polymorphisms in 11 candidate genes with the antidiabetic efficacy of gliclazide. A general linear regression model was used to test the association with adjustment for important covariates. RESULTS—After 8 weeks of gliclazide therapy, mean fasting plasma glucose (FPG) was reduced from 11.1 mmol/l at baseline to 7.7 mmol/l. In cohort 1, we genotyped all 25 SNPs (n = 661) and found that Ser1369Ala of the ABCC8 gene and rs5210 of the KCNJ11 gene were significantly associated with decreases in FPG (P = 0.002). We further genotyped Ser1369Ala in cohort 2 (n = 607) and confirmed the association identified in cohort 1. In the pooled analysis, compared with subjects with the Ser/Ser genotype, subjects with the Ala/Ala genotype had a 7.7% greater decrease in FPG (P < 0.001), an 11.9% greater decrease in 2-h plasma glucose (P = 0.003), and a 3.5% greater decrease in A1C (P = 0.06) after 8 weeks of treatment with gliclazide. CONCLUSIONS—In two independent cohorts of Chinese type 2 diabetic patients, we found consistent evidence that the Ser1369Ala variant in the ABCC8 gene can influence the antidiabetic efficacy of gliclazide.

A Common Mutation in the Defensin DEFB126 Causes Impaired Sperm Function and Subfertility

A frequent frameshift mutation in defensin DEFB126, a protein that adheres to the surface of human sperm, weakens its ability to penetrate cervical mucus-like gels and causes low fertility. Defensin-Deficient Sperm Get Stuck Like Robert Burns’ best laid schemes of mice and men, the joining of egg and sperm “gang aft agley” (transl., often go awry)—and it’s no wonder, considering the many molecular events that must be correctly executed for successful fertilization. The current clinical tests still fail to explain infertility in almost one-fifth of infertile couples. Now, Tollner et al. pinpoint one more critical cog in this vital process: Men who carry a genetic variant of a certain sperm surface protein are less fertile than normal. This common but life-altering deviation likely accounts for some of the currently unexplained cases of infertility. β-Defensin is a protein made in the paired coils of the epididymis, which carries sperm from testes. This defensin is secreted as the sperm travels by and is integrated into the glycocalyx, a protein-sugar coating on the sperm surface. Surface-hugging β-defensins protect sperm from immune attack and help them to penetrate the cervical mucus in the female. While cloning the human version of this defensin, the authors found a mutated variant that was surprisingly prevalent; about 20% of the European, Chinese, and Japanese men that the authors examined carried the variation on both chromosomes (del/del). Although they did not uniformly display deficiencies usually associated with infertility (such as inadequate semen volume and low sperm motility), sperm from del/del men did show lower lectin binding relative to controls; this measure was shown to be a marker for sperm-associated O-linked oligosaccharides that cannot attach to the mutated defensin. The del/del sperm were poor penetrators of hyaluronic acid, an in vitro surrogate for cervical mucus. But did the presence of the defensin variant actually cause lower fertility? In a group of 509 newly married Chinese couples, the authors showed that it did. Wives of men with the del/del genotype were only 60% as likely to get pregnant as were women who mated with men who carried wild-type or wt/del genotypes, and the time from enrollment in the study to the live birth of a child was 2 months longer in the former group. The impaired fertility among carriers of this deletion might imply that these individuals are headed for extinction, but their prevalence in the population indicates otherwise. How can this be? The authors speculate that carriers of a single copy of the mutated defensin may have an as yet undefined survival advantage over wild-type carriers, an evolutionary situation known as balancing selection. Whatever the reason for variation persistence, our new understanding of β-defensin will enable better appreciation of human fertility and help to keep our reproductive plans on track. A glycosylated polypeptide, β-defensin 126 (DEFB126), derived from the epididymis and adsorbed onto the sperm surface, has been implicated in immunoprotection and efficient movement of sperm in mucosal fluids of the female reproductive tract. Here, we report a sequence variant in DEFB126 that has a two-nucleotide deletion in the open reading frame, which generates an abnormal mRNA. The allele frequency of this variant sequence was high in both a European (0.47) and a Chinese (0.45) population cohort. Binding of the Agaricus bisporus lectin to the sperm surface glycocalyx was significantly lower in men with the homozygous variant (del/del) genotype than in those with either a del/wt or a wt/wt genotype, suggesting an altered sperm glycocalyx with fewer O-linked oligosaccharides in del/del men. Moreover, sperm from del/del carriers exhibited an 84% reduction in the rate of penetration of a hyaluronic acid gel, a surrogate for cervical mucus, compared to the other genotypes. This reduction in sperm performance in hyaluronic acid gels was not a result of decreased progressive motility (average curvilinear velocity) or morphological deficits. Nevertheless, DEFB126 genotype and lectin binding were correlated with sperm performance in the penetration assays. In a prospective cohort study of newly married couples who were trying to conceive by natural means, couples were less likely to become pregnant and took longer to achieve a live birth if the male partner was homozygous for the variant sequence. This common sequence variation in DEFB126, and its apparent effect of impaired reproductive function, will allow a better understanding, clinical evaluation, and possibly treatment of human infertility.

Genetic and Environmental Contributions to Phenotypic Components of Metabolic Syndrome: A Population-based Twin Study

The increasing prevalence of metabolic syndrome (MS) poses a serious public‐health problem worldwide. Effective prevention and intervention require improved understanding of the factors that contribute to MS. We analyzed data on a large twin cohort to estimate genetic and environmental contributions to MS and to major MS components and their intercorrelations: waist circumference (WC), systolic (SBP) and diastolic blood pressure (DBP), fasting plasma glucose (FPG), triglycerides (TGs), and high‐density lipoprotein–cholesterol (HDL‐C). We applied structural equation modeling to determine genetic and environmental structure of MS and its major components, using 1,617 adult female twin pairs recruited from rural China. The heritability estimate for MS was 0.42 (95% confidence interval (CI): 0.00–0.83) in this sample with low MS prevalence (4.4%). For MS components, heritability estimates were statistically significant and ranged from 0.13 to 0.64 highest for WC, followed by TG, SBP, DBP, HDL‐C, and FPG. HDL‐C was mainly influenced by common environmental factors (0.62, 95% CI: 0.58–0.62), whereas the other five MS components were largely influenced by unique environmental factors (0.32–0.44). Bivariate Cholesky decomposition analysis indicated that the clinical clustering of MS components may be explained by shared genetic and/or environmental factors. Our study underscores the importance of examining MS components as intercorrelated traits, and to carefully consider environmental and genetic factors in studying MS etiology.

Organophosphorous pesticide exposures and sperm quality

Many Americans are exposed to low levels of organophosphorous (OP) pesticides. It is unclear whether these exposures impact sperm production. We investigated whether there was an association between urinary OP insecticide metabolites and sperm concentration and motility in newly married men from a rural area of eastern Peoples Republic of China. Ninety-four cases and 95 controls were included based on their median residual value of sperm concentration and motility after adjusting for relevant covariates. Their urine was analyzed for six dialkylphosphate (DAP) compounds. After adjustment for demographic and exposure variables, the odds of being a case were greater (odds ratio=1.30, 95% confidence interval 1.02-1.65) in men with higher urinary concentrations of dimethylphosphate (DMP) compared to men with lower levels. No significant differences between cases and controls were found among the other DAP concentrations. DMP exposure and sperm concentration and motility should be explored further in environmental exposure studies.

Patterns and interrelationships of body-fat measures among rural Chinese children aged 6 to 18 years.

OBJECTIVES. Our goal was to compare BMI and waist circumference with dual-energy radiograph absorptiometry–based measures of adiposity and to describe the pattern and interrelations of these surrogate and direct adiposity measures in prepubertal and pubertal rural Chinese children. METHODS. This was a cross-sectional study of 2493 children aged 6 to 18 years from a population-based cohort of twin pairs. Dual-energy radiograph absorptiometry–based measurements included total body fat, percentage of body fat, trunk fat, and percentage of trunk fat. Age- and gender-specific patterns and interrelationships among BMI, waist circumference, and dual-energy radiograph absorptiometry–based measurements were described by using smoothing plots and age- and gender-specific correlation analyses. RESULTS. In girls, BMI, waist circumference, total body fat, percentage of body fat, trunk fat, and percentage of trunk fat all increased linearly with age. In boys, BMI and waist circumference increased linearly with age, but total body fat, percentage of body fat, and trunk fat did not increase significantly with age. In both genders, percentage of trunk fat reached a nadir around 12 years of age and then increased with age. Before puberty (6–11 years), BMI and waist circumference were correlated well with total body fat, percentage of body fat, and trunk fat in both genders. During puberty (12–18 years), the correlations between BMI and each of the dual-energy radiograph absorptiometry–based measurements were higher in girls than in boys. Similar trends were found in the correlations between waist circumference and each of the dual-energy radiograph absorptiometry–based measurements. CONCLUSIONS. In this relatively lean rural Chinese population, BMI and waist circumference were highly correlated with each other and were good surrogates of total body fat, trunk fat, and percentage of body fat in prepubertal children of both genders and in pubertal girls. However, both BMI and waist circumference overestimated total and trunk fat, especially percentage of body fat in pubertal boys.

Effect of environmental tobacco smoke on levels of urinary hormone markers

Our recent study showed a dose–response relationship between environmental tobacco smoke (ETS) and the risk of early pregnancy loss. Smoking is known to affect female reproductive hormones. We explored whether ETS affects reproductive hormone profiles as characterized by urinary pregnanediol-3-glucuronide (PdG) and estrone conjugate (E1C) levels. We prospectively studied 371 healthy newly married nonsmoking women in China who intended to conceive and had stopped contraception. Daily records of vaginal bleeding, active and passive cigarette smoking, and daily first-morning urine specimens were collected for up to 1 year or until a clinical pregnancy was achieved. We determined the day of ovulation for each menstrual cycle. The effects of ETS exposure on daily urinary PdG and E1C levels in a ±10 day window around the day of ovulation were analyzed for conception and nonconception cycles, respectively. Our analysis included 344 nonconception cycles and 329 conception cycles. In nonconception cycles, cycles with ETS exposure had significantly lower urinary E1C levels (β= –0.43, SE = 0.08, p < 0.001 in log scale) compared with the cycles without ETS exposure. There was no significant difference in urinary PdG levels in cycles having ETS exposure (β= –0.07, SE = 0.15, p = 0.637 in log scale) compared with no ETS exposure. Among conception cycles, there were no significant differences in E1C and PdG levels between ETS exposure and nonexposure. In conclusion, ETS exposure was associated with significantly lower urinary E1C levels among nonconception cycles, suggesting that the adverse reproductive effect of ETS may act partly through its antiestrogen effects.

Adiposity measures and blood pressure in Chinese children and adolescents

Objective: To investigate the association of adiposity measures with blood pressure (BP) in Chinese children and adolescents. Design: A cross-sectional study. Participants: 1330 boys and 1170 girls aged 6–18 years from a rural population-based cohort of twins studied in Anhui, China, 1998–2000. Outcome measures: Adiposity measures included body mass index (BMI), total body fat and trunk fat assessed by dual-energy x-ray absorptiometry. BMI was divided into fat mass index (FMI) and lean mass index (LMI) in the analysis. Major outcomes included: systolic (S) and diastolic (D) BP. Both linear and logistic regressions were performed to assess gender-specific associations between various adiposity measures and BP, with adjustment for age and height. Generalised estimating equations were used to account for intra-twin pair correlations. Results: Mean BMI and percentage body fat in children aged 6–11 years were 14.9 kg/m2 and 9.7%, respectively; corresponding measures in children aged 12–18 years were 17.8 kg/m2 and 14.2%. Adiposity measures were more strongly associated with SBP (p<0.05 in all age strata) than DBP (p<0.05 only in children aged 6–11 years). Both FMI (β = 1.26–2.37) and LMI (β = 1.00–1.71) are associated with SBP across age and gender strata after adjustment for age and height (p<0.05). Conclusions: These results indicate that, in this relatively lean population of Chinese children and adolescents, BP, particularly SBP, is positively associated with measures of adiposity. Of all the adiposity measures, BMI is the strongest predictor of BP.

Prevalence and Associated Factors of Diabetes and Impaired Fasting Glucose in Chinese Hypertensive Adults Aged 45 to 75 Years

Objective This study examined the prevalence of impaired fasting glucose (IFG) and diabetes and their associated factors in 17,184 Chinese hypertensive adults aged 45–75 years. Methods A cross-sectional investigation was carried out in a rural area of Lianyungang, China. Previously undiagnosed diabetes [fasting plasma glucose (FPG) ≥7.0mmol/l] and IFG (6.1–6.9mmol/l) were defined based on FPG concentration. Previously diagnosed diabetes was determined on the basis of self-report. Total diabetes included both previously diagnosed diabetes and previously undiagnosed diabetes. Results The prevalence of previously diagnosed diabetes, undiagnosed diabetes, and IFG were 3.4%, 9.8%, and 14.1%, respectively. About 74.2% of the participants with diabetes had not previously been diagnosed. In the multivariable logistic-regression model, older age, men, antihypertensive treatment, obesity (BMI ≥25kg/m2), abdominal obesity (waist circumference ≥90cm for men and ≥80cm for women), non-current smoking, a family history of diabetes, higher heart rate, lower physical activity levels, and inland residence (versus coastal) were significantly associated with both total diabetes and previously undiagnosed diabetes. Furthermore, methylene- tetrahydrofolate reductase (MTHFR) 677 TT genotype was an independent associated factor for total diabetes, and current alcohol drinking was an independent associated factor for previously undiagnosed diabetes. At the same time, older age, men, abdominal obesity, non-current smoking, current alcohol drinking, a family history of diabetes, higher heart rate, and inland residence (versus coastal) were important independent associated factors for IFG. Conclusion In conclusion, we found a high prevalence of diabetes in Chinese hypertensive adults. Furthermore, about three out of every four diabetic adults were undiagnosed. Our results suggest that population-level measures aimed at the prevention, identification (even if only based on the FPG evaluation), and treatment of diabetes should be urgently taken to overcome the diabetes epidemic in Chinese hypertensive adults.

Individual and joint association of α1A-adrenergic receptor Arg347Cys polymorphism and plasma irbesartan concentration with blood pressure therapeutic response in Chinese hypertensive subjects

Individual variability in the therapeutic response to an antihypertensive drug could have a genetic basis. We investigated whether the α1A‐adrenergic receptor (α1A‐AR) Arg347Cys polymorphism is associated with the blood pressure (BP) therapeutic response to irbesartan and whether the association could be altered by the plasma irbesartan level.