Chen Liu

Common variants in or near FGF5, CYP17A1 and MTHFR genes are associated with blood pressure and hypertension in Chinese Hans

Objectives Recent genome-wide association studies have identified a number of variants influencing blood pressure. We aimed to examine whether these associations can be replicated in Chinese. Methods We genotyped eight of these variants (in or near FGF5, CYP17A1, MTHFR, ZNF652, PLCD3, ATP2B1, c10orf107) in a population-based cohort of Chinese Hans (N = 3210). Logistics regression and generalized linear analyses were applied to test for association of each variant with hypertension risk and blood pressure (BP), BMI, waistline and high-sensitivity C-reactive protein (hsCRP), respectively. Results Six variants showed directionally consistent association with blood pressure and risk of hypertension, of which four (FGF5, two in CYP17A1, MTHFR) reached significance. The associations were most pronounced for FGF5-rs16998073 [SBP: β = 1.97 mmHg/allele, P = 0.0006; DBP: β = 0.95 mmHg/allele, P = 0.0008, hypertension: odds ratio (OR) 1.36/allele, P = 0.0001]. Effect size of FGF5-rs16998073 on SBP and hypertension were significantly more pronounced in Han Chinese compared to white Europeans. None of these variants was associated with BMI, waistline or hsCRP that are the well established risk factors for hypertension. The genetic risk score, calculated as the sum of BP-increasing alleles of FGF5-rs16998073, CYP17A1-rs11191548, CYP17A1-rs1004467 and MTHFR-rs17367504, was significantly associated with increased SBP (1.16 mmHg/allele, P = 9.01E–5), DBP (0.51 mmHg/allele, P = 4.40E–4) and hypertension risk (OR = 1.22/allele, P = 2.74E–7). Conclusion Variants in or near FGF5, CYP17A1 and MTHFR contributed to variation in BP and hypertension risk. Effect sizes of these three loci tended to be larger in Chinese than in white Europeans, but more studies with larger sample size are required for a definitive conclusion.

Association of GCKR rs780094, alone or in combination with GCK rs1799884, with type 2 diabetes and related traits in a Han Chinese population

Aims/hypothesisThe GCKR rs780094 and GCK rs1799884 polymorphisms have been reported to be associated with dyslipidaemia and type 2 diabetes in white Europeans. The aim of this study was to replicate these associations in Han Chinese individuals and to identify the potential mechanisms underlying these associations.MethodsThe single nucleotide polymorphisms rs780094 and rs1799884 were genotyped in a population-based sample of Han Chinese individuals (n = 3,210) and tested for association with risk of type 2 diabetes and related phenotypes.ResultsThe GCKR rs780094 A allele was marginally associated with reduced risk of type 2 diabetes (OR 0.85, 95% CI 0.73–1.00, p value under an additive model [p(add)] = 0.05) and significantly associated with reduced risk of impaired fasting glucose (IFG) or type 2 diabetes (OR 0.86, 95% CI 0.77–0.96, p[add] = 0.0032). It was also significantly associated with decreased fasting glucose and increased HOMA of beta cell function (HOMA-B) and fasting triacylglycerol levels (p[add] = 0.0169–5.3 × 10−6), but not with HOMA of insulin sensitivity (HOMA-S). The associations with type 2 diabetes and IFG remained significant after adjustment for BMI, while adjustment for HOMA-B abolished the associations. The GCKR rs780094 was also associated with obesity and BMI, independently of its association with type 2 diabetes. The GCK rs1799884 A allele was significantly associated with decreased HOMA-B (p[add] = 0.0005), but not with type 2 diabetes or IFG. Individuals with increasing numbers of risk alleles for both variants had significantly lower HOMA-B (p[add] = 5.8 × 10−5) in the combined analysis.Conclusions/interpretationConsistent with observations in white Europeans, the GCKR rs780094 polymorphism contributes to the risk of type 2 diabetes and dyslipidaemia in Han Chinese individuals. In addition, we showed that the effect on type 2 diabetes is probably mediated through impaired beta cell function rather than through obesity.

Variants in GLIS3 and CRY2 Are Associated with Type 2 Diabetes and Impaired Fasting Glucose in Chinese Hans

Background Recent genome-wide association studies have identified a number of common variants associated with fasting glucose homeostasis and type 2 diabetes in populations of European origin. This is a replication study to examine whether such associations are also observed in Chinese Hans. Methods We genotyped nine variants in or near MADD, ADRA2A, CRY2, GLIS3, PROX1, FADS1, C2CD4B, IGF1 and IRS1 in a population-based cohort including 3,210 unrelated Chinese Hans from Beijing and Shanghai. Results We confirmed the associations of GLIS3-rs7034200 with fasting glucose (beta = 0.07 mmol/l, P = 0.03), beta cell function (HOMA-B) (beta = −3.03%, P = 0.009), and type 2 diabetes (OR [95%CI]  = 1.27 [1.09–1.49], P = 0.003) after adjustment for age, sex, region and BMI. The association for type 2 diabetes remained significant after adjusting for other diabetes related risk factors including family history of diabetes, lipid profile, medication information, hypertension and life style factors, while further adjustment for HOMA-B abolished the association. The A-allele of CRY2-rs11605924 was moderately associated with increased risk of combined IFG/type 2 diabetes (OR [95%CI]  = 1.15[1.01–1.30], P = 0.04). SNPs in or near MADD, ADRA2A, PROX1, FADS1, C2CD4B, IGF1, and IRS1 did not exhibit significant associations with type 2 diabetes or related glycemic traits (P≥0.10). Conclusions In conclusion, our results indicate the associations of GLIS3 locus with type 2 diabetes and impaired fasting glucose in Chinese Hans, partially mediated through impaired beta-cell function. In addition, we also found modest evidence for the association of CRY2-rs11605924 with combined IFG/type 2 diabetes.

MTNR1B rs10830963 is associated with fasting plasma glucose, HbA1C and impaired beta-cell function in Chinese Hans from Shanghai

BackgroundGenome-wide association studies (GWAS) in White Europeans have shown that genetic variation rs10830963 in melatonin receptor 1B gene (MTNR1B) is associated with fasting glucose and type 2 diabetes, which has also been replicated in several Asian populations. As a variant in the gene involved in the regulation of circadian rhythms, the effect of the variant on sleep status remains unknown. This study aimed to investigate the effects of MTNR1B rs10830963 on fasting glucose, type 2 diabetes and sleep status in Chinese Hans.MethodsMTNR1B rs10830963 was genotyped in a population-based cohort including 3,210 unrelated Chinese Hans from Beijing and Shanghai, and tested for associations with risk of type 2 diabetes, diabetes-related traits and sleep status.ResultsWe confirmed the associations of MTNR1B rs10830963 with fasting glucose (beta = 0.11 mmol/l, 95%CI [0.03, 0.18], P = 0.005), glycated hemoglobin (HbA1c) (beta = 0.07%, 95%CI [0.02,0.12], P = 0.004) and homeostasis model assessment of beta-cell function (HOMA-B) (beta = -5.01%, 95%CI [-8.24,-1.77], P = 0.003) in the Shanghai, but not in the Beijing subpopulation (P ≥ 0.58). The effect size of MTNR1B rs10830963 on fasting glucose in Shanghai Chinese Hans was comparable to that reported from other Asian populations. We found no evidence of associations with type 2 diabetes (OR 1.05 [0.90-1.23], P = 0.54), homeostasis model assessment of insulin sensitivity (HOMA-S) (P = 0.86) or sleep status (P ≥ 0.44).ConclusionsA common variant in MTNR1B was associated with fasting glucose, HbA1C and HOMA-B but not with sleep status in Chinese Hans from Shanghai, strengthening the role of MTNR1B rs10830963 in fasting glycemia and impaired beta-cell function.

Common variants in KCNQ1 are associated with type 2 diabetes and impaired fasting glucose in a Chinese Han population

Common variants in KCNQ1 have recently been reported to be associated with type 2 diabetes in East Asians. We aimed to examine whether these common variants (rs2074196, rs2237892, rs2237895 and rs2237897) were also associated with type 2 diabetes in a population-based cohort of 3210 Chinese Hans and to explore the underlying mechanisms. The SNPs rs2237892, rs2237895 and rs2237897 were significantly associated with type 2 diabetes (OR: 1.33-1.36, P <or= 0.0009), impaired fasting glucose (IFG) (OR: 1.16-1.19, P <or= 0.0193) and combined IFG/type 2 diabetes (OR: 1.23-1.24, P <or= 0.0004), and the corresponding population attributable risks of type 2 diabetes for the three SNPs were 32.5, 18.8 and 35.8%, respectively. However, rs2074196 showed a weak, but significant association with IFG (OR: 1.18 [1.04-1.33], P = 0.009) and combined IFG/type 2 diabetes (OR: 1.17 [1.05-1.30], P = 0.0053), as well as a trend toward association with type 2 diabetes (OR: 1.15 [0.98-1.35], P = 0.0882), suggesting a different pattern of association when compared with the other three SNPs. The four SNPs were all significantly associated with HOMA-B (P <or= 0.042) while rs2237895 and rs22378897 also showed significant association with fasting glucose (P <or= 0.012). Notably, the associations with type 2 diabetes were markedly attenuated after adjusting for HOMA-B (OR(rs2237892): 1.33 [1.05-1.68], P = 0.018; OR(rs2237895): 1.24 [1.00-1.54], P = 0.0524; OR(rs2237897): 1.22[0.98-1.53], P = 0.09). Moreover, GCCC haplotype showed similar associations with type 2 diabetes (OR: 1.48 [1.17-1.85], P = 0.0008), IFG (OR: 1.32 [1.10-1.57], P = 0.0023), combined IFG/type 2 diabetes (OR: 1.37 [1.17-1.61], P = 8.7 x 10(-5)), and lower HOMA-B values (beta = -4.41 +/- 1.62, P = 0.006). These results suggest that KCNQ1 is a major type 2 diabetes gene in the Chinese Hans and it may confer type 2 diabetes risk by impaired beta-cell function.

Combined effects of 17 common genetic variants on type 2 diabetes risk in a Han Chinese population

Aims/hypothesisThe recent advent of genome-wide association studies has considerably accelerated the identification of type 2 diabetes loci. We aimed to investigate the combined effects of multiple genetic variants, alone or in combination with conventional risk factors, on type 2 diabetes and diabetes-related traits in Han Chinese.MethodsWe genotyped 17 variants in 17 loci in a population-based Han Chinese cohort including 3,210 unrelated individuals. A genetic risk score (GRS) was calculated on the basis of these variants. The discriminatory ability was assessed by the area under the receiver operating characteristics curve.ResultsThe odds ratio for type 2 diabetes and hyperglycaemia with each GRS point (per risk allele) was 1.18 (95% CI 1.12–1.23, p = 1.3 × 10−12) and 1.12 (95% CI 1.09–1.16, p = 7.5 × 10−14), respectively. Compared with participants with GRS ≤11.0 (7.63%), those with GRS ≥19.0 (8.87%) had a 4.58-fold higher risk (95% CI 2.49–8.42) of type 2 diabetes. The GRS also showed a significant association with lower beta cell function estimated by HOMA of beta cell function (p = 8.4 × 10−10). In addition, we observed significant interactive effects between GRS and BMI on fasting glucose and HbA1c levels (p = 0.04 and p = 0.03 for interaction, respectively). Discrimination of diabetes risk was improved (p < 0.001) when the GRS was added to a model including clinical risk factors. The AUCs were 0.62 and 0.77, respectively, for the GRS and conventional clinic risk factors alone, and 0.79 when the GRS was added.Conclusions/interpretationIn this Han Chinese population, the GRS of 17 combined variants modestly but significantly improved discrimination of the conventional risk factors for type 2 diabetes.

Associations of alcohol consumption with diabetes mellitus and impaired fasting glycemia among middle-aged and elderly Chinese

BackgroundThe U-shaped relationship between alcohol consumption and diabetes mellitus was observed among western populations. However, few studies have systematically evaluated the association in Chinese. We aimed to investigate the associations of alcohol consumption with diabetes mellitus and impaired fasting glycemia (IFG) among middle-aged and elderly Chinese.MethodsWe examined 1,458 men and 1,831 women aged 50 to 70 from Beijing and Shanghai China in a cross-sectional survey. Fasting glucose, adipokines and markers of inflammation were measured. Macronutrients and alcohol consumption were assessed with standardized questionnaires.ResultsCompared with abstainers, alcohol consumption was associated with a decreased risk of having diabetes mellitus in women (OR: 0.41, 95%CI: 0.22-0.78) after controlling for socio-demographic factors, physical activity, smoking, family income, family history of cardiovascular disease or diabetes, macronutrients intake, body mass index, and markers of inflammation and adipokines. In men, both low and high alcohol consumptions were associated with increased risks of having combined diabetes and IFG (ORs 1.36 [95%CI: 1.02-1.82] and 1.50 [95%CI: 1.04-2.15], respectively]. In the multivariable stratified analyses among men, moderate drinkers who had drinking days of ≥ 5 days/week had a deceased likelihood (OR: 0.61, 95%CI: 0.37-0.98) and liquor drinkers had an increased likelihood (OR: 1.47, 95%CI: 1.09-1.98) of having combined diabetes and IFG respectively, compared with the abstainers.ConclusionsAn approximately J-shaped association was observed between alcohol consumption and combined diabetes and IFG among men compared with abstainers in Chinese. Whether moderate alcohol intake could help decrease diabetic risk among Chinese people warrants further investigation.

Association of PCSK1 rs6234 with Obesity and Related Traits in a Chinese Han Population

Background Common variants in PCSK1 have been reported to be associated with obesity in populations of European origin. We aimed to replicate this association in Chinese. Methodology/Principal Findings Two PCSK1 variants rs6234 and rs6235 (in strong LD with each other, r2 = 0.98) were genotyped in a population-based cohort of 3,210 Chinese Hans. The rs6234 was used for further association analyses with obesity and related traits. We found no significant association of rs6234 with obesity, overweight, BMI, waist circumference, or body fat percentage (P>0.05) in all participants. However, the rs6234 G-allele showed a significant association with increased risk of combined phenotype of obesity and overweight (OR 1.21[1.03–1.43], P = 0.0193) and a trend toward association with obesity (OR 1.25[0.98–1.61], P = 0.08) in men, but not in women (P≥0.29). Consistently, the rs6234 G-allele showed significant association with increased BMI (P = 0.0043), waist circumference (P = 0.008) and body fat percentage (P = 0.0131) only in men, not in women (P≥0.24). Interestingly, the rs6234 G-allele was significantly associated with increased HOMA-B (P = 0.0059) and decreased HOMA-S (P = 0.0349) in all participants. Conclusion/Significance In this study, we found modest evidence for association of the PCSK1 rs6234 with BMI and overweight in men only but not in women, which suggested that PCSK1 rs6234 might not be an important contributor to obesity in Chinese Hans. However, further studies with larger sample sizes are needed to draw a firm conclusion.

Effects of Body Fat on the Associations of High-Molecular-Weight Adiponectin, Leptin and Soluble Leptin Receptor with Metabolic Syndrome in Chinese

Background Little is known regarding the associations between high-molecular-weight (HMW-) adiponectin, leptin and soluble leptin receptor (sOB-R) and metabolic syndrome (MetS) in Chinese. Also few studies elucidate the effects of inflammation and body fat mass on the relations. Methods Plasma HMW-adiponectin, leptin and sOB-R were measured among 1055 Chinese men and women (35∼54 yrs). Whole body and trunk fat mass were determined by Dual-energy X-ray absorptiometry. MetS was defined by the updated NCEP/ATPIII criterion for Asian-Americans. Results HMW-adiponectin was inversely associated with MetS in multivariate model including fat mass index (FMI), inflammatory markers, leptin and sOB-R (OR in the highest quartile  = 0.30, 95%CI 0.18∼0.50, P<.0001). Plasma sOB-R was also inversely associated with MetS independent of body fatness and inflammatory markers, whereas the association was somewhat attenuated after adjusting HMW-adiponectin (OR for the highest quartile  = 0.78, 95%CI 0.47∼1.32, P = 0.15). In contrast, leptin was associated with increased odds of MetS independent of inflammatory markers, HMW-adiponectin, and sOB-R (OR for the highest quartile  = 2.64, 95%CI 1.35∼5.18, P = 0.006), although further adjustment for FMI abolished this association. Conclusions HMW-adiponectin exhibited strong inverse associations with MetS independent of body composition, inflammation, leptin and sOB-R; while the associations of leptin and sOB-R were largely explained by fat mass or HMW-adiponectin, respectively.

Hypertriglyceridemic waist, cytokines and hyperglycaemia in Chinese

Eur J Clin Invest 2012; 42 (10): 1100–1111