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1.  Cardio-metabolic risk factors and prehypertension in persons without diabetes, hypertension, and cardiovascular disease 
BMC Public Health  2013;13:730.
Prehypertension has been shown to be an early risk factor of cardiovascular disease (CVD). We investigated the prevalence and pattern of cardiometabolic risk factors in prehypertension in three ethnic Asian populations in Singapore.
We examined data from Chinese (n = 1177), Malay (n = 774), and Indian (n = 985) adults aged 40–80 years who participated in three independent population based studies conducted from 2004–2011 in Singapore who were free of diabetes, hypertension and previous CVD. Prehypertension was defined as systolic blood pressure (BP) 120–139 mm Hg or diastolic BP 80–89 mm Hg. Random blood glucose, glycated haemoglobin (HbA1c), body mass index (BMI), triglycerides, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol were examined as indicators of adverse cardiometabolic profile. The association between metabolic variables and prehypertension was examined using logistic regression models adjusting for potential confounders.
The prevalence of prehypertension was 59.8% (Chinese), 68.9% (Malays) and 57.7% Indians. Higher levels of blood glucose, HbA1c and BMI were significantly associated with prehypertension in all three ethnic groups, odds ratio (95% confidence interval) of prehypertension in Chinese, Malays and Indians were: 1.42 (1.10, 1.83), 1.53 (1.05, 2.24), 1.49 (1.13, 1.98) for high-glucose; 3.50 (1.01, 12.18), 3.72 (1.29, 10.75), 2.79 (1.31, 5.94) for high-HbA1c; 1.86 (1.34, 2.56), 2.96 (2.10, 4.18), 1.68 (1.28, 2.20) for high-BMI. In addition, higher levels of LDL cholesterol in Chinese and higher levels of triglycerides were significantly associated with prehypertension. These associations persisted when metabolic variables were analysed as continuous variables.
Higher levels of blood glucose, HbA1c and BMI were associated with prehypertension in all three ethnic groups in Singapore. Screening for prehypertension and lifestyle modifications could potentially reduce the burden of CVD in otherwise healthy Asian adults living in Singapore.
PMCID: PMC3751051  PMID: 23919264
Prehypertension; Metabolic syndrome; Indian; Cardiometabolic
2.  Television screen time, but not computer use and reading time, is associated with cardio-metabolic biomarkers in a multiethnic Asian population: a cross-sectional study 
Recent evidence shows that sedentary behaviour may be an independent risk factor for cardiovascular diseases, diabetes, cancers and all-cause mortality. However, results are not consistent and different types of sedentary behaviour might have different effects on health. Thus the aim of this study was to evaluate the association between television screen time, computer/reading time and cardio-metabolic biomarkers in a multiethnic urban Asian population. We also sought to understand the potential mediators of this association.
The Singapore Prospective Study Program (2004–2007), was a cross-sectional population-based study in a multiethnic population in Singapore. We studied 3305 Singaporean adults of Chinese, Malay and Indian ethnicity who did not have pre-existing diseases and conditions that could affect their physical activity. Multiple linear regression analysis was used to assess the association of television screen time and computer/reading time with cardio-metabolic biomarkers [blood pressure, lipids, glucose, adiponectin, C reactive protein and homeostasis model assessment of insulin resistance (HOMA-IR)]. Path analysis was used to examine the role of mediators of the observed association.
Longer television screen time was significantly associated with higher systolic blood pressure, total cholesterol, triglycerides, C reactive protein, HOMA-IR, and lower adiponectin after adjustment for potential socio-demographic and lifestyle confounders. Dietary factors and body mass index, but not physical activity, were potential mediators that explained most of these associations between television screen time and cardio-metabolic biomarkers. The associations of television screen time with triglycerides and HOMA-IR were only partly explained by dietary factors and body mass index. No association was observed between computer/ reading time and worse levels of cardio-metabolic biomarkers.
In this urban Asian population, television screen time was associated with worse levels of various cardio-metabolic risk factors. This may reflect detrimental effects of television screen time on dietary habits rather than replacement of physical activity.
PMCID: PMC3680020  PMID: 23718927
Physical activity; Sedentary behaviour; Television screen time; Cardio-metabolic biomarkers
3.  Genome-wide association analyses identify multiple loci associated with central corneal thickness and keratoconus 
Lu, Yi | Vitart, Veronique | Burdon, Kathryn P | Khor, Chiea Chuen | Bykhovskaya, Yelena | Mirshahi, Alireza | Hewitt, Alex W | Koehn, Demelza | Hysi, Pirro G | Ramdas, Wishal D | Zeller, Tanja | Vithana, Eranga N | Cornes, Belinda K | Tay, Wan-Ting | Tai, E Shyong | Cheng, Ching-Yu | Liu, Jianjun | Foo, Jia-Nee | Saw, Seang Mei | Thorleifsson, Gudmar | Stefansson, Kari | Dimasi, David P | Mills, Richard A | Mountain, Jenny | Ang, Wei | Hoehn, René | Verhoeven, Virginie J M | Grus, Franz | Wolfs, Roger | Castagne, Raphaële | Lackner, Karl J | Springelkamp, Henriët | Yang, Jian | Jonasson, Fridbert | Leung, Dexter Y L | Chen, Li J | Tham, Clement C Y | Rudan, Igor | Vatavuk, Zoran | Hayward, Caroline | Gibson, Jane | Cree, Angela J | MacLeod, Alex | Ennis, Sarah | Polasek, Ozren | Campbell, Harry | Wilson, James F | Viswanathan, Ananth C | Fleck, Brian | Li, Xiaohui | Siscovick, David | Taylor, Kent D | Rotter, Jerome I | Yazar, Seyhan | Ulmer, Megan | Li, Jun | Yaspan, Brian L | Ozel, Ayse B | Richards, Julia E | Moroi, Sayoko E | Haines, Jonathan L | Kang, Jae H | Pasquale, Louis R | Allingham, R Rand | Ashley-Koch, Allison | Mitchell, Paul | Wang, Jie Jin | Wright, Alan F | Pennell, Craig | Spector, Timothy D | Young, Terri L | Klaver, Caroline C W | Martin, Nicholas G | Montgomery, Grant W | Anderson, Michael G | Aung, Tin | Willoughby, Colin E | Wiggs, Janey L | Pang, Chi P | Thorsteinsdottir, Unnur | Lotery, Andrew J | Hammond, Christopher J | van Duijn, Cornelia M | Hauser, Michael A | Rabinowitz, Yaron S | Pfeiffer, Norbert | Mackey, David A | Craig, Jamie E | Macgregor, Stuart | Wong, Tien Y
Nature genetics  2013;45(2):155-163.
Central corneal thickness (CCT) is associated with eye conditions including keratoconus and glaucoma. We performed a meta-analysis on >20,000 individuals in European and Asian populations that identified 16 new loci associated with CCT at genome-wide significance (P < 5 × 10−8). We further showed that 2 CCT-associated loci, FOXO1 and FNDC3B, conferred relatively large risks for keratoconus in 2 cohorts with 874 cases and 6,085 controls (rs2721051 near FOXO1 had odds ratio (OR) = 1.62, 95% confidence interval (CI) = 1.4–1.88, P = 2.7 × 10−10, and rs4894535 in FNDC3B had OR = 1.47, 95% CI = 1.29–1.68, P = 4.9 × 10−9). FNDC3B was also associated with primary open-angle glaucoma (P = 5.6 × 10−4; tested in 3 cohorts with 2,979 cases and 7,399 controls). Further analyses implicate the collagen and extracellular matrix pathways in the regulation of CCT.
PMCID: PMC3720123  PMID: 23291589
4.  Pathways-Driven Sparse Regression Identifies Pathways and Genes Associated with High-Density Lipoprotein Cholesterol in Two Asian Cohorts 
PLoS Genetics  2013;9(11):e1003939.
Standard approaches to data analysis in genome-wide association studies (GWAS) ignore any potential functional relationships between gene variants. In contrast gene pathways analysis uses prior information on functional structure within the genome to identify pathways associated with a trait of interest. In a second step, important single nucleotide polymorphisms (SNPs) or genes may be identified within associated pathways. The pathways approach is motivated by the fact that genes do not act alone, but instead have effects that are likely to be mediated through their interaction in gene pathways. Where this is the case, pathways approaches may reveal aspects of a trait's genetic architecture that would otherwise be missed when considering SNPs in isolation. Most pathways methods begin by testing SNPs one at a time, and so fail to capitalise on the potential advantages inherent in a multi-SNP, joint modelling approach. Here, we describe a dual-level, sparse regression model for the simultaneous identification of pathways and genes associated with a quantitative trait. Our method takes account of various factors specific to the joint modelling of pathways with genome-wide data, including widespread correlation between genetic predictors, and the fact that variants may overlap multiple pathways. We use a resampling strategy that exploits finite sample variability to provide robust rankings for pathways and genes. We test our method through simulation, and use it to perform pathways-driven gene selection in a search for pathways and genes associated with variation in serum high-density lipoprotein cholesterol levels in two separate GWAS cohorts of Asian adults. By comparing results from both cohorts we identify a number of candidate pathways including those associated with cardiomyopathy, and T cell receptor and PPAR signalling. Highlighted genes include those associated with the L-type calcium channel, adenylate cyclase, integrin, laminin, MAPK signalling and immune function.
Author Summary
Genes do not act in isolation, but interact in complex networks or pathways. By accounting for such interactions, pathways analysis methods hope to identify aspects of a disease or trait's genetic architecture that might be missed using more conventional approaches. Most existing pathways methods take a univariate approach, in which each variant within a pathway is separately tested for association with the phenotype of interest. These statistics are then combined to assess pathway significance. As a second step, further analysis can reveal important genetic variants within significant pathways. We have previously shown that a joint-modelling approach using a sparse regression model can increase the power to detect pathways influencing a quantitative trait. Here we extend this approach, and describe a method that is able to simultaneously identify pathways and genes that may be driving pathway selection. We test our method using simulations, and apply it to a study searching for pathways and genes associated with high-density lipoprotein cholesterol in two separate East Asian cohorts.
PMCID: PMC3836716  PMID: 24278029
5.  Early Retinal Arteriolar Changes and Peripheral Neuropathy in Diabetes 
Diabetes Care  2012;35(5):1098-1104.
To examine the association between early retinal arteriolar abnormalities and diabetic peripheral neuropathy (DPN).
Data from 608 people (aged 40–80 years) with diabetes from the population-based Singapore Malay Eye Study were analyzed. Participants underwent binocular two-field digital retinal photography and quantitative sensory testing. DPN was defined as an abnormal response to a monofilament or neurothesiometer test. Quantitative changes of retinal vascular caliber and arteriolar bifurcation geometry were measured using a computer-based program. Qualitative retinal signs of retinopathy and retinal arteriolar wall signs were graded by standardized methods.
DPN was present in 155 people (25.5%). After adjusting for age, sex, diabetes duration, HbA1c, cardiovascular risk factors, antihypertensive medication use, and peripheral arterial disease, people with suboptimal arteriolar caliber (odds ratio 1.94 [95% CI 1.22–3.10]), larger arteriolar branching coefficient (1.58 [1.03–2.42]), diabetic retinopathy (1.82 [1.20–2.75]), and focal arteriolar narrowing (2.92 [1.48–5.76]) were more likely to have DPN. Participants with a greater number of retinal microvascular signs were more likely to have DPN than those without retinal changes (6.11 [2.11–17.71] for two or more signs and 3.47 [1.18–10.21] for one sign compared with none).
Individuals with diabetes with early retinal arteriolar abnormalities are more likely to have DPN, independent of hyperglycemia and major vascular risk factors. These data support the hypothesis that early microvascular dysfunction, evident in the retina, is an independent risk factor for DPN.
PMCID: PMC3329839  PMID: 22374638
6.  Obesity and the Microvasculature: A Systematic Review and Meta-Analysis 
PLoS ONE  2013;8(2):e52708.
Overweight and obesity are thought to significantly influence a person's risk of cardiovascular disease, possibly via its effect on the microvasculature. Retinal vascular caliber is a surrogate marker of microvascular disease and a predictor of cardiovascular events. The aim of this systematic review and meta-analysis was to determine the association between body mass index (BMI) and retinal vascular caliber.
Methods and Findings
Relevant studies were identified by searches of the MEDLINE and EMBASE databases from 1966 to August 2011. Standardized forms were used for data extraction. Among over 44,000 individuals, obese subjects had narrower arteriolar and wider venular calibers when compared with normal weight subjects, independent of conventional cardiovascular risk factors. In adults, a 1 kg/m2 increase in BMI was associated with a difference of 0.07 μm [95% CI: −0.08; −0.06] in arteriolar caliber and 0.22 μm [95% CI: 0.21; 0.23] in venular caliber. Similar results were found for children.
Higher BMI is associated with narrower retinal arteriolar and wider venular calibers. Further prospective studies are needed to examine whether a causative relationship between BMI and retinal microcirculation exists.
PMCID: PMC3566162  PMID: 23405065
7.  Natural positive selection and north–south genetic diversity in East Asia 
Recent reports have identified a north–south cline in genetic variation in East and South-East Asia, but these studies have not formally explored the basis of these clinical differences. Understanding the origins of these variations may provide valuable insights in tracking down the functional variants in genomic regions identified by genetic association studies. Here we investigate the genetic basis of these differences with genome-wide data from the HapMap, the Human Genome Diversity Project and the Singapore Genome Variation Project. We implemented four bioinformatic measures to discover genomic regions that are considerably differentiated either between two Han Chinese populations in the north and south of China, or across 22 populations in East and South-East Asia. These measures prioritized genomic stretches with: (i) regional differences in the allelic spectrum for SNPs common to the two Han Chinese populations; (ii) differential evidence of positive selection between the two populations as quantified by integrated haplotype score (iHS) and cross-population extended haplotype homozygosity (XP-EHH); (iii) significant correlation between allele frequencies and geographical latitudes of the 22 populations. We also explored the extent of linkage disequilibrium variations in these regions, which is important in combining genetic association studies from North and South Chinese. Two of the regions that emerged are found in HLA class I and II, suggesting that the HLA imputation panel from the HapMap may not be directly applicable to every Chinese sample. This has important implications to autoimmune studies that plan to impute the classical HLA alleles to fine map the SNP association signals.
PMCID: PMC3234507  PMID: 21792231
positive selection; population genetics; clinal variation; linkage disequilibrium variation
8.  Nutrigenetics and Nutrigenomics: Viewpoints on the Current Status and Applications in Nutrition Research and Practice 
Nutrigenetics and nutrigenomics hold much promise for providing better nutritional advice to the public generally, genetic subgroups and individuals. Because nutrigenetics and nutrigenomics require a deep understanding of nutrition, genetics and biochemistry and ever new ‘omic’ technologies, it is often difficult, even for educated professionals, to appreciate their relevance to the practice of preventive approaches for optimising health, delaying onset of disease and diminishing its severity. This review discusses (i) the basic concepts, technical terms and technology involved in nutrigenetics and nutrigenomics; (ii) how this emerging knowledge can be applied to optimise health, prevent and treat diseases; (iii) how to read, understand and interpret nutrigenetic and nutrigenomic research results, and (iv) how this knowledge may potentially transform nutrition and dietetic practice, and the implications of such a transformation. This is in effect an up-to-date overview of the various aspects of nutrigenetics and nutrigenomics relevant to health practitioners who are seeking a better understanding of this new frontier in nutrition research and its potential application to dietetic practice.
PMCID: PMC3121546  PMID: 21625170
Dietetics; Nutrigenetics; Nutrigenomics; Nutrition Research; Personalised nutrition
9.  Clinical features and treatment of maturity onset diabetes of the young (MODY) 
Maturity onset diabetes of the young (MODY) is a heterogeneous group of disorders that result in β-cell dysfunction. It is rare, accounting for just 1%–2% of all diabetes. It is often misdiagnosed as type 1 or type 2 diabetes, as it is often difficult to distinguish MODY from these two forms. However, diagnosis allows appropriate individualized care, depending on the genetic etiology, and allows prognostication in family members. In this review, we discuss features of the common causes of MODY, as well as the treatment and diagnosis of MODY.
PMCID: PMC3363133  PMID: 22654519
type 1 diabetes; type 2 diabetes; HNF1A; HNF4A; HNF1B; GCK
10.  Candidate Gene Association Study for Diabetic Retinopathy in Persons with Type 2 Diabetes: The Candidate Gene Association Resource (CARe) 
Cardiovascular disease candidate genes, including genes previously associated with type 2 diabetes and diabetic nephropathy, were not associated with diabetic retinopathy, although a limited number of variants merit further investigation in larger cohorts.
To investigate whether variants in cardiovascular candidate genes, some of which have been previously associated with type 2 diabetes (T2D), diabetic retinopathy (DR), and diabetic nephropathy (DN), are associated with DR in the Candidate gene Association Resource (CARe).
Persons with T2D who were enrolled in the study (n = 2691) had fundus photography and genotyping of single nucleotide polymorphisms (SNPs) in 2000 candidate genes. Two case definitions were investigated: Early Treatment Diabetic Retinopathy Study (ETDRS) grades ≥14 and ≥30. The χ2 analyses for each CARe cohort were combined by Cochran-Mantel-Haenszel (CMH) pooling of odds ratios (ORs) and corrected for multiple hypothesis testing. Logistic regression was performed with adjustment for other DR risk factors. Results from replication in independent cohorts were analyzed with CMH meta-analysis methods.
Among 39 genes previously associated with DR, DN, or T2D, three SNPs in P-selectin (SELP) were associated with DR. The strongest association was to rs6128 (OR = 0.43, P = 0.0001, after Bonferroni correction). These associations remained significant after adjustment for DR risk factors. Among other genes examined, several variants were associated with DR with significant P values, including rs6856425 tagging α-l-iduronidase (IDUA) (P = 2.1 × 10−5, after Bonferroni correction). However, replication in independent cohorts did not reveal study-wide significant effects. The P values after replication were 0.55 and 0.10 for rs6128 and rs6856425, respectively.
Genes associated with DN, T2D, and vascular diseases do not appear to be consistently associated with DR. A few genetic variants associated with DR, particularly those in SELP and near IDUA, should be investigated in additional DR cohorts.
PMCID: PMC3183981  PMID: 21873659
11.  Association between the APOA2 promoter polymorphism and body-weight in Mediterranean and Asian populations. Replication of a gene-saturated fat interaction 
The APOA2 gene has been associated with obesity and insulin resistance (IR) in animal and human studies with controversial results. We have reported an APOA2-saturated fat interaction determining body mass index (BMI) and obesity in American populations. This work aims to extend our findings to European and Asian populations.
Cross-sectional study in 4602 subjects from 2 independent populations: A high cardiovascular risk Mediterranean population (n=907 men and women; aged 67+/−6 years) and a multiethnic Asian population (n=2506 Chinese, n=605 Malays and n=494 Asian Indians; aged 39+/−12 years), participating in a Singapore National Health Survey. Anthropometric, clinical, biochemical, lifestyle and dietary variables were determined. Homeostasis model assessment of IR (HOMA-IR) was used in Asians. We analyzed gene-diet interactions between the APOA2 −265T>C polymorphism and saturated fat intake (=22 g/d) on anthropometric measures and IR.
Frequency of CC subjects differed among populations (1%–15%). We confirmed a recessive effect of the APOA2 polymorphism, and replicated the APOA2–saturated fat interaction on body-weight. In Mediterranean individuals, the CC genotype was associated with a 6.8% greater BMI in those consuming a high (P=0.018), but not a low (P=0.316) saturated fat diet. Likewise, the CC genotype was significantly associated with higher obesity prevalence in Chinese and Asian Indians only with a high-saturated fat intake (P=0.036). We also found a significant APOA2-saturated fat interaction in determining IR in Chinese and Asian Indians (P=0.026).
The influence of the APOA2 −265T>C polymorphism on body-weight-related measures was modulated by saturated fat in Mediterranean and Asian populations.
PMCID: PMC3030929  PMID: 20975728
Obesity; gene-diet interaction; insulin resistance; saturated fat; APOA2
12.  Validity of the international physical activity questionnaire and the Singapore prospective study program physical activity questionnaire in a multiethnic urban Asian population 
Physical activity patterns of a population remain mostly assessed by the questionnaires. However, few physical activity questionnaires have been validated in Asian populations. We previously utilized a combination of different questionnaires to assess leisure time, transportation, occupational and household physical activity in the Singapore Prospective Study Program (SP2). The International Physical Activity Questionnaire (IPAQ) has been developed for a similar purpose. In this study, we compared estimates from these two questionnaires with an objective measure of physical activity in a multi-ethnic Asian population.
Physical activity was measured in 152 Chinese, Malay and Asian Indian adults using an accelerometer over five consecutive days, including a weekend. Participants completed both the physical activity questionnaire in SP2 (SP2PAQ) and IPAQ long form. 43subjects underwent a second set of measurements on average 6 months later to assess reproducibility of the questionnaires and the accelerometer measurements. Spearman correlations were used to evaluate validity and reproducibility and correlations for validity were corrected for within-person variation of accelerometer measurements. Agreement between the questionnaires and the accelerometer measurements was also evaluated using Bland Altman plots.
The corrected correlation with accelerometer estimates of energy expenditure from physical activity was better for the SP2PAQ (vigorous activity: r = 0.73; moderate activity: r = 0.27) than for the IPAQ (vigorous activity: r = 0.31; moderate activity: r = 0.15). For moderate activity, the corrected correlation between SP2PAQ and the accelerometer was higher for Chinese (r = 0.38) and Malays (r = 0.57) than for Indians (r = -0.09). Both questionnaires overestimated energy expenditure from physical activity to a greater extent at higher levels of physical activity than at lower levels of physical activity. The reproducibility for moderate activity (accelerometer: r = 0.68; IPAQ: r = 0.58; SP2PAQ: r = 0.55) and vigorous activity (accelerometer: 0.52; IPAQ: r = 0.38; SP2PAQ: r = 0.75) was moderate to high for all instruments.
The agreement between IPAQ and accelerometer measurements of energy expenditure from physical activity was poor in our Asian study population. The SP2PAQ showed good validity and reproducibility for vigorous activity, but performed less well for moderate activity particularly in Indians. Further effort is needed to develop questionnaires that better capture moderate activity in Asian populations.
PMCID: PMC3212806  PMID: 21995825
13.  Coffee and tea consumption in relation to inflammation and basal glucose metabolism in a multi-ethnic Asian population: a cross-sectional study 
Nutrition Journal  2011;10:61.
Higher coffee consumption has been associated with a lower risk of type 2 diabetes in cohort studies, but the physiological pathways through which coffee affects glucose metabolism are not fully understood. The aim of this study was to evaluate the associations between habitual coffee and tea consumption and glucose metabolism in a multi-ethnic Asian population and possible mediation by inflammation.
We cross-sectionally examined the association between coffee, green tea, black tea and Oolong tea consumption and glycemic (fasting plasma glucose, HOMA-IR, HOMA-beta, plasma HbA1c) and inflammatory (plasma adiponectin and C-reactive protein) markers in a multi-ethnic Asian population (N = 4139).
After adjusting for multiple confounders, we observed inverse associations between coffee and HOMA-IR (percent difference: - 8.8% for ≥ 3 cups/day versus rarely or never; Ptrend = 0.007), but no significant associations between coffee and inflammatory markers. Tea consumption was not associated with glycemic markers, but green tea was inversely associated with plasma C-reactive protein concentrations (percent difference: - 12.2% for ≥ 1 cup/day versus < 1 cup/week; Ptrend = 0.042).
These data provide additional evidence for a beneficial effect of habitual caffeinated coffee consumption on insulin sensitivity, and suggest that this effect is unlikely to be mediated by anti-inflammatory mechanisms.
PMCID: PMC3130641  PMID: 21631956
14.  Cholesterol-raising diterpenes in types of coffee commonly consumed in Singapore, Indonesia and India and associations with blood lipids: A survey and cross sectional study 
Nutrition Journal  2011;10:48.
To measure the content of cholesterol-raising diterpenes in coffee sold at the retailer level in Singapore, Indonesia and India and to determine the relationship of coffee consumption with lipid levels in a population-based study in Singapore.
Survey and cross-sectional study in local coffee shops in Singapore, Indonesia and India to measure the diterpene content in coffee, and a population-based study in Singapore to examine the relationship of coffee consumption and blood lipid levels. Interviews and coffee samples (n = 27) were collected from coffee shops in Singapore, Indonesia and India. In addition, 3000 men and women who were Chinese, Malay, and Indian residents of Singapore participated in a cross-sectional study.
Results and Discussion
The traditional 'sock' method of coffee preparation used in Singapore resulted in cafestol concentrations comparable to European paper drip filtered coffee (mean 0.09 ± SD 0.064 mg/cup). This amount would result in negligible predicted increases in serum cholesterol and triglyceride concentrations. Similarly low amounts of cafestol were found in Indian 'filter' coffee that used a metal mesh filter (0.05 ± 0.05 mg/cup). Coffee samples from Indonesia using the 'sock' method (0.85 ± 0.41 mg/cup) or a metal mesh filter (0.98 mg/cup) contained higher amounts of cafestol comparable to espresso coffee. Unfiltered coffee from Indonesia contained an amount of cafestol (4.43 mg/cup) similar to Scandinavian boiled, Turkish and French press coffee with substantial predicted increases in serum cholesterol (0.33 mmol/l) and triglycerides (0.20 mmol/l) concentrations for consumption of 5 cups per day. In the Singaporean population, higher coffee consumption was not substantially associated with serum lipid concentrations after adjustment for potential confounders [LDL-cholesterol: 3.07 (95% confidence interval 2.97-3.18) for <1 cup/week versus 3.12 (2.99-3.26) for ≥ 3 cups/day; p trend 0.12].
Based on the low levels of diterpenes found in traditionally prepared coffee consumed in Singapore and India, coffee consumption in these countries does not appear to be a risk factor for elevation of serum cholesterol, whereas samples tested from Indonesia showed mixed results depending on the type of preparation method used.
PMCID: PMC3115845  PMID: 21569629
15.  Adverse Associations between Visceral Adiposity, Brain Structure, and Cognitive Performance in Healthy Elderly 
The link between central adiposity and cognition has been established by indirect measures such as body mass index (BMI) or waist–hip ratio. Magnetic resonance imaging (MRI) quantification of central abdominal fat has been linked to elevated risk of cardiovascular and cerebro-vascular disease. However it is not known how quantification of visceral fat correlates with cognitive performance and measures of brain structure. We filled this gap by characterizing the relationships between MRI measures of abdominal adiposity, brain morphometry, and cognition, in healthy elderly. Methods: A total of 184 healthy community dwelling elderly subjects without cognitive impairment participated in this study. Anthropometric and biochemical markers of cardiovascular risk, neuropsychological measurements as well as MRI of the brain and abdomen fat were obtained. Abdominal images were segmented into subcutaneous adipose tissue and visceral adipose tissue (VAT) adipose tissue compartments. Brain MRI measures were analyzed quantitatively to determine total brain volume, hippocampal volume, ventricular volume, and cortical thickness. Results: VAT showed negative association with verbal memory (r = 0.21, p = 0.005) and attention (r = 0.18, p = 0.01). Higher VAT was associated with lower hippocampal volume (F = 5.39, p = 0.02) and larger ventricular volume (F = 6.07, p = 0.02). The participants in the upper quartile of VAT had the lowest hippocampal volume even after adjusting for age, gender, hypertension, and BMI (b = −0.28, p = 0.005). There was a significant age by VAT interaction for cortical thickness in the left prefrontal region. Conclusion: In healthy older adults, elevated VAT is associated with negative effects on cognition, and brain morphometry.
PMCID: PMC3171695  PMID: 21949507
cognitive aging; visceral adiposity; hippocampus; neuropsychological assessment; MRI
16.  Patterns of physical activity in different domains and implications for intervention in a multi-ethnic Asian population: a cross-sectional study 
BMC Public Health  2010;10:644.
The benefits of regular physical activity for quality of life and disease prevention have been well documented. Identification of low activity groups would facilitate interventional programs. Many studies have focussed on leisure time activity, which may not capture the spectrum of physical activity relevant to disease prevention. Furthermore, few studies have been conducted in urban Asian settings.
We evaluated physical activity in different domains (leisure time, occupational, household and transportation) and its sociodemographic determinants in 4750 adult Chinese, Malay, and Asian Indian Singaporeans. Physical activity was assessed using locally validated questionnaires.
Occupational and household activity contributed substantially more to total physical activity than leisure time or transportation activity. However, when only activity of at least moderate intensity was considered leisure time activity contributed most to total physical activity. Higher socio-economic status was associated with more leisure time activity, but less total physical activity due to reduced activity in the other domains. Chinese ethnicity was also associated with less total physical activity as a result of less activity in non-leisure time domains.
In assessing levels of physical activity and recommending changes, it is important to consider physical activity in different domains. Focus on leisure-time physical activity alone could identify the wrong groups for intervention and miss opportunities for increasing physical activity in populations.
PMCID: PMC2976750  PMID: 20973981
17.  Identification of New Genetic Risk Variants for Type 2 Diabetes 
PLoS Genetics  2010;6(9):e1001127.
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.
Author Summary
Type 2 diabetes, a complex disease affecting more than a billion people worldwide, is believed to be caused by both environmental and genetic factors. Although some studies have shown that certain genes may make some people more susceptible to type 2 diabetes than others, the genes reported to date have only a small effect and account for a small proportion of type 2 diabetes cases. Furthermore, few of these studies have been conducted in Asian populations, although Asians are known to be more susceptible to insulin resistance than people living in Western countries, and incidence of type 2 diabetes has been increasing alarmingly in Asian countries. We conducted a multi-stage study involving 9,794 type 2 diabetes cases and 14,615 controls, predominantly Asians, to discover genes related to susceptibility to type 2 diabetes. We identified 3 genetic regions that are related to increased risk of type 2 diabetes.
PMCID: PMC2940731  PMID: 20862305
18.  Genetic Variation in KCNQ1 Associates With Fasting Glucose andβ-Cell Function 
Diabetes  2009;58(6):1445-1449.
The potassium voltage-gated channel, KQT-like subfamily, member 1 (KCNQ1) has been found through a genome-wide association study to be a strong candidate for conferring susceptibility to type 2 diabetes in East Asian and European populations. Our objective was to describe the association between polymorphisms at the KCNQ1 locus with insulin resistance, β-cell function, and other type 2 diabetes–related traits in a sample of Chinese, Malays, and Asian Indians living in Singapore.
We examined the associations between four previously reported KCNQ1 single-nucleotide polymorphisms (SNPs) with type 2 diabetes–related traits in 3,734 participants from the population-based 1998 Singapore National Health Survey cohort (2,520 Chinese, 693 Malay, and 521 Asian Indians). Insulin resistance was calculated from fasting insulin and glucose using the homeostasis model assessment method, whereas pancreatic β-cell function was assessed using the corrected insulin response at 120 min (CIR120).
SNPs rs2237897, rs2237892, and rs2283228 were significantly associated with type 2 diabetes (odds ratio [OR] 1.48, P = 3 × 10−4; OR 1.38, P = 0.002; OR 1.31, P = 0.012, respectively). Within the Chinese population, the risk alleles for rs2237897, rs2237892, and rs2283228 were significantly associated with higher fasting glucose levels (P = 0.014, 0.011, and 0.034, respectively) and reduced CIR120(P = 0.007, 0.013, and 0.014, respectively). A similar trend was observed among the Malay and Asian Indian minority groups, although this did not reach statistical significance because of limited sample sizes.
The increased risk for type 2 diabetes associated with KCNQ1 is likely to be caused by a reduction in insulin secretion. Further studies will be useful to replicate these findings and to fully delineate the role of KCNQ1 and its related pathways in disease pathogenesis.
PMCID: PMC2682664  PMID: 19252135
19.  Common Missense Variant in the Glucokinase Regulatory Protein Gene Is Associated With Increased Plasma Triglyceride and C-Reactive Protein but Lower Fasting Glucose Concentrations 
Diabetes  2008;57(11):3112-3121.
OBJECTIVE—Using the genome-wide association approach, we recently identified the glucokinase regulatory protein gene (GCKR, rs780094) region as a novel quantitative trait locus for plasma triglyceride concentration in Europeans. Here, we sought to study the association of GCKR variants with metabolic phenotypes, including measures of glucose homeostasis, to evaluate the GCKR locus in samples of non-European ancestry and to fine- map across the associated genomic interval.
RESEARCH DESIGN AND METHODS—We performed association studies in 12 independent cohorts comprising >45,000 individuals representing several ancestral groups (whites from Northern and Southern Europe, whites from the U.S., African Americans from the U.S., Hispanics of Caribbean origin, and Chinese, Malays, and Asian Indians from Singapore). We conducted genetic fine-mapping across the ∼417-kb region of linkage disequilibrium spanning GCKR and 16 other genes on chromosome 2p23 by imputing untyped HapMap single nucleotide polymorphisms (SNPs) and genotyping 104 SNPs across the associated genomic interval.
RESULTS—We provide comprehensive evidence that GCKR rs780094 is associated with opposite effects on fasting plasma triglyceride (Pmeta = 3 × 10−56) and glucose (Pmeta = 1 × 10−13) concentrations. In addition, we confirmed recent reports that the same SNP is associated with C-reactive protein (CRP) level (P = 5 × 10−5). Both fine-mapping approaches revealed a common missense GCKR variant (rs1260326, Pro446Leu, 34% frequency, r2 = 0.93 with rs780094) as the strongest association signal in the region.
CONCLUSIONS—These findings point to a molecular mechanism in humans by which higher triglycerides and CRP can be coupled with lower plasma glucose concentrations and position GCKR in central pathways regulating both hepatic triglyceride and glucose metabolism.
PMCID: PMC2570409  PMID: 18678614
20.  FTO Variants Are Associated With Obesity in the Chinese and Malay Populations in Singapore 
Diabetes  2008;57(10):2851-2857.
OBJECTIVE— Association between genetic variants at the FTO locus and obesity has been consistently observed in populations of European ancestry and inconsistently in non-Europeans. The aim of this study was to examine the effects of FTO variants on obesity and type 2 diabetes in Southeast Asian populations.
RESEARCH DESIGN AND METHODS— We examined associations between nine previously reported FTO single nucleotide polymorphisms (SNPs) with obesity, type 2 diabetes, and related traits in 4,298 participants (2,919 Chinese, 785 Malays, and 594 Asian Indians) from the 1998 Singapore National Health Survey (NHS98) and 2,996 Malays from the Singapore Malay Eye Study (SiMES).
RESULTS— All nine SNPs exhibited strong linkage disequilibrium (r2 = 0.6–0.99), and minor alleles were associated with obesity in the same direction as previous studies with effect sizes ranging from 0.42 to 0.68 kg/m2 (P < 0.0001) in NHS98 Chinese, 0.65 to 0.91 kg/m2 (P < 0.02) in NHS98 Malays, and 0.52 to 0.64 kg/m2 (P < 0.0001) in SiMES Malays after adjustment for age, sex, smoking, alcohol consumption, and exercise. The variants were also associated with type 2 diabetes, though not after adjustment for BMI (with the exception of the SiMES Malays: odds ratio 1.17–1.22; P ≤ 0.026).
CONCLUSIONS— FTO variants common among European populations are associated with obesity in ethnic Chinese and Malays in Singapore. Our data do not support the hypothesis that differences in allele frequency or genetic architecture underlie the lack of association observed in some populations of Asian ancestry. Examination of gene-environment interactions involving variants at this locus may provide further insights into the role of FTO in the pathogenesis of human obesity and diabetes.
PMCID: PMC2551698  PMID: 18599522
21.  Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans 
Nature genetics  2008;40(2):189-197.
Blood concentrations of lipoproteins and lipids are heritable1 risk factors for cardiovascular disease2,3. 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 issue4) 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 disease5. Understanding the molecular, cellular and clinical consequences of the newly identified loci may inform therapy and clinical care.
PMCID: PMC2682493  PMID: 18193044
22.  Evaluation of Dietary Effects on Hepatic Lipids in High Fat and Placebo Diet Fed Rats by In Vivo MRS and LC-MS Techniques 
PLoS ONE  2014;9(3):e91436.
Background & Aims
Dietary saturated fatty acids contribute to the development of fatty liver and have pathogenic link to systemic inflammation. We investigated the effects of dietary fat towards the pathogenesis of non-alcoholic fatty liver disease by longitudinal in vivo magnetic resonance spectroscopy (MRS) and in vitro liquid chromatography coupled with mass spectrometry (LC-MS).
All measurements were performed on rats fed with high fat diet (HFD) and chow diet for twenty four weeks. Longitudinal MRS measurements were performed at the 12th, 18th and 24th weeks. Liver tissues were analyzed by LC-MS, histology and gene transcription studies after terminal in vivo experiments.
Liver fat content of HFD rats for all ages was significantly (P<0.05) higher compared to their respective chow diet fed rats. Unsaturation indices estimated from MRS and LC-MS data of chow diet fed rats were significantly higher (P<0.05) than HFD fed rats. The concentration of triglycerides 48∶1, 48∶2, 50∶1, 50∶2, 50∶3, 52∶1, 52∶2, 52∶3, 54∶3 and 54∶2 was significantly higher (P<0.05) in HFD rats. The concentration for some polyunsaturated triglycerides 54∶7, 56∶8, 56∶7, 58∶11, 58∶10, 58∶9, 58∶8 and 60∶10 was significantly higher (P<0.05) in chow diet fed rats compared to HFD rats. Lysophospholipid concentrations including LPC and LPE were higher in HFD rats at 24 weeks indicating the increased risk of diabetes. The expression of CD36, PPARα, SCD1, SREBF1 and UCP2 were significantly upregulated in HFD rats.
We demonstrated the early changes in saturated and unsaturated lipid composition in fatty liver by in vivo MRS and ex vivo LC-MS. The higher LPC concentration in HFD rats indicated a higher risk of developing diabetes. Early metabolic perturbations causing changes in lipid composition can be evaluated by the unsaturation index and correlated to the non alcoholic fatty liver disease.
PMCID: PMC3956606  PMID: 24638096
23.  Joint Effects of Known Type 2 Diabetes Susceptibility Loci in Genome-Wide Association Study of Singapore Chinese: The Singapore Chinese Health Study 
PLoS ONE  2014;9(2):e87762.
Genome-wide association studies (GWAS) have identified genetic factors in type 2 diabetes (T2D), mostly among individuals of European ancestry. We tested whether previously identified T2D-associated single nucleotide polymorphisms (SNPs) replicate and whether SNPs in regions near known T2D SNPs were associated with T2D within the Singapore Chinese Health Study.
2338 cases and 2339 T2D controls from the Singapore Chinese Health Study were genotyped for 507,509 SNPs. Imputation extended the genotyped SNPs to 7,514,461 with high estimated certainty (r2>0.8). Replication of known index SNP associations in T2D was attempted. Risk scores were computed as the sum of index risk alleles. SNPs in regions ±100 kb around each index were tested for associations with T2D in conditional fine-mapping analysis.
Of 69 index SNPs, 20 were genotyped directly and genotypes at 35 others were well imputed. Among the 55 SNPs with data, disease associations were replicated (at p<0.05) for 15 SNPs, while 32 more were directionally consistent with previous reports. Risk score was a significant predictor with a 2.03 fold higher risk CI (1.69–2.44) of T2D comparing the highest to lowest quintile of risk allele burden (p = 5.72×10−14). Two improved SNPs around index rs10923931 and 5 new candidate SNPs around indices rs10965250 and rs1111875 passed simple Bonferroni corrections for significance in conditional analysis. Nonetheless, only a small fraction (2.3% on the disease liability scale) of T2D burden in Singapore is explained by these SNPs.
While diabetes risk in Singapore Chinese involves genetic variants, most disease risk remains unexplained. Further genetic work is ongoing in the Singapore Chinese population to identify unique common variants not already seen in earlier studies. However rapid increases in T2D risk have occurred in recent decades in this population, indicating that dynamic environmental influences and possibly gene by environment interactions complicate the genetic architecture of this disease.
PMCID: PMC3919750  PMID: 24520337
24.  Impact of Measurement Error on Testing Genetic Association with Quantitative Traits 
PLoS ONE  2014;9(1):e87044.
Measurement error of a phenotypic trait reduces the power to detect genetic associations. We examined the impact of sample size, allele frequency and effect size in presence of measurement error for quantitative traits. The statistical power to detect genetic association with phenotype mean and variability was investigated analytically. The non-centrality parameter for a non-central F distribution was derived and verified using computer simulations. We obtained equivalent formulas for the cost of phenotype measurement error. Effects of differences in measurements were examined in a genome-wide association study (GWAS) of two grading scales for cataract and a replication study of genetic variants influencing blood pressure. The mean absolute difference between the analytic power and simulation power for comparison of phenotypic means and variances was less than 0.005, and the absolute difference did not exceed 0.02. To maintain the same power, a one standard deviation (SD) in measurement error of a standard normal distributed trait required a one-fold increase in sample size for comparison of means, and a three-fold increase in sample size for comparison of variances. GWAS results revealed almost no overlap in the significant SNPs (p<10−5) for the two cataract grading scales while replication results in genetic variants of blood pressure displayed no significant differences between averaged blood pressure measurements and single blood pressure measurements. We have developed a framework for researchers to quantify power in the presence of measurement error, which will be applicable to studies of phenotypes in which the measurement is highly variable.
PMCID: PMC3901720  PMID: 24475218
25.  Familial Young-Onset Diabetes, Pre-Diabetes and Cardiovascular Disease Are Associated with Genetic Variants of DACH1 in Chinese 
PLoS ONE  2014;9(1):e84770.
In Asia, young-onset type 2 diabetes (YOD) is characterized by obesity and increased risk for cardiovascular disease (CVD). In a genome-wide association study (GWAS) of 99 Chinese obese subjects with familial YOD diagnosed before 40-year-old and 101 controls, the T allele of rs1408888 in intron 1 of DACH1(Dachshund homolog 1) was associated with an odds ratio (OR) of 2.49(95% confidence intervals:1.57–3.96, P = 8.4×10−5). Amongst these subjects, we found reduced expression of DACH1 in peripheral blood mononuclear cells (PBMC) from 63 cases compared to 65 controls (P = 0.02). In a random cohort of 1468 cases and 1485 controls, amongst top 19 SNPs from GWAS, rs1408888 was associated with type 2 diabetes with a global P value of 0.0176 and confirmation in a multiethnic Asian case-control cohort (7370/7802) with an OR of 1.07(1.02–1.12, Pmeta = 0.012). In 599 Chinese non-diabetic subjects, rs1408888 was linearly associated with systolic blood pressure and insulin resistance. In a case-control cohort (n = 953/953), rs1408888 was associated with an OR of 1.54(1.07–2.22, P = 0.019) for CVD in type 2 diabetes. In an autopsy series of 173 non-diabetic cases, TT genotype of rs1408888 was associated with an OR of 3.31(1.19–9.19, P = 0.0214) and 3.27(1.25–11.07, P = 0.0184) for coronary heart disease (CHD) and coronary arteriosclerosis. Bioinformatics analysis revealed that rs1408888 lies within regulatory elements of DACH1 implicated in islet development and insulin secretion. The T allele of rs1408888 of DACH1 was associated with YOD, prediabetes and CVD in Chinese.
PMCID: PMC3896349  PMID: 24465431

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