Cumulative effect and predictive value of genetic variants associated with type 2 diabetes in Han Chinese: a case-control study.

BACKGROUND: Genome-wide association studies (GWAS) have identified dozens of single nucleotide polymorphisms (SNPs) associated with type 2 diabetes risk. We have previously confirmed the associations of genetic variants in HHEX, CDKAL1, VEGFA and FTO with type 2 diabetes in Han Chinese. However, the cumulative effect and predictive value of these GWAS identified SNPs on the risk of type 2 diabetes in Han Chinese are largely unknown. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a two-stage case-control study consisting of 2,925 cases and 3,281 controls to examine the association of 30 SNPs identified by GWAS with type 2 diabetes in Han Chinese. Significant associations were found for proxy SNPs at KCNQ1 [odds ratio (OR) = 1.41, P = 9.91 × 10-16 for rs2237897], CDKN2A/CDKN2B (OR = 1.30, P = 1.34 × 10-10 for rs10811661), CENTD2 (OR = 1.28, P = 9.88 × 10-4 for rs1552224) and SLC30A8 (OR = 1.19, P = 1.43 × 10-5 for rs13266634). We further evaluated the cumulative effect on type 2 diabetes of these 4 SNPs, in combination with 5 SNPs at HHEX, CDKAL1, VEGFA and FTO reported previously. Individuals carrying 12 or more risk alleles had a nearly 4-fold increased risk for developing type 2 diabetes compared with those carrying less than 6 risk alleles [adjusted OR = 3.68, 95% confidence interval (CI): 2.76-4.91]. Adding the genetic factors to clinical factors slightly improved the prediction of type 2 diabetes, with the area under the receiver operating characteristic curve increasing from 0.76 to 0.78. However, the difference was statistically significant (P < 0.0001). CONCLUSIONS/SIGNIFICANCE: We confirmed associations of SNPs in KCNQ1, CDKN2A/CDKN2B, CENTD2 and SLC30A8 with type 2 diabetes in Han Chinese. The utilization of genetic information may improve the accuracy of risk prediction in combination with clinical characteristics for type 2 diabetes.

Genetic variants at 10q23.33 are associated with plasma lipid levels in a Chinese population.

Plasma lipid abnormalities are implicated in the pathogenic process of type 2 diabetes. The IDE-KIF11-HHEX gene cluster on chromosome 10q23.33 has been identified as a susceptibility locus for type 2 diabetes. We hypothesized that genetic variants at 10q23.33 may be associated with plasma lipid concentrations. Seven tagging single nucleotide polymorphisms (SNPs: rs7923837, rs2488075, rs947591, rs11187146, rs5015480, rs4646957 and rs1111875) at 10q23.33 were genotyped in 3,281 subjects from a Han Chinese population, using the TaqMan OpenArray and Sequenom MassARRAY platforms. Multiple linear regression analyses showed that SNP rs7923837 in the 3'-flanking region of HHEX was significantly associated with triglyceride levels (P = 0.019, 0.031 mmol/L average decrease per minor G allele) and that rs2488075 and rs947591 in the downstream region of HHEX were significantly associated with total cholesterol levels (P = 0.041, 0.058 mmol/L average decrease per minor C allele and P = 0.018, 0.063 mmol/L average decrease per minor A allele, respectively). However, the other four SNPs (rs11187146, rs5015480, rs4646957 and rs1111875) were not significantly associated with any plasma lipid concentrations in this Chinese population. Our data suggest that genetic variants in the IDE-KIF11-HHEX gene cluster at 10q23.33 may partially explain the variation of plasma lipid levels in the Han Chinese population. Further studies are required to confirm these findings in other populations.

[Association of polymorphisms of potassium voltage-gated channel, KQT-like subfamily, member 1 and type 2 diabetes in Jiangsu province, China].

OBJECTIVE: To study the association of polymorphisms in the potassium voltage-gated channel, KQT-like subfamily,member 1(KCNQ1) gene with type 2 diabetes in Chinese population from Jiangsu province. METHODS: Subjects consisting of 2925 cases and 3281 controls were enrolled from a community based cohort study of type 2 diabetes in Wuxi in 2007 and a community based cross-sectional survey on chronic non-communicable disease in Nantong in 2009. Epidemiological questionnaire survey and physical examinations were conducted and 10 h overnight fasting blood samples of 5 ml were drawn for all subjects.Genotypes were determined by TaqMan OpenArray Genotyping System and i-PLEX Sequenom MassARRAY platform. The relationship between KCNQ1 gene polymorphism and risk of type 2 diabetes after adjustment for age,sex and body mass index (BMI) was analyzed. RESULTS: The C allele of rs2237897, rs2237892 and rs2237895 at KCNQ1 increased the risk of type 2 diabetes with adjusted OR (95%CI) value being 1.41(1.30-1.54), 1.35(1.24-1.47), 1.22(1.12-1.33) respectively (all P value < 0.05) under the additive genetic model after adjusted by age,sex and BMI. Stratification analyses in additive genetic model showed that the C allele of rs2237897 increased the risk of type 2 diabetes in subgroups stratified by age ( ≤ 56 years and > 56 years), sex (females and males), BMI (< 24 kg/m(2) and ≥ 24 kg/m(2)) with OR (95%CI) value being 1.39(1.22-1.59), 1.43(1.28-1.60), 1.40(1.26-1.55), 1.44(1.26-1.66), 1.48(1.33-1.66), 1.34(1.17-1.53) respectively (all P value< 0.05). CONCLUSION: Polymorphisms of rs2237897, rs2237892 and rs2237895 in the KCNQ1 gene were associated with occurrence of type 2 diabetes among Jiangsu province population.

Genetic variant in fat mass and obesity-associated gene associated with type 2 diabetes risk in Han Chinese.

BACKGROUND: Genome-wide association study (GWAS) has identified that rs8050136 C/A polymorphism in fat mass and obesity-associated gene (FTO) was associated with the risk of type 2 diabetes (T2D) in Europeans. But this association was abolished after adjustment for body mass index (BMI), suggesting that the effect of rs8050136 on T2D risk might be mediated by BMI in Europeans. However, the findings in subsequent studies were inconsistent among Asian populations. To determine whether rs8050136 polymorphism in FTO is independently associated with the risk of T2D in Chinese, we conducted a case-control study with 2,925 T2D patients and 3,281 controls in Han Chinese. RESULTS: Logistic regression revealed that the A allele of rs8050136 was significantly associated with an increased risk of T2D, independent of BMI (odds ratio (OR) = 1.17, 95% confidence interval (95% CI) = 1.03-1.32, p = 0.016). Meta-analysis containing 10 reported studies and our data with a total of 15,819 cases and 18,314 controls further confirmed the association between rs8050136 polymorphism and T2D risk in East Asians (OR = 1.13, 95% CI = 1.07-1.19). CONCLUSIONS: Our findings indicate that the genetic variant in FTO may contribute to T2D risk in Han Chinese and rs8050136 polymorphism may be a genetic marker for T2D susceptibility.

Genetic variants of IDE-KIF11-HHEX at 10q23.33 associated with type 2 diabetes risk: a fine-mapping study in Chinese population.

BACKGROUND: Genome-wide association studies (GWAS) in populations of European ancestry have mapped a type 2 diabetes susceptibility region to chromosome 10q23.33 containing IDE, KIF11 and HHEX genes (IDE-KIF11-HHEX), which has also been replicated in Chinese populations. However, the functional relevance for genetic variants at this locus is still unclear. It is critical to systematically assess the relationship of genetic variants in this region with the risk of type 2 diabetes. METHODOLOGY/PRINCIPAL FINDINGS: A fine-mapping study was conducted by genotyping fourteen tagging single-nucleotide polymorphisms (SNPs) in a 290-kb linkage disequilibrium (LD) region using a two-stage case-control study of type 2 diabetes in a Chinese Han population. Suggestive associations (P<0.05) observed from 1,200 cases and 1,200 controls in the first stage were further replicated in 1,725 cases and 2,081 controls in the second stage. Seven tagging SNPs were consistently associated with type 2 diabetes in both stages (P<0.05), with combined odds ratios (ORs) ranging from 1.14 to 1.33 in the combined analysis. The most significant locus was rs7923837 [OR = 1.33, 95% confidence interval (CI): 1.21-1.47] at the 3'-flanking region of HHEX gene. SNP rs1111875 was found to be another partially independent locus (OR = 1.23, 95% CI: 1.13-1.35) in this region that was associated with type 2 diabetes risk. A cumulative effect of rs7923837 and rs1111875 was observed with individuals carrying 1, 2, and 3 or 4 risk alleles having a 1.27, 1.44, and 1.73-fold increased risk, respectively, for type 2 diabetes (P for trend = 4.1E-10). CONCLUSIONS/SIGNIFICANCE: Our results confirm that genetic variants of the IDE-KIF11-HHEX region at 10q23.33 contribute to type 2 diabetes susceptibility and suggest that rs7923837 may represent the strongest signal related to type 2 diabetes risk in the Chinese Han population.

Genetic variants on chromosome 6p21.1 and 6p22.3 are associated with type 2 diabetes risk: a case-control study in Han Chinese.

Recent genome-wide association studies have identified several single nucleotide polymorphisms (SNPs) on chromosome 6p21.1 and 6p22.3 as type 2 diabetes (T2D) susceptibility loci in the European and Japanese populations. However, these SNPs have not been well evaluated in Chinese population. Here, we performed a case-control study with 2925 T2D cases and 3281 controls in a Chinese population. We used TaqMan OpenArray and Sequenom MassARRAY to genotype the four SNPs (rs4712523, rs7756992, rs4712524 and rs6931514) in CDKAL1 (cyclin-dependent kinase 5 regulatory subunit-associated protein 1-like 1) at 6p22.3 and one SNP (rs9472138) near vascular endothelial growth factor A (VEGFA) at 6p21.1. All the five SNPs were significantly associated with T2D risk with overall effects (odds ratio, OR) from 1.19 to 1.29 in the additive genetic model (rs6931514: OR=1.29, 95% confidence intervals (95% CI)=1.19-1.39, P=5.6 × 10(-10); rs7756992: OR=1.23, 95% CI=1.15-1.32, P=1.2 × 10(-8); rs4712523: OR=1.25, 95% CI=1.15-1.35, P=3.8 × 10(-8); rs4712524: OR=1.24, 95% CI=1.15-1.35, P=6.8 × 10(-8); rs9472138: OR=1.19, 95% CI=1.05-1.34, P=006). Conditional analysis identified two independent signals (rs6931514 at 6p22.3 and rs9472138 at 6p21.1) that were significantly associated with T2D. Compared with the wild homozygote of rs6931514 and rs9472138, subjects with variant alleles of the two SNPs had increased risk for T2D susceptibility in a dose-response manner (P(trend)=7.4 × 10(-12)). Our findings indicated that genetic variants of CDKAL1 and VEGFA on chromosome 6 may contribute to T2D risk in Chinese population, especially for rs9472138 at 6p21.1 identified for the first time to significantly increase the T2D risk in Chinese individuals.

[Relationship between polymorphisms of X-ray repair cross-complementing group 1 gene Arg194Trp, Arg399Gln and susceptibility of breast cancer].

OBJECTIVE: To study the relationship between two polymorphisms, Arg194Trp and Arg399Glu, of DNA repair gene X-ray repair cross-complementing group 1 (XRCC1) and the susceptibility of breast cancer in Chinese women. METHODS: A case-control study with 698 histologically-confirmed female breast cancer cases and 813 cancer-free controls frequency-matched by age and residential area was conducted, and the genotypes were determined by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assays. Logistic regression analysis was used to evaluate the odds ratios (ORs) and 95% confidence intervals (CIs) of XRCC1 Arg194Trp and Arg399Glu with susceptibility of breast cancer. A Meta-analysis was used to evaluate the association of Arg399Glu with breast cancer in Chinese women. RESULTS: The genotype frequencies of Arg/Arg, Arg/Trp, Trp/Trp, Arg/Trp + Trp/Trp of XRCC1 gene 194 locus were 48.81% (327/670), 39.85% (267/670), 11.34% (76/670), 51.19% (343/670) in cases and 48.80% (387/793), 41.99% (333/793), 9.21% (73/793), 51.20% (406/793) in controls. Compared to Arg/Arg, the adjusted ORs (95%CIs) were 0.98 (0.75 - 1.28), 1.17 (0.76 - 1.80), 1.09 (0.86 - 1.40). The frequencies of Arg/Arg, Arg/Trp, Trp/Trp, Arg/Gln + Gln/Gln of XRCC1 399 locus were 52.40% (349/666), 38.29% (255/666), 9.31%(62/666), 47.60% (317/666) in cases and 52.22% (412/789), 38.53% (304/789), 9.25% (73/789), 47.78%(377/789) in controls. Compared to Arg/Arg, the adjusted ORs (95%CIs) were 0.93(0.63 - 1.08), 0.96 (0.42 - 1.09), 0.91 (0.62 - 1.05). No significant associations were found between these two polymorphisms and breast cancer risk, also in subgroups stratified by menopause status, history of breast-feed, reproduction and taking oral contraceptives. The overall ORs (95%CIs) of 399 Arg/Trp + Trp/Trp vs Arg/Arg from Meta analysis was 0.97 (0.85 - 1.10). CONCLUSION: The XRCC1 Arg194Trp and Arg399Gln may not play an important role in the susceptibility of breast cancer in Chinese women.

The characteristics of impaired fasting glucose associated with obesity and dyslipidaemia in a Chinese population.

BACKGROUND: Different populations have diverse patterns of relationships between Impaired Fasting Glucose (IFG) and obesity and lipid markers, it is important to investigate the characteristics of associations between IFG and other related risk factors including body mass index (BMI), waist circumstance (WC), serum lipids and blood pressure (BP) in a Chinese population. METHODS: This was a case-control study of 648 IFG subjects and 1,296 controls derived from a large-scale, community-based, cross-sectional survey of 10,867 participants. Each subject received a face-to-face interview, physical examination, and blood tests, including fasting blood glucose and lipids. Student's t-test, Chi-square test, Spearman correlation and multiple logistic regressions were used for the statistical analyses. RESULTS: Fasting plasma glucose (FPG) was positively correlated with BMI, WC, systolic blood pressure (SBP), diastolic blood pressure (DBP), triglyceride (TG), and total cholesterol (TC), and was negatively correlated with high density lipoprotein-cholesterol (HDL-C) (all p < 0.05). BMI was more strongly correlated with IFG than with WC. The correlation coefficient of FPG was remarkably higher with TG (0.244) than with TC (0.134) and HDL-C (-0.192). TG was an important predictor of IFG, with odds ratios of 1.76 (95%CI: 1.31-2.36) for subjects with borderline high TG level (1.70 mmol/l < or = TG < 2.26 mmol/l) and 3.13 (95% CI: 2.50-3.91) for those with higher TG level (TG > or = 2.26 mmol/l), when comparing to subjects with TG < 1.70 mmol/l. There was a significant dose-response relationship between the number of abnormal variables and increased risk of IFG. CONCLUSIONS: In this Chinese population, both BMI and WC were important predictors of IFG. Abnormal TG as a lipid marker was more strongly associated with IFG than were TC and HDL-C. These factors should be taken into consideration simultaneously for prevention of IFG.

A tailored target intervention on influence factors of quality of life in Chinese patients with hypertension.

Studies suggested that hypertension was associated with impaired health-related quality of life and it is important to find a proper and feasible management of hypertension in the community. This study evaluates the effect of a tailored target intervention on influence factors of quality of life in Chinese patients with hypertension. A cross-sectional survey was carried out to investigate 644 patients with hypertension by using the Chinese version of the short form-36, and 195 patients were screened out to participate in the tailored target intervention. Multivariate linear regression analyses showed that age, gender, educational level, high intake of fried food, household income, attitude, knowledge, blood pressure, symptoms, serious events during the past year, duration of hypertension, and number of taking anti-hypertensive medicine were significantly correlated with quality of life. Grade-based management by community physicians and physical exercise had a positive effect on quality of life. After the 6-month intervention, the control rate of hypertension was increased from 32.0% to 39.4%, and the mean systolic and diastolic blood pressure values were significantly decreased to 137.2 and 85.7 mmHg vs. 140.9 and 87.6 mmHg at baseline, respectively. The intervention program resulted in overall improvement on total score of quality of life and mean scores of all the domains except social functioning in patients with hypertension. In view of the influence factors of quality of life, taking the tailored target intervention could not only improve the quality of life of hypertensive patients, but also effectively increase the control rate of hypertension.

[Association between calpain-10 gene polymorphism and risk of type 2 diabetes mellitus: a meta analysis].

OBJECTIVE: The purpose of this study was to approach the relation of SNP43, SNP44 locus, main haplotypes and haplotype combinations with type 2 diabetes mellitus (T2DM). METHODS: According to the theory and principles of systematic review, data from case-control studies regarding the association between calpain-10 (CAPN10) gene and T2DM were derived through electronic search of PubMed and Chinese journals databases. To gain a more precise estimation of the relationship, a stratified Meta-analysis with four subgroups was performed according to the races. Publication bias was also assessed. RESULTS: The association with T2DM in different races was evaluated. In Mongoloid race, SNP43-G allele, G/G genotype and 111/221 haplotype combination showed notable association with T2DM with ORs (95%CI) as 1.368 (1.155 - 1.620), 1.437 (1.186 - 1.741) and 2.762 (1.287 - 5.927) respectively. In Caucasoid race, SNP44-C allele, 111/111 hapotype combination showed strong relationship with T2DM with ORs (95%CI) as 1.144 (1.023 - 1.278), 1.291(1.050 - 1.586) respectively. In Hybrid race, only one positive finding was obtained which was SNP44-C allele with OR (95%CI) as 1.653 (1.025 - 2.665). CONCLUSION: SNP43-G allele, G/G genotype, 111/221 were risk factors to Mongoloid race. And SNP-C allele, 111/111 haplotype combination were risk factors to Caucasoid race, and SNP44-C allele to Hybrid race.

[Study on the prevalence rate and immunity of hepatitis B virus infection among urban adults aged over 20 years in Wuxi, Jiangsu province].

OBJECTIVE: To study the relationship on the prevalence rate of hepatitis B virus (HBV) infection and hepatitis B vaccination in urban citizens aged over 20 years old which would led to the development of strategies on HBV control. METHODS: A total of 3744 subjects from general population were randomly selected in this study. Both ELISA and radio immunoassay were used to test five items of HBV infection, including HBsAg, anti-HBs, HBeAg, anti-HBe and anti-HBc. RESULTS: The overall standardized infection rate of HBV was 51.7%, and HBsAg, anti-HBs, HBeAg, anti-HBe and anti-HBc were 4.5%, 48.5%, 0.3%, 3.5% and 51.4%, respectively. The two lowest HBsAg positive rates were found in the groups under 30 years old (2.9%) and students (2.6%). Anti-HBc rate among men was significantly higher than seen in women (P < 0.05), and showing a trend of increase with age (chi2 for trend = 256.2, P < 0.001). The standardized rates of HB vaccination in this population was 17.6% and decreasing rapidly with age (P < 0.05). People who had been vaccinated had both lower rates of HBsAg and HBV infection but higher rate of anti-HBs than those who had not (P < 0.05). CONCLUSION: HB vaccination in adults showed a reducing rate of HBV infection in the general population. Together with the enhancement of expanded program on immunization towards HB vaccination in neonates, much attention should be paid to HB vaccination in adults.