Huaixing Li

Identification of New Genetic Risk Variants for Type 2 Diabetes

Although more than 20 genetic susceptibility loci have been reported for type 2 diabetes (T2D), most reported variants have small to moderate effects and account for only a small proportion of the heritability of T2D, suggesting that the majority of inter-person genetic variation in this disease remains to be determined. We conducted a multistage, genome-wide association study (GWAS) within the Asian Consortium of Diabetes to search for T2D susceptibility markers. From 590,887 SNPs genotyped in 1,019 T2D cases and 1,710 controls selected from Chinese women in Shanghai, we selected the top 2,100 SNPs that were not in linkage disequilibrium (r2<0.2) with known T2D loci for in silico replication in three T2D GWAS conducted among European Americans, Koreans, and Singapore Chinese. The 5 most promising SNPs were genotyped in an independent set of 1,645 cases and 1,649 controls from Shanghai, and 4 of them were further genotyped in 1,487 cases and 3,316 controls from 2 additional Chinese studies. Consistent associations across all studies were found for rs1359790 (13q31.1), rs10906115 (10p13), and rs1436955 (15q22.2) with P-values (per allele OR, 95%CI) of 6.49×10−9 (1.15, 1.10–1.20), 1.45×10−8 (1.13, 1.08–1.18), and 7.14×10−7 (1.13, 1.08–1.19), respectively, in combined analyses of 9,794 cases and 14,615 controls. Our study provides strong evidence for a novel T2D susceptibility locus at 13q31.1 and the presence of new independent risk variants near regions (10p13 and 15q22.2) reported by previous GWAS.

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.

Allelochemicals released by rice roots and residues in soil

A few rice (Oryza sativa L.) varieties or rice straw produce and release allelochemicals into soil in which interfere with the growth of neighboring or successive plants. Allelopathic rice PI312777 and Huagan-1 at their early growth stages released momilactone B, 3-isopropyl-5-acetoxycyclohexene-2-one-1, and 5,7,4′-trihydroxy-3′,5′-dimethoxyflavone into soil at phytotoxic levels, but non-allelopathic rice Huajingxian did not. Both allelopathic and non-allelopathic rice residues released momilactone B and lignin-related phenolic acids (p-hydroxybenzoic, p-coumaric, ferulic, syringic and vanillic acids) into the soil during residue decomposition to inhibit successive plants. The results indicated that allelochemicals involved in rice allelopathy from living and dead plants are substantially different. Interestingly, the concentrations of the allelochemicals released from the allelopathic rice seedlings in soil increased dramatically when they were surrounded with Echinochloa crus-galli. The concentrations of the allelochemicals were over 3-fold higher in the presence of E. crus-galli than in the absence of E. crus-galli. However, the same case did not occur in non-allelopathic Huajingxian seedlings surrounded with E. crus-galli. In addition to allelochemical exudation being promoted by the presence of E. crus-galli, allelopathic rice seedlings also increased allelochemical exudation in response to exudates of germinated E. crus-galli seeds or lepidimoide, an uronic acid derivative exuded from E. crus-galli seeds. These results imply that allelopathic rice seedlings can sense certain allelochemicals released by E. crus-galli into the soil, and respond by increased production of allelochemicals inhibitory to E. crus-galli. This study suggests that rice residues of both allelopathic and non-allelopathic varieties release similar concentrations and types of allelochemicals to inhibit successive plants. In contrast, living rice plants of certain allelopathic varieties appear to be able to detect the presence of interspecific neighbors and respond by increased allelochemicals.

Anthropometric predictors of coronary heart disease in Chinese women

OBJECTIVE: To evaluate the associations of body size and fat distribution with incidence of coronary heart disease (CHD) in Chinese women.DESIGN: Population-based, prospective cohort study.SUBJECTS: A total of 67 334 women aged 40–70 y, who had no prior history of CHD, stroke, and cancer at study recruitment.MEASUREMENTS: Weight, standing and sitting heights, circumferences of waist and hip, and ratios of the anthropometric measurements. Outcome: incidence of CHD (non-fatal myocardial infarction (MI) or fatal CHD).RESULTS: After a mean follow-up of 2.5 y (168 164 person-years), there were 70 incident cases of CHD (49 non-fatal MIs and 21 CHD deaths). Body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), waist-to-standing height ratio (WHtR), waist-to-sitting height ratio (WsHtR), and conicity index were all positively associated with the risk of CHD. With the exception of WHR, all other anthropometric indexes only predicted the risk of CHD among women ≤55 y of age at enrollment. The relative risks (RRs) between extreme tertiles of BMI were 9.0 (95% CI, 2.0–41.5; P for trend=0.002) for younger women vs 1.3 (0.6–3.0; P for trend=0.83) for older women. Similarly, the RRs for WC, WHtR, WsHtR, and conicity index were 6.1 (1.8–21.4) vs 1.9 (0.6–5.4), 9.4 (2.6–33.8) vs 1.2 (0.5–3.1), 15.2 (3.3–69.1) vs 1.0 (0.4–2.5), and 7.8 (2.2–28.0) vs 0.9 (0.4–2.3) for the young and elderly, respectively. In contrast, the RR for WHR was 3.2 (1.1–9.1) for the young and 2.9 (1.0–8.4) for the elderly.CONCLUSIONS: WHR was positively associated with the risk of CHD in both younger and older women, while other anthropometrics, including BMI, were related to CHD risk primarily among younger women.

Genome-wide association study in a Chinese population identifies a susceptibility locus for type 2 diabetes at 7q32 near PAX4.

Aims/hypothesisMost genetic variants identified for type 2 diabetes have been discovered in European populations. We performed genome-wide association studies (GWAS) in a Chinese population with the aim of identifying novel variants for type 2 diabetes in Asians.MethodsWe performed a meta-analysis of three GWAS comprising 684 patients with type 2 diabetes and 955 controls of Southern Han Chinese descent. We followed up the top signals in two independent Southern Han Chinese cohorts (totalling 10,383 cases and 6,974 controls), and performed in silico replication in multiple populations.ResultsWe identified CDKN2A/B and four novel type 2 diabetes association signals with p < 1 × 10−5 from the meta-analysis. Thirteen variants within these four loci were followed up in two independent Chinese cohorts, and rs10229583 at 7q32 was found to be associated with type 2 diabetes in a combined analysis of 11,067 cases and 7,929 controls (pmeta = 2.6 × 10−8; OR [95% CI] 1.18 [1.11, 1.25]). In silico replication revealed consistent associations across multiethnic groups, including five East Asian populations (pmeta = 2.3 × 10−10) and a population of European descent (p = 8.6 × 10−3). The rs10229583 risk variant was associated with elevated fasting plasma glucose, impaired beta cell function in controls, and an earlier age at diagnosis for the cases. The novel variant lies within an islet-selective cluster of open regulatory elements. There was significant heterogeneity of effect between Han Chinese and individuals of European descent, Malaysians and Indians.Conclusions/interpretationOur study identifies rs10229583 near PAX4 as a novel locus for type 2 diabetes in Chinese and other populations and provides new insights into the pathogenesis of type 2 diabetes.

Genome-Wide Association Study Meta-Analysis Reveals Transethnic Replication of Mean Arterial and Pulse Pressure Loci

We conducted a genome-wide association study meta-analysis of mean arterial pressure and pulse pressure among 26 600 East Asian participants (stage 1) followed by replication study of up to 28 783 participants (stage 2). For novel loci, statistical significance was determined by a P<5.0×10–8 in joint analysis of stage 1 and stage 2 data. For loci reported by the previous mean arterial and pulse pressure genome-wide association study meta-analysis in Europeans, evidence of transethnic replication was determined by consistency in effect direction and a Bonferroni-corrected P<1.4×10–3. No novel loci were identified by the current study. Five independent mean arterial pressure variants demonstrated robust evidence for transethnic replication including rs17249754 at ATP2B1 (P=7.5×10–15), rs2681492 at ATP2B1 (P=3.4×10–7), rs11191593 at NT5C2 (1.1×10–6), rs3824755 at CYP17A1 (P=1.2×10–6), and rs13149993 at FGF5 (P=2.4×10–4). Two additional variants showed suggestive evidence of transethnic replication (consistency in effect direction and P<0.05), including rs319690 at MAP4 (P=0.014) and rs1173771 at NPR3 (P=0.018). For pulse pressure, robust evidence of replication was identified for 2 independent variants, including rs17249754 at ATP2B1 (P=1.2×10–5) and rs11191593 at NT5C2 (P=1.1×10–3), with suggestive evidence of replication among an additional 2 variants including rs3824755 at CYP17A1 (P=6.1×10–3) and rs2681492 at ATP2B1 (P=9.0×10–3). Replicated variants demonstrated consistency in effect sizes between East Asian and European samples, with effect size differences ranging from 0.03 to 0.24 mm Hg for mean arterial pressure and from 0.03 to 0.21 mm Hg for pulse pressure. In conclusion, we present the first evidence of transethnic replication of several mean arterial and pulse pressure loci in an East Asian population.

A meta-analysis of genome-wide association studies for adiponectin levels in East Asians identifies a novel locus near WDR11-FGFR2

Blood levels of adiponectin, an adipocyte-secreted protein correlated with metabolic and cardiovascular risks, are highly heritable. Genome-wide association (GWA) studies for adiponectin levels have identified 14 loci harboring variants associated with blood levels of adiponectin. To identify novel adiponectin-associated loci, particularly those of importance in East Asians, we conducted a meta-analysis of GWA studies for adiponectin in 7827 individuals, followed by two stages of replications in 4298 and 5954 additional individuals. We identified a novel adiponectin-associated locus on chromosome 10 near WDR11-FGFR2 (P = 3.0 × 10(-14)) and provided suggestive evidence for a locus on chromosome 12 near OR8S1-LALBA (P = 1.2 × 10(-7)). Of the adiponectin-associated loci previously described, we confirmed the association at CDH13 (P = 6.8 × 10(-165)), ADIPOQ (P = 1.8 × 10(-22)), PEPD (P = 3.6 × 10(-12)), CMIP (P = 2.1 × 10(-10)), ZNF664 (P = 2.3 × 10(-7)) and GPR109A (P = 7.4 × 10(-6)). Conditional analysis at ADIPOQ revealed a second signal with suggestive evidence of association only after conditioning on the lead SNP (Pinitial = 0.020; Pconditional = 7.0 × 10(-7)). We further confirmed the independence of two pairs of closely located loci (<2 Mb) on chromosome 16 at CMIP and CDH13, and on chromosome 12 at GPR109A and ZNF664. In addition, the newly identified signal near WDR11-FGFR2 exhibited evidence of association with triglycerides (P = 3.3 × 10(-4)), high density lipoprotein cholesterol (HDL-C, P = 4.9 × 10(-4)) and body mass index (BMI)-adjusted waist-hip ratio (P = 9.8 × 10(-3)). These findings improve our knowledge of the genetic basis of adiponectin variation, demonstrate the shared allelic architecture for adiponectin with lipids and central obesity and motivate further studies of underlying mechanisms.

Association of TMPRSS6 polymorphisms with ferritin, hemoglobin, and type 2 diabetes risk in a Chinese Han population

BACKGROUND Transmembrane protease serine 6 (TMPRSS6) regulates iron homeostasis by inhibiting the expression of hepcidin. Multiple common variants in TMPRSS6 were significantly associated with serum iron in recent genome-wide association studies, but their effects in the Chinese remain to be elucidated. OBJECTIVE The objective was to determine whether the TMPRSS6 single nucleotide polymorphisms (SNPs) rs855791(V736A) and rs4820268(D521D) were associated with blood hemoglobin and plasma ferritin concentrations and risk of type 2 diabetes in Chinese individuals. DESIGN The SNPs rs855791(V736A) and rs4820268(D521D) in the TMPRSS6 gene were genotyped and tested for their associations with plasma iron and type 2 diabetes risk in 1574 unrelated Chinese Hans from Beijing. RESULTS The 2 TMPRSS6 SNPs rs855791(V736A) and rs4820268(D521D) were both significantly associated with plasma ferritin (P ≤ 0.0058), hemoglobin (P ≤ 0.0013), iron overload risk (P ≤ 0.0068), and type 2 diabetes risk (P ≤ 0.0314). None of the associations with hemoglobin or plasma ferritin remained significant (P ≥ 0.1229) when the 2 variants were both included in one linear regression model. A haplotype carrying both iron-lowering alleles from the 2 TMPRSS SNPs showed significant associations with lower hemoglobin (P = 0.0014), lower plasma ferritin (P = 0.0027), and a reduced risk of iron overload (P = 0.0017) and of type 2 diabetes (P = 0.0277). CONCLUSIONS These findings suggest that TMPRSS6 variants were significantly associated with plasma ferritin, hemoglobin, risk of iron overload, and type 2 diabetes in Chinese Hans. The type 2 diabetes risk conferred by the TMPRSS6 SNPs is possibly mediated by plasma ferritin.

Meta-analysis of genome-wide association studies of adult height in East Asians identifies 17 novel loci

Human height is associated with risk of multiple diseases and is profoundly determined by an individuals genetic makeup and shows a high degree of ethnic heterogeneity. Large-scale genome-wide association (GWA) analyses of adult height in Europeans have identified nearly 180 genetic loci. A recent study showed high replicability of results from Europeans-based GWA studies in Asians; however, population-specific loci may exist due to distinct linkage disequilibrium patterns. We carried out a GWA meta-analysis in 93 926 individuals from East Asia. We identified 98 loci, including 17 novel and 81 previously reported loci, associated with height at P < 5 × 10(-8), together explaining 8.89% of phenotypic variance. Among the newly identified variants, 10 are commonly distributed (minor allele frequency, MAF > 5%) in Europeans, with comparable frequencies with in Asians, and 7 single-nucleotide polymorphisms are with low frequency (MAF < 5%) in Europeans. In addition, our data suggest that novel biological pathway such as the protein tyrosine phosphatase family is involved in regulation of height. The findings from this study considerably expand our knowledge of the genetic architecture of human height in Asians.

Multiple nonglycemic genomic loci are newly associated with blood level of glycated hemoglobin in East Asians.

Glycated hemoglobin A1c (HbA1c) is used as a measure of glycemic control and also as a diagnostic criterion for diabetes. To discover novel loci harboring common variants associated with HbA1c in East Asians, we conducted a meta-analysis of 13 genome-wide association studies (GWAS; N = 21,026). We replicated our findings in three additional studies comprising 11,576 individuals of East Asian ancestry. Ten variants showed associations that reached genome-wide significance in the discovery data set, of which nine (four novel variants at TMEM79 [P value = 1.3 × 10−23], HBS1L/MYB [8.5 × 10−15], MYO9B [9.0 × 10−12], and CYBA [1.1 × 10−8] as well as five variants at loci that had been previously identified [CDKAL1, G6PC2/ABCB11, GCK, ANK1, and FN3KI]) showed consistent evidence of association in replication data sets. These variants explained 1.76% of the variance in HbA1c. Several of these variants (TMEM79, HBS1L/MYB, CYBA, MYO9B, ANK1, and FN3K) showed no association with either blood glucose or type 2 diabetes. Among individuals with nondiabetic levels of fasting glucose (<7.0 mmol/L) but elevated HbA1c (≥6.5%), 36.1% had HbA1c <6.5% after adjustment for these six variants. Our East Asian GWAS meta-analysis has identified novel variants associated with HbA1c as well as demonstrated that the effects of known variants are largely transferable across ethnic groups. Variants affecting erythrocyte parameters rather than glucose metabolism may be relevant to the use of HbA1c for diagnosing diabetes in these populations.