Meian He

A Genome-Wide Association Study Identifies GRK5 and RASGRP1 as Type 2 Diabetes Loci in Chinese Hans

Substantial progress has been made in identification of type 2 diabetes (T2D) risk loci in the past few years, but our understanding of the genetic basis of T2D in ethnically diverse populations remains limited. We performed a genome-wide association study and a replication study in Chinese Hans comprising 8,569 T2D case subjects and 8,923 control subjects in total, from which 10 single nucleotide polymorphisms were selected for further follow-up in a de novo replication sample of 3,410 T2D case and 3,412 control subjects and an in silico replication sample of 6,952 T2D case and 11,865 control subjects. Besides confirming seven established T2D loci (CDKAL1, CDKN2A/B, KCNQ1, CDC123, GLIS3, HNF1B, and DUSP9) at genome-wide significance, we identified two novel T2D loci, including G-protein–coupled receptor kinase 5 (GRK5) (rs10886471: P = 7.1 × 10−9) and RASGRP1 (rs7403531: P = 3.9 × 10−9), of which the association signal at GRK5 seems to be specific to East Asians. In nondiabetic individuals, the T2D risk-increasing allele of RASGRP1-rs7403531 was also associated with higher HbA1c and lower homeostasis model assessment of β-cell function (P = 0.03 and 0.0209, respectively), whereas the T2D risk-increasing allele of GRK5-rs10886471 was also associated with higher fasting insulin (P = 0.0169) but not with fasting glucose. Our findings not only provide new insights into the pathophysiology of T2D, but may also shed light on the ethnic differences in T2D susceptibility.

Cohort Profile: The Dongfeng–Tongji cohort study of retired workers

China has seen rapid socio-economic and epidemiolo-gical changes over the past several decades. Economicgrowth plus shifts in environment, lifestyles and diethave increased life expectancy, but they have also ledto a higher burden of chronic, non-communicablediseases. Stroke, coronary heart disease (CHD), cancerand diabetes account for 80% of the deaths and 70%of the disability-adjusted life-years lost in China.

ABO Blood Group and Risk of Coronary Heart Disease in Two Prospective Cohort Studies

Objective—Epidemiological data regarding the association between ABO blood groups and risk of coronary heart disease (CHD) have been inconsistent. We sought to investigate the associations between ABO blood group and CHD risk in prospective cohort studies. Methods and Results—Two large, prospective cohort studies (the Nurses’ Health Study [NHS] including 62 073 women and the Health Professionals Follow-up Study [HPFS] including 27 428 men) were conducted with more than 20 years of follow-up (26 years in NHS and 24 years in HPFS). A meta-analysis was performed to summarize the associations from the present study and previous studies. In NHS, during 1 567 144 person-years of follow-up, 2055 participants developed CHD; in HPFS, 2015 participants developed CHD during 517 312 person-years of follow-up. ABO blood group was significantly associated with the risk of developing CHD in both women and men (log-rank test; P=0.0048 and 0.0002, respectively). In the combined analysis adjusted for cardiovascular risk factors, compared with participants with blood group O, those with blood groups A, B, or AB were more likely to develop CHD (adjusted hazard ratios [95% CI] for incident CHD were 1.06 [0.99–1.15], 1.15 [1.04–1.26], and 1.23 [1.11–1.36], respectively). Overall, 6.27% of the CHD cases were attributable to inheriting a non-O blood group. Meta-analysis indicated that non-O blood group had higher risk of CHD (relative risk =1.11; 95% CI, 1.05–1.18; P=0.001) compared with O blood group. Conclusion—These data suggest that ABO blood group is significantly associated with CHD risk. Compared with other blood groups, those with the blood type O have moderately lower risk of developing CHD.

Associations Between Single Nucleotide Polymorphisms on Chromosome 9p21 and Risk of Coronary Heart Disease in Chinese Han Population

Objectives—We aimed to determine whether the single nucleotide polymorphisms (SNPs) on chromosome 9p21 were associated with coronary heart disease (CHD) in a Chinese Han population. Methods and Results—We determined the genotypes of rs2383206 and rs2383207 on chromosome 9p21 in 1360 CHD patients and 1360 age- and sex-frequency–matched controls from an unrelated Chinese Han population. GG genotypes in rs2383207 occurred more frequently in CHD patients compared to controls, and the odds ratio (OR) was 1.52 (95% CI 1.13 to 2.04), after adjusting for conventional risk factors. In stratified analysis, the risk associated with the GG genotype of the two SNPs was stronger in subjects who were males, less than 60 years old, overweight, and smokers. The SNP rs2383207 had significant interactions with gender and smoking (P=0.018 and 0.037, respectively). The risk allele G of rs2383207 plus family history of CHD had a cumulative association with CHD (P for trend, 1.0×10−6); the OR for CHD was 4.59 (95% CI 2.52 to 8.37) for those with all the risk factors as compared with subjects without any of the factors. Conclusions—The SNP rs2383207 on chromosome 9p21 is significantly associated with CHD in Chinese. This SNP combined with family history has a cumulative association with CHD.

Genome-wide association study in Chinese identifies novel loci for blood pressure and hypertension

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.

Plasma levels of Hsp70 and anti-Hsp70 antibody predict risk of acute coronary syndrome

Although immune reactions against heat shock proteins have been implicated in the pathogenesis of atherosclerosis, conflicting associations between Hsp70, anti-Hsp70 antibody and coronary heart disease (CHD) have been reported. This study assessed whether there is a significant association between extracellular human Hsp70, anti-Hsp70 antibody and acute coronary syndrome (ACS) and stable angina (SA), and examined dynamic changes in Hsp70 and anti-Hsp70 antibody levels induced by acute myocardial infarction (AMI). Plasma Hsp70 and anti-Hsp70 antibody levels in 291 patients with ACS (179 AMI, 112 unstable angina), 126 patients with SA and 417 age and sex-matched healthy subjects, and in 40 patients after admission for AMI, and on day 2, 3, and 7 after the onset of AMI were determined using enzyme-linked immunosorbent assays. Hsp70 levels were significantly higher in ACS and SA and anti-Hsp70 antibody levels were only markedly lower in ACS than controls. After adjustment for traditional CHD risk factors, increasing levels of Hsp70 were significantly associated with an increased risk and severity of ACS (P for trend < 0.001), whereas increasing levels of anti-Hsp70 antibody were associated with a decreased risk of ACS (P for trend = 0.0003). High levels of Hsp70 combined with low levels of anti-Hsp70 antibody had a joint effect on the risk of ACS (OR, 5.14, 95% CI, 3.00-8.79; P < 0.0001). In patients with AMI, Hsp70 levels decreased rapidly from days 1-7 after onset, whereas anti-Hsp70 antibody levels increased in patients with AMI. These findings suggest that higher Hsp70 levels or lower anti-Hsp70 antibody levels are independently associated with a higher risk of ACS. Higher Hsp70 levels and lower anti-Hsp70 antibody levels combine to further increase this risk.

Elevated heat shock protein 60 levels are associated with higher risk of coronary heart disease in Chinese.

Background— Although heat shock protein 60 (Hsp60) is implicated in the pathogenesis of atherosclerosis, its role in coronary heart disease (CHD) is uncertain. This study explored the influence of circulating Hsp60 on CHD in a large case-control study, as well as the impact of acute myocardial infarction on Hsp60 levels in a prospective study. Methods and Results— Plasma Hsp60 and anti-Hsp60 antibody levels were determined by immunoassay. In the case-control study (1003 patients with CHD, 1003 matched control subjects), Hsp60 levels were higher in patients with CHD and were related to CHD (OR comparing extreme quartiles=4.14, P<0.0001). This association remained after adjustment for traditional risk factors (P for trend <0.0001). Individuals having high levels of Hsp60 (greater than the median of 160.24 ng/mL) and anti-Hsp60 antibody (greater than the median of 38.42 U/mL) were at a greater risk of CHD than those with low levels (OR 2.30, P<0.0001). Stronger additive effects (OR 14.04, P<0.0001) were apparent at higher Hsp60 and anti-Hsp60 antibody levels (>1000 ng/mL and greater than the median of 38.42 U/mL, respectively). The simultaneous presence of high Hsp60 and anti-Hsp60 antibody levels, current smoking, hypertension, and diabetes were cumulatively associated with CHD. Individuals who had any 4 or more of these 5 factors had an OR of 38.61 for CHD (P<0.0001) compared with individuals who had none of these factors. For the prospective study, blood was drawn from 20 patients immediately after admission for acute myocardial infarction and 2, 3, and 7 days thereafter. Hsp60 levels were significantly higher on the day of and the day after arrival than 7 days after an acute myocardial infarction (P=0.011 and P=0.026, respectively). Conclusions— Elevated Hsp60 levels are associated with an increased risk for CHD, and Hsp60 and anti-Hsp60 antibody levels combine to increase this risk. In addition, acute myocardial infarction induces Hsp60 release.

Insulin-Like Growth Factor Axis and Risk of Type 2 Diabetes in Women

IGF-I shares structural homology and in vitro metabolic activity with insulin. Laboratory models suggest that IGF-I and its binding proteins IGFBP-1 and IGFBP-2 have potentially beneficial effects on diabetes risk, whereas IGFBP-3 may have adverse effects. We therefore conducted a prospective nested case-control investigation of incident diabetes (n = 742 case subjects matched 1:1 to control subjects) and its associations with IGF-axis protein levels in the Nurses’ Health Study, a cohort of middle-aged women. The median time to diabetes was 9 years. Statistical analyses were adjusted for multiple risk factors, including insulin and C-reactive protein. Diabetes risk was fivefold lower among women with baseline IGFBP-2 levels in the top versus bottom quintile (odds ratio [OR]q5–q1 = 0.17 [95% CI 0.08–0.35]; P trend < 0.0001) and was also negatively associated with IGFBP-1 levels (ORq5–q1 = 0.37 [0.18–0.73]; P trend = 0.0009). IGFBP-3 was positively associated with diabetes (ORq5–q1 = 2.05 [1.20–3.51]; P trend = 0.002). Diabetes was not associated with total IGF-I levels, but free IGF-I and diabetes had a significant association that varied (P interaction = 0.003) by insulin levels above the median (ORq5–q1 = 0.48 [0.26–0.90]; P trend = 0.0001) versus below the median (ORq5–q1 = 2.52 [1.05–6.06]; P trend < 0.05). Thus, this prospective study found strong associations of incident diabetes with baseline levels of three IGFBPs and free IGF-I, consistent with hypotheses that the IGF axis might influence diabetes risk.

Genome-Wide Association Study Identifies Variants at the IL18-BCO2 Locus Associated With Interleukin-18 Levels

Objective—Interleukin-18 (IL-18) is a proinflammatory cytokine involved in the processes of innate and acquired immunities and associated with cardiovascular disease and type 2 diabetes. We sought to identify the common genetic variants associated with IL-18 levels. Methods and Results—We performed a 2-stage genome-wide association study among women of European ancestry from the Nurses’ Health Study (NHS) and Women’s Genome Health Study (WGHS). IL-18 levels were measured by ELISA. In the discovery stage (NHS, n=1523), 7 single-nucleotide polymorphisms (SNPs) at the IL18-BCO2 locus were associated with IL-18 concentrations at the 1×10−5 significance level. The strongest association was found for SNP rs2115763 in the BCO2 gene (P=6.31×10−8). In silico replication in WGHS (435 women) confirmed these findings. The combined analysis of the 2 studies indicated that SNPs rs2115763, rs1834481, and rs7106524 reached a genome-wide significance level (P<5×10−8). Forward selection analysis indicated that SNPs rs2115763 and rs1834481 were independently associated with IL-18 levels (P=0.0002 and 0.0006, respectively). The 2 SNPs together explained 2.9% of variation of plasma IL-18 levels. Conclusion—This study identified several novel variants at the IL18-BCO2 locus associated with IL-18 levels.

The effects of shift work on sleeping quality, hypertension and diabetes in retired workers

Background Shift work has been associated with adverse health effects by disturbing circadian rhythms. However,its potential long-term health effects and the persistent effects after leaving shifts have not been well established. Methods and Results We studied 26,463 workers from Tongji-Dongfeng Cohort in China. All the participants are retired employees of Dongfeng Motor Company. Information on demographics, occupational history and medical history were gathered through questionnaires. After adjusting potential confounders in the logistic regression models, shift work was associated with poor sleeping quality, diabetes and hypertension independently. We observed significant effects of shift work on poor sleeping quality, diabetes and hypertension; the ORs (95%CI) are 1.18 (1.09–1.27), 1.10 (1.03–1.17) and 1.05 (1.01–1.09) respectively. In the further analysis, we found elevated ORs (95%CI) for participants with poor sleeping quality, the ORs (95%CI) are 1.34 (1.08–1.60), 1.13 (1.05–1.21), 1.05 (1.03–1.07) and 1.05 (1.01–1.09) for 1–4, 5–9, 10–19, ≥20 years of shift work respectively. However, with the extension of leaving shift work duration, the effects of shift work on sleep quality gradually reduced. Conclusions Shift work may be an independent risk factor for sleeping quality, diabetes and hypertension even in retired workers. Applicable intervention strategies are needed for prevention of sleep loss, diabetes, and hypertension for shift workers.