E. Shyong Tai

Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans

Blood concentrations of lipoproteins and lipids are heritable risk factors for cardiovascular disease. Using genome-wide association data from three studies (n = 8,816 that included 2,758 individuals from the Diabetes Genetics Initiative specific to the current paper as well as 1,874 individuals from the FUSION study of type 2 diabetes and 4,184 individuals from the SardiNIA study of aging-associated variables reported in a companion paper in this issue) and targeted replication association analyses in up to 18,554 independent participants, we show that common SNPs at 18 loci are reproducibly associated with concentrations of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and/or triglycerides. Six of these loci are new (P < 5 × 10−8 for each new locus). Of the six newly identified chromosomal regions, two were associated with LDL cholesterol (1p13 near CELSR2, PSRC1 and SORT1 and 19p13 near CILP2 and PBX4), one with HDL cholesterol (1q42 in GALNT2) and five with triglycerides (7q11 near TBL2 and MLXIPL, 8q24 near TRIB1, 1q42 in GALNT2, 19p13 near CILP2 and PBX4 and 1p31 near ANGPTL3). At 1p13, the LDL-associated SNP was also strongly correlated with CELSR2, PSRC1, and SORT1 transcript levels in human liver, and a proxy for this SNP was recently shown to affect risk for coronary artery disease. Understanding the molecular, cellular and clinical consequences of the newly identified loci may inform therapy and clinical care.

SNPs in KCNQ1 are associated with susceptibility to type 2 diabetes in East Asian and European populations

We conducted a genome-wide association study using 207,097 SNP markers in Japanese individuals with type 2 diabetes and unrelated controls, and identified KCNQ1 (potassium voltage-gated channel, KQT-like subfamily, member 1) to be a strong candidate for conferring susceptibility to type 2 diabetes. We detected consistent association of a SNP in KCNQ1 (rs2283228) with the disease in several independent case-control studies (additive model P = 3.1 × 10−12; OR = 1.26, 95% CI = 1.18–1.34). Several other SNPs in the same linkage disequilibrium (LD) block were strongly associated with type 2 diabetes (additive model: rs2237895, P = 7.3 × 10−9; OR = 1.32, 95% CI = 1.20–1.45, rs2237897, P = 6.8 × 10−13; OR = 1.41, 95% CI = 1.29–1.55). The association of these SNPs with type 2 diabetes was replicated in samples from Singaporean (additive model: rs2237895, P = 8.5 × 10−3; OR = 1.14, rs2237897, P = 2.4 × 10−4; OR = 1.22) and Danish populations (additive model: rs2237895, P = 3.7 × 10−11; OR = 1.24, rs2237897, P = 1.2 × 10−4; OR = 1.36).

Genetic loci for retinal arteriolar microcirculation

Narrow arterioles in the retina have been shown to predict hypertension as well as other vascular diseases, likely through an increase in the peripheral resistance of the microcirculatory flow. In this study, we performed a genome-wide association study in 18,722 unrelated individuals of European ancestry from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium and the Blue Mountain Eye Study, to identify genetic determinants associated with variations in retinal arteriolar caliber. Retinal vascular calibers were measured on digitized retinal photographs using a standardized protocol. One variant (rs2194025 on chromosome 5q14 near the myocyte enhancer factor 2C MEF2C gene) was associated with retinal arteriolar caliber in the meta-analysis of the discovery cohorts at genome-wide significance of P-value <5×10−8. This variant was replicated in an additional 3,939 individuals of European ancestry from the Australian Twins Study and Multi-Ethnic Study of Atherosclerosis (rs2194025, P-value = 2.11×10−12 in combined meta-analysis of discovery and replication cohorts). In independent studies of modest sample sizes, no significant association was found between this variant and clinical outcomes including coronary artery disease, stroke, myocardial infarction or hypertension. In conclusion, we found one novel loci which underlie genetic variation in microvasculature which may be relevant to vascular disease. The relevance of these findings to clinical outcomes remains to be determined.

Meta-analysis of genome-wide association studies identifies eight new loci for type 2 diabetes in east Asians.

We conducted a three-stage genetic study to identify susceptibility loci for type 2 diabetes (T2D) in east Asian populations. We followed our stage 1 meta-analysis of eight T2D genome-wide association studies (6,952 cases with T2D and 11,865 controls) with a stage 2 in silico replication analysis (5,843 cases and 4,574 controls) and a stage 3 de novo replication analysis (12,284 cases and 13,172 controls). The combined analysis identified eight new T2D loci reaching genome-wide significance, which mapped in or near GLIS3, PEPD, FITM2-R3HDML-HNF4A, KCNK16, MAEA, GCC1-PAX4, PSMD6 and ZFAND3. GLIS3, which is involved in pancreatic beta cell development and insulin gene expression, is known for its association with fasting glucose levels. The evidence of an association with T2D for PEPD and HNF4A has been shown in previous studies. KCNK16 may regulate glucose-dependent insulin secretion in the pancreas. These findings, derived from an east Asian population, provide new perspectives on the etiology of T2D.

Meta-analysis of genome-wide association studies identifies common variants associated with blood pressure variation in East Asians

We conducted a meta-analysis of genome-wide association studies of systolic (SBP) and diastolic (DBP) blood pressure in 19,608 subjects of east Asian ancestry from the AGEN-BP consortium followed up with de novo genotyping (n = 10,518) and further replication (n = 20,247) in east Asian samples. We identified genome-wide significant (P < 5 × 10−8) associations with SBP or DBP, which included variants at four new loci (ST7L-CAPZA1, FIGN-GRB14, ENPEP and NPR3) and a newly discovered variant near TBX3. Among the five newly discovered variants, we obtained significant replication in the independent samples for all of these loci except NPR3. We also confirmed seven loci previously identified in populations of European descent. Moreover, at 12q24.13 near ALDH2, we observed strong association signals (P = 7.9 × 10−31 and P = 1.3 × 10−35 for SBP and DBP, respectively) with ethnic specificity. These findings provide new insights into blood pressure regulation and potential targets for intervention.

Genome-wide association study in individuals of South Asian ancestry identifies six new type 2 diabetes susceptibility loci

We carried out a genome-wide association study of type-2 diabetes (T2D) in individuals of South Asian ancestry. Our discovery set included 5,561 individuals with T2D (cases) and 14,458 controls drawn from studies in London, Pakistan and Singapore. We identified 20 independent SNPs associated with T2D at P < 10−4 for testing in a replication sample of 13,170 cases and 25,398 controls, also all of South Asian ancestry. In the combined analysis, we identified common genetic variants at six loci (GRB14, ST6GAL1, VPS26A, HMG20A, AP3S2 and HNF4A) newly associated with T2D (P = 4.1 × 10−8 to P = 1.9 × 10−11). SNPs at GRB14 were also associated with insulin sensitivity (P = 5.0 × 10−4), and SNPs at ST6GAL1 and HNF4A were also associated with pancreatic beta-cell function (P = 0.02 and P = 0.001, respectively). Our findings provide additional insight into mechanisms underlying T2D and show the potential for new discovery from genetic association studies in South Asians, a population with increased susceptibility to T2D.

Rationale and Methodology for a Population-Based Study of Eye Diseases in Malay People: The Singapore Malay Eye Study (SiMES)

Purpose: Although there are approximately 200 million people of Malay ethnicity living in Asia, the burden and risk factors of blinding eye diseases in this ethnic group are unknown. This study summarizes the rationale and study design of a population-based study of eye diseases among adult Malays in Singapore. Methods: A population-based cross-sectional study of Malays was designed in Singapore. The sampling frame consisted of all Malays aged 40–79 living in designated study areas in southwestern Singapore. From a list of 16,069 names provided by the Ministry of Home Affairs, age-stratified random sampling was used to select 5,600 names (1,400 people from each decade of 40–49, 50–59, 60–69, and 70–79 years). The target sample size for this study was 3,150 persons. Selected individuals were invited to a centralized clinic by letters, telephone calls, and home visits. Participants underwent standardized interview and assessment of blood pressure, anthropometry, presenting and best-corrected visual acuity, subjective refraction, ocular biometry, Goldmann tonometry, slit-lamp biomicroscopy, optic disc imaging, digital lens, and retinal photography. Blood and urine samples were collected for biochemical analyses and further stored for future studies. Selected participants also had gonioscopic examination, visual fields test, and assessment of ankle and brachial blood pressure to detect presence of peripheral vascular disease. Conclusions: This study provides population-based data on the prevalence of and risk factors for age-related eye diseases in people of Malay ethnicity in Singapore. Data from this study allow further understanding of the etiology and impact of eye diseases in this ethnic group.

A genome-wide association study of nasopharyngeal carcinoma identifies three new susceptibility loci

To identify genetic susceptibility loci for nasopharyngeal carcinoma (NPC), a genome-wide association study was performed using 464,328 autosomal SNPs in 1,583 NPC affected individuals (cases) and 1,894 controls of southern Chinese descent. The top 49 SNPs from the genome-wide association study were genotyped in 3,507 cases and 3,063 controls of southern Chinese descent from Guangdong and Guangxi. The seven supportive SNPs were further confirmed by transmission disequilibrium test analysis in 279 trios from Guangdong. We identified three new susceptibility loci, TNFRSF19 on 13q12 (rs9510787, Pcombined = 1.53 × 10−9, odds ratio (OR) = 1.20), MDS1-EVI1 on 3q26 (rs6774494, Pcombined = 1.34 × 10−8, OR = 0.84) and the CDKN2A-CDKN2B gene cluster on 9p21 (rs1412829, Pcombined = 4.84 × 10−7, OR = 0.78). Furthermore, we confirmed the role of HLA by revealing independent associations at rs2860580 (Pcombined = 4.88 × 10−67, OR = 0.58), rs2894207 (Pcombined = 3.42 × 10−33, OR = 0.61) and rs28421666 (Pcombined = 2.49 × 10−18, OR = 0.67). Our findings provide new insights into the pathogenesis of NPC by highlighting the involvement of pathways related to TNFRSF19 and MDS1-EVI1 in addition to HLA molecules.

Prevalence and Risk Factors for Diabetic Retinopathy : The Singapore Malay Eye Study

PURPOSE To describe the prevalence and risk factors of diabetic retinopathy in Asian Malays. DESIGN Population-based cross-sectional study. PARTICIPANTS Persons with diabetes of Malay ethnicity aged 40 to 80 years in Singapore. METHODS Diabetes mellitus was defined as random glucose of 11.1 mmol/l or more, use of diabetic medication, or a physician diagnosis of diabetes. Retinal photographs taken from both eyes were graded for diabetic retinopathy using the modified Airlie House classification system. MAIN OUTCOME MEASURES Any diabetic retinopathy, retinopathy grades, macular edema, or vision-threatening retinopathy. RESULTS Of the 3261 persons who participated in this study, 757 (23.1%) had diabetes and gradable retinal photographs. In persons with diabetes, the overall prevalence of any retinopathy was 35.0% (95% confidence interval [CI], 28.2-43.4), the overall prevalence of macular edema was 5.7% (95% CI, 3.2-9.9), and the overall prevalence of vision-threatening retinopathy was 9.0% (95% CI, 5.8-13.8). Compared with men, women had significantly higher proportions with more severe diabetic retinopathy, moderate (12% vs. 4%) and severe (3% vs. 0.2%) nonproliferative retinopathy, proliferative retinopathy (7% vs. 2%), and vision-threatening retinopathy (13% vs. 3%). In multiple logistic regression, independent risk factors for any retinopathy were longer diabetes duration (odds ratio [OR], 1.07; 95% CI, 1.04-1.09, per year increase), higher hemoglobin A1(c) (OR, 1.21; 95% CI, 1.10-1.33, per % increase), hypertension (OR, 1.85; 95% CI, 1.04-3.30), and higher pulse pressure (OR, 1.34, 95% CI, 1.19-1.51, per 10-mmHg increase); older age (OR, 0.73; 95% CI, 0.57-0.93, per decade increase) and higher total cholesterol levels (OR, 0.75; 95% CI, 0.63-0.89, per 1-mmol/l increase) were protective of any retinopathy. Vision-threatening retinopathy additionally was associated with previous stroke (OR, 3.74; 95% CI, 1.24-11.26), cardiovascular disease (OR, 2.23; 95% CI, 1.08-4.62), and chronic kidney disease (OR, 4.45; 95% CI, 2.18-9.07). Female gender was not an independent risk factor for diabetic retinopathy after adjusting for metabolic and socioeconomic risk factors. CONCLUSIONS One in 10 Malay adults with diabetes in Singapore has vision-threatening diabetic retinopathy. Risk factors for retinopathy in this population are largely similar to white populations elsewhere, suggesting that control of these risk factors may reduce both the prevalence and impact of retinopathy.

Meta-analysis identifies common variants associated with body mass index in east Asians.

Multiple genetic loci associated with obesity or body mass index (BMI) have been identified through genome-wide association studies conducted predominantly in populations of European ancestry. We performed a meta-analysis of associations between BMI and approximately 2.4 million SNPs in 27,715 east Asians, which was followed by in silico and de novo replication studies in 37,691 and 17,642 additional east Asians, respectively. We identified ten BMI-associated loci at genome-wide significance (P < 5.0 × 10−8), including seven previously identified loci (FTO, SEC16B, MC4R, GIPR-QPCTL, ADCY3-DNAJC27, BDNF and MAP2K5) and three novel loci in or near the CDKAL1, PCSK1 and GP2 genes. Three additional loci nearly reached the genome-wide significance threshold, including two previously identified loci in the GNPDA2 and TFAP2B genes and a newly identified signal near PAX6, all of which were associated with BMI with P < 5.0 × 10−7. Findings from this study may shed light on new pathways involved in obesity and demonstrate the value of conducting genetic studies in non-European populations.