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Observational and Genetic Associations of Body Mass Index and Hepatobiliary Diseases in a Relatively Lean Chinese Population.
Pang, Y, Kartsonaki, C, Lv, J, Millwood, IY, Yu, C, Guo, Y, Chen, Y, Bian, Z, Yang, L, Chen, J, et al
JAMA network open. 2020;(10):e2018721
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Abstract
IMPORTANCE There is some support for the existence of genetic associations between adiposity and certain hepatobiliary diseases in Western populations. However, there is little evidence of such genetic associations in China, where the causes of these diseases may differ from those in Western populations and the mean body mass index (BMI) is much lower. OBJECTIVES To compare the observational associations of BMI with hepatobiliary diseases and liver biomarkers with the genetic associations between BMI and these factors and to assess whether the genetic associations of BMI with liver diseases differed by hepatitis B virus infection status. DESIGN, SETTING, AND PARTICIPANTS This cohort study used data from the prospective China Kadoorie Biobank, including 473 938 adults aged 30 to 79 years without hepatobiliary diseases at baseline from 10 diverse areas in China from June 25, 2004, to July 15, 2008. A random sample of 75 736 participants with genotyping data was included in the Mendelian randomization analysis. Follow-up was completed January 1, 2017 (median [interquartile range] length of follow-up, 10.2 [9.2-11.1] years). Data were analyzed from January to October 2019. EXPOSURES Measured BMI obtained during the baseline survey and genetically instrumented BMI derived using 92 single-nucleotide variations. MAIN OUTCOMES AND MEASURES Incident cases of hepatobiliary diseases, liver enzymes, fatty liver index, and fibrosis score. RESULTS Among 473 938 individuals (276 041 [58.2%] women), the mean (SD) age was 52 (10.9) years and mean (SD) BMI was 23.8 (3.4). Baseline BMI was associated with higher risks of chronic liver disease (adjusted risk ratio per 1-SD increase, 1.14; 95% CI, 1.11 to 1.17) and gallbladder disease (adjusted risk ratio per 1-SD increase, 1.29; 95% CI, 1.27 to 1.31), with heterogeneity by disease subtype (P < .001). Genetically instrumented BMI was associated with higher risks of chronic liver disease (risk ratio per 1-SD increase, 1.55; 95% CI, 1.08 to 2.24) and gallbladder disease (risk ratio per 1-SD increase, 1.40; 95% CI, 1.11 to 1.76), with no heterogeneity between subtypes. A meta-analysis of the genetic associations in China Kadoorie Biobank and those calculated in UK Biobank gave a risk ratio of 1.55 (95% CI, 1.30 to 1.84) for chronic liver disease and 1.42 (95% CI, 1.22 to 1.64) for gallbladder disease. In the China Kadoorie Biobank study, there were positive genetic associations of BMI with liver enzymes, steatosis, and fibrosis scores, consistent with observational associations. The genetic associations of BMI with liver diseases and biomarkers did not differ by hepatitis B virus infection status. CONCLUSIONS AND RELEVANCE In this cohort study of a relatively lean Chinese population, there were positive genetic associations of BMI with hepatobiliary diseases. These results suggest that maintaining a healthy weight through diet and physical activity may help prevent hepatobiliary diseases.
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Novel FBN1 Heterozygous Mutations Identified in Chinese Families with Marfan Syndrome.
Yao, X, Wu, J, Chen, J
Annals of clinical and laboratory science. 2019;(4):539-545
Abstract
OBJECTIVE To detect the mutations in the fibronectin-1 gene (FBN1) of four Chinese families with autosomal dominant Marfan syndrome (MFS), and to discuss the associated phenotypes. METHODS We examined ten patients, and five non-carriers, in four Chinese families with autosomal dominant Marfan syndrome (MFS) for FBN1 mutations. Comprehensive physical, ophthalmic, and cardiovascular examinations were performed on the family members. The FBN1 gene was amplified with PCR from the DNA of the patients and their relatives. The amplified products were sequenced and compared with a reference sequence from the GenBank database. The changes in the structure and function of the protein caused by the amino acid substitution were investigated with a bioinformatics analysis. RESULTS In our study, sequencing FBN1 revealed three novel mutations, and one mutation which was found earlier in 2012. One of the novel mutations is c.649T>C in exon 7, which results in the substitution tryptophan by arginine at codon 217 (p.Trp217Arg), the other is a splice defect in intron 39 (c.4816+1G>A), and the third one is c.407G>T in exon 5, which altered an amino acid at residue 136 from Cysteine to Phenylalanine (p.Cys136Phe). The recurrent mutation was c.4151T>C in exon 34, resulting in methionine being replaced by threonine (p.Met1384Thr). The occurrence of the mutations correlated strongly with the phenotypes of the patients, and no mutation was detected in the normal relatives of the affected patients. CONCLUSIONS In this study, three novel and a recurrent FBN1 mutations were detected. The results expand the mutation spectrum of FBN1, helping in the study of molecular pathogenesis of MFS and Marfan-related disorders.
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Association between tea consumption and risk of cancer: a prospective cohort study of 0.5 million Chinese adults.
Li, X, Yu, C, Guo, Y, Bian, Z, Shen, Z, Yang, L, Chen, Y, Wei, Y, Zhang, H, Qiu, Z, et al
European journal of epidemiology. 2019;(8):753-763
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Abstract
Current experimental and epidemiological studies provide inconsistent evidence toward the association between tea consumption and cancer incidence. We investigated whether tea consumption was associated with the incidence of all cancers and six leading types of cancer (lung cancer, stomach cancer, colorectal cancer, liver cancer, female breast cancer and cervix uteri cancer) among 455,981 participants aged 30-79 years in the prospective cohort China Kadoorie Biobank. Tea consumption was assessed at baseline (2004-2008) with an interviewer-administered questionnaire. Cancer cases were identified by linkage to the national health insurance system. Cox proportional hazard regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). In the present population, daily tea consumers were more likely to be current smokers and daily alcohol consumers. 22,652 incident cancers occurred during 10.1 years follow-up (5.04 cases/1000 person-years). When we restricted analyses to non-smokers and non-excessive alcohol consumers to minimize confounding, tea consumption was not associated with all cancers (daily consumers who added tea leaves > 4.0 g/day vs. less-than-weekly consumers: HR, 1.03; 95%CI, 0.93-1.13), lung cancer (HR, 1.08; CI, 0.84-1.40), colorectal cancer (HR, 1.08; CI, 0.81-1.45) and liver cancer (HR, 1.08; CI, 0.75-1.55), yet might be associated with increased risk of stomach cancer (HR, 1.46; CI, 1.07-1.99). In both less-than-daily and daily tea consumers, all cancer risk increased with the amount of tobacco smoked or alcohol consumed. Our findings suggest tea consumption may not provide preventive effect against cancer incidence.
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Genome-Wide Association Study Meta-Analysis of Long-Term Average Blood Pressure in East Asians.
Li, C, Kim, YK, Dorajoo, R, Li, H, Lee, IT, Cheng, CY, He, M, Sheu, WH, Guo, X, Ganesh, SK, et al
Circulation. Cardiovascular genetics. 2017;(2):e001527
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BACKGROUND Genome-wide single marker and gene-based meta-analyses of long-term average (LTA) blood pressure (BP) phenotypes may reveal novel findings for BP. METHODS AND RESULTS We conducted genome-wide analysis among 18 422 East Asian participants (stage 1) followed by replication study of ≤46 629 participants of European ancestry (stage 2). Significant single-nucleotide polymorphisms and genes were determined by a P<5.0×10-8 and 2.5×10-6, respectively, in joint analyses of stage-1 and stage-2 data. We identified 1 novel ARL3 variant, rs4919669 at 10q24.32, influencing LTA systolic BP (stage-1 P=5.03×10-8, stage-2 P=8.64×10-3, joint P=2.63×10-8) and mean arterial pressure (stage-1 P=3.59×10-9, stage-2 P=2.35×10-2, joint P=2.64×10-8). Three previously reported BP loci (WBP1L, NT5C2, and ATP2B1) were also identified for all BP phenotypes. Gene-based analysis provided the first robust evidence for association of KCNJ11 with LTA systolic BP (stage-1 P=8.55×10-6, stage-2 P=1.62×10-5, joint P=3.28×10-9) and mean arterial pressure (stage-1 P=9.19×10-7, stage-2 P=9.69×10-5, joint P=2.15×10-9) phenotypes. Fourteen genes (TMEM180, ACTR1A, SUFU, ARL3, SFXN2, WBP1L, CYP17A1, C10orf32, C10orf32-ASMT, AS3MT, CNNM2, and NT5C2 at 10q24.32; ATP2B1 at 12q21.33; and NCR3LG1 at 11p15.1) implicated by previous genome-wide association study meta-analyses were also identified. Among the loci identified by the previous genome-wide association study meta-analysis of LTA BP, we transethnically replicated associations of the KCNK3 marker rs1275988 at 2p23.3 with LTA systolic BP and mean arterial pressure phenotypes (P=1.27×10-4 and 3.30×10-4, respectively). CONCLUSIONS We identified 1 novel variant and 1 novel gene and present the first direct evidence of relevance of the KCNK3 locus for LTA BP among East Asians.
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Exploring causal associations of alcohol with cardiovascular and metabolic risk factors in a Chinese population using Mendelian randomization analysis.
Taylor, AE, Lu, F, Carslake, D, Hu, Z, Qian, Y, Liu, S, Chen, J, Shen, H, Smith, GD
Scientific reports. 2015;:14005
Abstract
Observational studies suggest that moderate alcohol consumption may be protective for cardiovascular disease, but results may be biased by confounding and reverse causality. Mendelian randomization, which uses genetic variants as proxies for exposures, can minimise these biases and therefore strengthen causal inference. Using a genetic variant in the ALDH2 gene associated with alcohol consumption, rs671, we performed a Mendelian randomization analysis in 1,712 diabetes cases and 2,076 controls from Nantong, China. Analyses were performed using linear and logistic regression, stratified by sex and diabetes status. The A allele of rs671 was strongly associated with reduced odds of being an alcohol drinker in all groups, but prevalence of alcohol consumption amongst females was very low. The A allele was associated with reduced systolic and diastolic blood pressure and decreased total and HDL cholesterol in males. The A allele was also associated with decreased triglyceride levels, but only robustly in diabetic males. There was no strong evidence for associations between rs671 and any outcomes in females. Our results suggest that associations of alcohol consumption with blood pressure and HDL-cholesterol are causal. Alcohol also appeared to have adverse effects on triglyceride levels, although this may be restricted to diabetics.
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Development of population pharmacokinetics model of icotinib with non-linear absorption characters in healthy Chinese volunteers to assess the CYP2C19 polymorphism and food-intake effect.
Hu, P, Chen, J, Liu, D, Zheng, X, Zhao, Q, Jiang, J
European journal of clinical pharmacology. 2015;(7):843-50
Abstract
PURPOSE Icotinib is a potent and selective inhibitor of epidermal growth factor receptors (EGFR) approved to treat non-small cell lung cancer (NSCLC). However, its high variability may impede its application. The objectives of this analysis were to assess plasma pharmacokinetics and identify covariates that may explain variability in icotinib absorption and/or disposition following single dose of icotinib in healthy volunteers. METHODS Data from two clinical studies (n = 22) were analyzed. One study was designed as three-period and Latin-squared (six sequence) trial to evaluate dose proportionality, and the other one was designed as two-way crossover trial to evaluate food effect on pharmacokinetics (PK) characters. Icotinib concentrations in plasma were analyzed using non-linear mixed-effects model (NONMEM) method. The model was used to assess influence of food, demographic characteristics, measurements of blood biochemistry, and CYP2C19 genotype on PK characters of icotinib in humans. The final model was diagnosed by goodness-of-fit plots and evaluated by visual predictive check (VPC) and bootstrap methods. RESULTS A two-compartment model with saturated absorption character was developed to capture icotinib pharmacokinetics. Typical value of clearance, distribution clearance, central volume of distribution, maximum absorption rate were 29.5 L/h, 24.9 L/h, 18.5 L, 122.2 L and 204,245 μg/h, respectively. When icotinib was administrated with food, bioavailability was estimated to be increased by 48%. Inter-occasion variability was identified to affect on maximum absorption rate constant in food-effect study. CL was identified to be significantly influenced by age, albumin concentration (ALB), and CYP2C19 genotype. No obvious bias was found by VPC and bootstrap methods. CONCLUSIONS The developed model can capture icotinib pharmacokinetics well in healthy volunteers. Food intake can increase icotinib exposure. Three covariates, age, albumin concentration, and CYP2C19 genotype, were identified to significantly affect icotinib PK profiles in healthy subjects.
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Genome-wide association study in Chinese identifies novel loci for blood pressure and hypertension.
Lu, X, Wang, L, Lin, X, Huang, J, Charles Gu, C, He, M, Shen, H, He, J, Zhu, J, Li, H, et al
Human molecular genetics. 2015;(3):865-74
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Abstract
Hypertension is a common disorder and the leading risk factor for cardiovascular disease and premature deaths worldwide. Genome-wide association studies (GWASs) in the European population have identified multiple chromosomal regions associated with blood pressure, and the identified loci altogether explain only a small fraction of the variance for blood pressure. The differences in environmental exposures and genetic background between Chinese and European populations might suggest potential different pathways of blood pressure regulation. To identify novel genetic variants affecting blood pressure variation, we conducted a meta-analysis of GWASs of blood pressure and hypertension in 11 816 subjects followed by replication studies including 69 146 additional individuals. We identified genome-wide significant (P < 5.0 × 10(-8)) associations with blood pressure, which included variants at three new loci (CACNA1D, CYP21A2, and MED13L) and a newly discovered variant near SLC4A7. We also replicated 14 previously reported loci, 8 (CASZ1, MOV10, FGF5, CYP17A1, SOX6, ATP2B1, ALDH2, and JAG1) at genome-wide significance, and 6 (FIGN, ULK4, GUCY1A3, HFE, TBX3-TBX5, and TBX3) at a suggestive level of P = 1.81 × 10(-3) to 5.16 × 10(-8). These findings provide new mechanistic insights into the regulation of blood pressure and potential targets for treatments.
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Genome-wide linkage and regional association study of blood pressure response to the cold pressor test in Han Chinese: the genetic epidemiology network of salt sensitivity study.
Yang, X, Gu, D, He, J, Hixson, JE, Rao, DC, Lu, F, Mu, J, Jaquish, CE, Chen, J, Huang, J, et al
Circulation. Cardiovascular genetics. 2014;(4):521-8
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BACKGROUND Blood pressure (BP) response to cold pressor test (CPT) is associated with increased risk of cardiovascular disease. We performed a genome-wide linkage scan and regional association analysis to identify genetic determinants of BP response to CPT. METHODS AND RESULTS A total of 1961 Chinese participants completed the CPT. Multipoint quantitative trait linkage analysis was performed, followed by single-marker and gene-based analyses of variants in promising linkage regions (logarithm of odds ≥2). A suggestive linkage signal was identified for systolic BP response to CPT at 20p13 to 20p12.3, with a maximum multipoint logarithm of odds score of 2.37. On the basis of regional association analysis with 1351 single nucleotide polymorphisms in the linkage region, we found that marker rs2326373 at 20p13 was significantly associated with mean arterial pressure responses to CPT (P=8.8×10(-6)) after false discovery rate adjustment for multiple comparisons. A similar trend was also observed for systolic BP response (P=0.03) and diastolic BP response (P=4.6×10(-5)). Results of gene-based analyses showed that variants in genes MCM8 and SLC23A2 were associated with systolic BP response to CPT (P=4.0×10(-5) and 2.7×10(-4), respectively), and variants in genes MCM8 and STK35 were associated with mean arterial pressure response to CPT (P=1.5×10(-5) and 5.0×10(-5), respectively). CONCLUSIONS Within a suggestive linkage region on chromosome 20, we identified a novel variant associated with BP responses to CPT. We also found gene-based associations of MCM8, SLC23A2, and STK35 in this region. Additional work is warranted to confirm these findings. CLINICAL TRIAL REGISTRATION URL http://www.clinicaltrials.gov; Unique identifier: NCT00721721.
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Common variants in the CDH7 gene are associated with major depressive disorder in the Han Chinese population.
Li, X, Wang, Q, He, K, Li, Z, Chen, J, Li, W, Wen, Z, Shen, J, Qiang, Y, Ji, J, et al
Behavior genetics. 2014;(2):97-101
Abstract
Cadherin-7 (CDH7) gene encodes a calcium dependent cell-cell adhesion glycoprotein. Gene loci of cadherins family have been supposed to be involved in the pathogenesis of psychiatric disorders. Recent genome-wide association study also demonstrated that CDH7 was significant associated with bipolar disorder. Due to the fact that the same genetic risk factor can be shared by different kinds of psychiatric disorders, we examined whether CDH7 is also associated with major depressive disorder (MDD) in this study, with a large Han Chinese sample set. We carried out a 2-stage case-control study to examine the association between CDH7 and MDD in the Han Chinese population. Ten tag SNPs were genotyped using Taqman technology in 1,045 MDD patients and 1,520 healthy controls. Single-nucleotide polymorphisms with significance were additionally genotyped in another independent sample set with 576 MDD cases and 576 healthy controls. Among ten genotyped SNPs, rs1444067 and rs12605720 was found to be significantly associated with MDD (rs1444067: P(allele) = 0.00571, OR 0.830, 95 % CI 0.728-0.947; rs12605720: P(allele) = 0.00321, OR 1.245, 95 % CI 1.076-1.441). We successfully replicated these two SNPs association with independent sample sets (rs1444067: P(allele) = 0.00518; rs12605720: P(allele) = 0.0227). Finally we have combined these results by a meta-analysis (rs1444067: P(allele) = 0.000174, OR 0.817; rs12605720: P(allele) = 0.000199, OR 1.255). Our results support CDH7 to be a risk factor of MDD in the Han Chinese population. However, further studies with more markers and independent samples were suggested to validate our findings.
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Genome-wide association study in Han Chinese identifies four new susceptibility loci for coronary artery disease.
Lu, X, Wang, L, Chen, S, He, L, Yang, X, Shi, Y, Cheng, J, Zhang, L, Gu, CC, Huang, J, et al
Nature genetics. 2012;(8):890-4
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Abstract
We performed a meta-analysis of 2 genome-wide association studies of coronary artery disease comprising 1,515 cases and 5,019 controls followed by replication studies in 15,460 cases and 11,472 controls, all of Chinese Han ancestry. We identify four new loci for coronary artery disease that reached the threshold of genome-wide significance (P < 5 × 10(-8)). These loci mapped in or near TTC32-WDR35, GUCY1A3, C6orf10-BTNL2 and ATP2B1. We also replicated four loci previously identified in European populations (in or near PHACTR1, TCF21, CDKN2A-CDKN2B and C12orf51). These findings provide new insights into pathways contributing to the susceptibility for coronary artery disease in the Chinese Han population.