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Recently identified susceptibility alleles from Genome-Wide Association Studies (GWAS) for breast cancer provide an option to stratify women for their breast-cancer risk based on these alleles. This may allow greater precision in targeting preventive efforts at genetically high-risk groups. Given the variation in allele frequencies between populations, the utility of such risk-stratification may vary in different populations. We examined the possibility for individualized disease risk stratification based on common breast cancer risk alleles, and its potential impact on population-based screening in a population of Asian women. We assigned allele frequencies based on available data from the Singapore Genome Variation project and tested the utility of 13 previously validated single nucleotide polymorphisms in predicting risk using simulation and originally reported relative risks. We also tested how these markers performed collectively in distinguishing risk groups and evaluated their possible use for individualized mammography screening. Our analysis suggests that the risk profile generated by 13 single nucleotide polymorphisms as identified through GWAS provides different risk profiles between ethnic groups (population genetic mean relative risk = 0.698, 0.617, 0.661, 0.743 for Caucasians, Singapore Chinese, Singaporean Malays, and Singaporean Indians, respectively) but that it does not provide sufficient discrimination to be useful in individualized prevention. Furthermore, these markers are not useful in risk stratification for population-based screening programs due to both cost and under-diagnosis of breast cancers in the general population. The clinical use of single, common, low-penetrance genes for breast cancer risk prediction in an Asian setting is currently limited.

Background: Male breast cancer is a rare disease as its incidence rate is about 0.5% to 1% of that of female breast cancer. Given its scarcity, few studies have assessed the risk and prognosis. Methods: We performed a multi-national population based study of 569,771 female breast cancer patients and 3,615 male breast cancer patients diagnosed in Denmark, Finland, Switzerland, Norway, Singapore and Sweden from 1943 to 2007. We calculated incidence and mortality as well as overall survival for both sexes. Life table analysis and Cox proportional hazard model were used to analyze the survival. Results: The overall incidence rates, adjusted to the World Standard Population, of breast cancer were 60.2 per 100,000 in women and 0.4 per 100,000 in men. Women were diagnosed with breast cancer at a younger median age (61.4 years) than men (68.9 years). Among the 203,093 patients (35%) with information on TNM stage, 50% of the women and 47% of men were classified as stage I whilst stage III and stage IV cases accounted for 11% and 20% for women and men respectively. The 5-year cumulative survival was 66.2% for women and 53.0% for men. The adjusted relative risk of death was 24% higher in men [HR 1.24 (95% CI, 1.19-1.28)] as compared to women after controlling for age and time at diagnosis. Men had an 18% higher relative risk of death [HR 1.18 (95% CI, 1.09-1.27)] compared to women after further adjustment for TNM stage. Conclusion: Male breast cancer patients have later onset and worse prognosis than female patients. This may be due to the difference in tumour characteristics and treatment. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-11-08.

BACKGROUND: Few studies have validated the effectiveness of public health interventions in reducing influenza spread in real‐life settings. We aim to validate these measures used during the 2009 pandemic. METHODS: From 22 June to 9 October 2009, we performed a prospective observational cohort study using paired serum samples and symptom review among 3 groups of Singapore military personnel. "Normal" units were subjected to prevailing pandemic response policies. "Essential" units and health care workers had additional public health interventions (eg, enhanced surveillance with isolation, segregation, personal protective equipment). Samples were tested by hemagglutination inhibition; the principal outcome was seroconversion to 2009 influenza A(H1N1). RESULTS: In total, 1015 individuals in 14 units completed the study, with 29% overall seroconversion. Seroconversion among essential units (17%) and health care workers (11%) was significantly lower than that in normal units (44%) (P = .001). Symptomatic illness attributable to influenza was also lower in essential units (5%) and health care workers (2%) than in normal units (12%) (P = .06). Adjusted for confounders, unit type was the only significant variable influencing overall seroconversion ( P < .05). From multivariate analysis within each unit, age (P < .001) and baseline antibody titer (P = .012 ) were inversely related to seroconversion risk. CONCLUSIONS: Public health measures are effective in limiting influenza transmission in closed environments.

TOC Summary: Infection was associated with occupational and nonoccupational risk factors., We describe incidence and risk factors for pandemic (H1N1) 2009 virus infection in healthcare personnel during the June–September 2009 epidemic in Singapore. Personnel contributed 3 serologic samples during June–October 2009, with seroconversion defined as a >4-fold increase in hemagglutination inhibition titers to pandemic (H1N1) 2009. Of 531 participants, 35 showed evidence of seroconversion. Seroconversion rates were highest in nurses (28/290) and lowest in allied health staff (2/116). Significant risk factors on multivariate analysis were being a nurse (adjusted odds ratio [aOR] 4.5, 95% confidence interval [CI] 1.0–19.6) and working in pandemic (H1N1) 2009 isolation wards (aOR 4.5, 95% CI 1.3–15.6). Contact with pandemic (H1N1) 2009–infected colleagues (aOR 2.5, 95% CI 0.9–6.6) and larger household size (aOR 1.2, 95% CI 1.0–1.4) were of borderline significance. Our study suggests that seroconversion was associated with occupational and nonoccupational risk factors.

Genome-wide association studies have discovered and confirmed a large number of loci that are implicated with disease susceptibility and severity. Polymorphisms that emerged from these studies are mostly indirectly associated to the phenotype, and the natural progression is to identify the causal variants that are functionally responsible for these association signals. Long stretches of high linkage disequilibrium (LD) benefitted the initial discovery phase in a genome-wide scan, allowing commercial genotyping products with imperfect coverage to detect genomic regions genuinely associated with the phenotype. However, regions of high LD confound the fine-mapping phase, as markers that are perfectly correlated to the causal variants display similar evidence of phenotypic association, hampering the process of differentiating the functional polymorphisms from neighboring surrogates. Here, we explore the potential of integrating information across different populations for narrowing the candidate region that a causal variant resides in, and compare the efficacy of this process of trans-population fine-mapping with the extent of variation in patterns of LD between the populations. In addition, we explore two different strategies for pooling data across multiple populations for the purpose of prioritizing the rankings of the causal variants. Our results clearly establish the benefits of trans-population analysis in reducing the number of possible candidates for the causal variants, particularly in genomic regions displaying strong evidence of inter-population LD variation. Directly integrating the statistical evidence by summing the test statistics outperforms the standard meta-analytic procedure. These findings have direct relevance to the design and analysis of ongoing fine-mapping studies.

Incidence of breast cancer is rising in Asian countries, and breast cancer is the most common cancer among Asian women. However, there are few recent descriptive reports on the epidemiology of breast cancer among Eastern and Southeastern Asian populations.We examined incidence trends for invasive breast cancer in women aged ≥20 years from 15 registries in Eastern (China, Japan, the Republic of Korea, Taiwan) and Southeastern Asia (the Philippines, Singapore, Thailand) for the period 1993-2002 mainly using data from Cancer Incidence in Five Continents, Volumes VIII and IX. We compared trends in annual incidence rates and age-specific incidence curves over a 10-year period. We also compared the incidence rates of Asian-Americans with the rates of their Asian counterparts.Breast cancer incidence rates increased gradually over time in all study populations. Rates were relatively high in Southeastern Asia and became progressively lower along a south-to-north gradient, with a fourfold geographic variation within the study populations. Age-specific incidence curves showed patterns that gradually changed according to incidence rates. Breast cancer incidence among Asian women living in the United States was 1.5-4 times higher than the corresponding incidence rate in the women's respective countries of origin.Breast cancer incidence is expected to continue to increase for the next 10 years in Asia and may approach rates reported among Asian-Americans. The number and mean age of breast cancer cases is expected to increase as the female Asian population ages, the prevalence of certain risk factors changes (early menarche, late menopause, low parity, late age at first live birth, and low prevalence of breastfeeding), and as Asian countries introduce mass screening programs.

Introduction: This paper examines the incidence, mortality and survival patterns among all Chinese residents with prostate cancer reported to the Singapore Cancer Registry in Singapore from 1968 to 2002 by metastatic staging. Materials and Methods: This is a retrospective population-based study including all prostate cancer cases aged over 20 reported to the Singapore Cancer Registry (SCR) from 1968 to 2002 who are Singapore Chinese residents. Follow-up was ascertained by matching with the National Death Register until 2002. Metastatic status was obtained from the SCR. Age-standardised incidence and mortality rates, as well as the 5-year relative survival ratios (RSRs), were obtained for each 5-year period and grouped by metastatic stage. A weighted linear regression was performed on the log-transformed age-standardised incidence and mortality rates over the study period. Results: In the most recent period of 1998 to 2002, the age-standardised incidence and mortality rates (per 100,000) for prostate cancer among the Chinese were 30.9 (95% CI, 29.1 to 32.8) and 9.6 (95% CI, 8.6 to 10.7), respectively. The percentage increase in the age-standardised incidence and age-standardised mortality rates per year were 5.6% and 6.0%, respectively, for all Chinese Singapore residents. There was an improvement in the 5-year RSRs for Chinese diagnosed with non-metastatic cases from 51.3% in 1973 to 1977, to 76.1% in 1998 to 2002. However, the RSR remains poor (range, 11.1% to 49.7%) for Chinese diagnosed with metastatic prostate cancer. Conclusions: Both age-standardised incidence and mortality rates for prostate cancer among Chinese Singapore residents are still on the rise especially since the 1990s. Since the 1990s, the improvement in RSRs was substantial for the Chinese non-metastatic cases. Key words: Non-metastatic, Population-based, Registry

The field of human genetic variations has progressed rapidly over the past few years. It has added much information and deepened our knowledge and understanding of the diversity of genetic variations in the human genome. This significant progress has been driven mainly by the developments of microarray and next generation sequencing technologies. The array-based methods have been widely used for large-scale copy number variation (CNV) detection in the human genome. The arrival of next generation sequencing technologies, which enabled the completion of several whole genome resequencing studies, has also resulted in a massive discovery of genetic variations. These studies have identified several hundred thousand short indels and a total of thousands of CNVs and other structural variations in the human genome. The discovery of these 'newer' types of genetic variations, indels, CNVs and copy neutral variations (inversions and translocations) has also widened the scope of genetic markers in human genetic and disease gene mapping studies. The aim of this review article is to summarize the latest developments in the discovery of human genetic variations and address the issue of inadequate coverage of genetic variations in the current genome-wide association studies, which mainly focuses on common SNPs. Finally, we also discuss the future directions in the field and their impacts on next generation genome-wide association studies.

Research on the role of copy number variations (CNVs) in the genetic risk of diseases in Asian populations has been hampered by a relative lack of reference CNV maps for Asian populations outside the East Asians. In this article, we report the population characteristics of CNVs in Chinese, Malay, and Asian Indian populations in Singapore. Using the Illumina Human 1M Beadchip array, we identify 1,174 CNV loci in these populations that corroborated with findings when the same samples were typed on the Affymetrix 6.0 platform. We identify 441 novel loci not previously reported in the Database of Genomic Variations (DGV). We observe a considerable number of loci that span all three populations and were previously unreported, as well as population-specific loci that are quite common in the respective populations. From this we observe the distribution of CNVs in the Asian Indian population to be considerably different from the Chinese and Malay populations. About half of the deletion loci and three-quarters of duplication loci overlap UCSC genes. Tens of loci show population differentiation and overlap with genes previously known to be associated with genetic risk of diseases. One of these loci is the CYP2A6 deletion, previously linked to reduced susceptibility to lung cancer. Hum Mutat 31:1–7, 2010. © 2010 Wiley-Liss, Inc.

Evolving research suggests that common and rare alleles jointly constitute the genetic landscape of complex disease. We studied the association between 43 pathway-related candidate genes with 'intermediate phenotype' (i.e. corresponding plasma protein) and diabetic nephropathy in a customised microarray of 1,536 SNPs.In this case-control study of type 2 diabetic Chinese individuals with and without diabetic nephropathy, cases (n = 545) were defined on the basis of a spot urinary albumin/creatinine ratio (ACR)113 mg/mmol; the value for controls (n = 503) was ACR3.3 mg/mmol. Genotyping was performed using Illumina GoldenGate assay.No single nucleotide polymorphism (SNP) remained significant in single locus analysis after correction for multiple testing. Therefore, we explored the best approximately 1% SNPs. Of these 13 SNPs, four clustered to a 5' end NADPH oxidase homologue 4 (NOX4) haplotype (GGCC frequency = 0.776) with estimated OR for diabetic nephropathy of 2.05 (95% CI 1.04-4.06) (heterozygous) and 2.48 (1.27-4.83) (homozygous) (p = 0.0055). The haplotype was correlated with plasma Cu/Zn superoxide dismutase (SOD) concentration, suggesting increased oxidative burden. Endothelin-1 SNP (rs1476046GA, frequency = 0.252) was correlated with plasma C-terminal pro-endothelin-1 concentrations with an estimated OR for diabetic nephropathy of (heterozygous) 1.26 (0.96-1.66) and (homozygous) 1.87 (1.13-3.12) (p = 0.0072). Nitric oxide synthase 1 (NOS1) 5' haplotype (TGTC frequency = 0.38) also revealed a suggestive association with diabetic nephropathy: heterozygous 1.26 (0.95-1.67), homozygous 1.57 (1.04-2.35) (p = 0.0073). A rare NADPH oxidase homologue 1 (NOX1)-coding non-synonymous SNP (Arg315His, frequency = 0.006) was found exclusively among cases.Our preliminary observations suggest that common haplotypes from NOX4 and endothelin-1 SNP correlated with plasma Cu/Zn SOD and C-terminal pro-endothelin-1 concentrations, respectively, and might have conferred diabetic nephropathy susceptibility. Common NOS1 and rare NOX1 variants also revealed a suggestive association with diabetic nephropathy. Future studies to validate our observation are needed.

Organophosphate (OP)-containing pesticides are widely used worldwide for domestic and industrial purposes. Studies on acute and chronic exposure to OPs have revealed numerous health effects attributed mainly to acetylcholinesterase (AChE) inhibition. The enzyme human serum paraoxonase (PON1) is involved in the detoxification of OP compounds. PON1 polymorphisms have been shown to affect susceptibility to OP exposure. We studied the effect of OP exposure on pest control workers and assessed the distribution of two common PON1 polymorphisms in our local population. The exposed group consisted of 103 workers from various pest control companies under the Singapore Pest Management Association while the 91 unexposed workers were from a lead stabilizer factory. For all workers, the mean age was 36.9 (20-70) years and the ethnic distribution was 38.1% Chinese, 44.3% Malay and 17.5% Indian. The mean+/-S.D. exposure duration among the pesticide workers was 10.4+/-8.4 years. The mean+/-S.D. RBC cholinesterase level was 18436.2+/-2078U/L and 18079.6+/-1576U/L for the exposed and unexposed groups, respectively (p=0.216). The mean+/-S.D. serum pseudocholinesterase was 11028.4+/-2867.4U/L and 9433.6+/-2022.6U/L in the exposed and unexposed groups, respectively (p0.0001). Mean paraoxonase activity was similar among Chinese and Malays (266.5 and 266.3U/L, respectively) whereas that of the Indians was significantly lower (165.6U/L). Our study showed that cholinesterase levels among the exposed were not lower than those in the unexposed group. PON1 polymorphisms differed among ethnic groups, implying that ethnicity could be an important surrogate for identifying susceptible groups in case of OP exposure. Although OP poisoning is rare among occupationally exposed workers in Singapore, this information is useful for other developing countries that have large populations of Chinese, Malays and Indians where OP exposure could be very high especially in agricultural settings.

Retinal arteriolar narrowing is a marker of microvascular damage from elevated blood pressure. Between August 2004 and June 2006, the authors examined the association between retinal vascular diameter and chronic kidney disease in a population-based cohort of 3,280 community-dwelling adults of Malay ethnicity aged 40-80 years living in Singapore. Chronic kidney disease was defined as 1) an estimated glomerular filtration rate (eGFR) of60 mL/minute/1.73 m(2) from serum creatinine or 2) the presence of micro/macroalbuminuria defined as urinary albumin:creatinine ratios ofor = 17 mg/g for men andor = 25 mg/g for women. Retinal arteriolar and venular diameters were measured and summarized as central retinal arteriolar equivalent (CRAE) and central retinal venular equivalent (CRVE). Individuals with reduced CRAE were more likely to have chronic kidney disease than those with increased CRAE. After controlling for age, gender, education, smoking, diabetes, hypertension, body mass index, and total and high density lipoprotein cholesterol, the authors found the odds ratio comparing the smallest with the largest CRAE quartile to be 1.42 (95% confidence interval: 1.03, 1.96; P(trend) = 0.02) for eGFR of60 mL/minute/1.73 m(2) and 1.80 (95% confidence interval: 1.11, 2.91; P(trend) = 0.01) for micro/macroalbuminuria. Retinopathy was also found to be positively associated with both eGFR and micro/macroalbuminuria. Retinal venular diameter was not associated with chronic kidney disease. These data suggest that retinal arteriolar narrowing is associated with chronic kidney disease, independent of diabetes and hypertension.

Aim To evaluate family history (FH) of type 2 diabetes (T2DM) as a risk factor for impaired fasting glucose (IFG), impaired glucose tolerance (IGT), T2DM and related metabolic traits in South East Asia and to compare the effects of a paternal versus maternal history. Methods We studied 4717 men and women (68% Chinese, 18% Malays and 14% Asian Indians) living in Singapore. FH was considered positive if at least one first degree relative had T2DM. Obesity, fasting lipids, glucose and insulin levels were measured for all subjects. Insulin resistance (IR) was estimated by homeostasis model assessment (HOMA). An oral glucose tolerance test was carried for all subjects except those on diabetes medication. Results A positive FH was associated with increased risk of IFG/IGT (OR = 1.67, 95% CI = 1.42–1.97) and T2DM (OR = 2.95, 95% CI = 2.36–3.70) as well as higher levels of obesity, HOMA-IR, fasting triglyceride (TG), and lower levels of high density lipoprotein (HDL) cholesterol and HOMA-β. A maternal history of T2DM appeared to have a greater impact on obesity-related traits than a paternal history of T2DM. Compared to individuals with no FH of T2DM, a maternal history was associated with (i) greater body mass index (BMI) (24.15 kg/m 2 vs. 23.42 kg/m 2 , p = 0.016) and waist-to-hip ratio (WHR) (0.874 vs. 0.865, p = 0.037) in men; and (ii) greater WHR (0.788 vs. 0.779, p = 0.004), fasting triglyceride (1.23 mmol/L vs. 1.09 mmol/L, p p p = 0.005) and 2-h plasma glucose (6.01 mmol/L vs. 5.78 mmol/L, p = 0.001) and lower HDL-C (1.41 mmol/L vs. 1.47 mmol/L, p = 0.031) in women. Conclusion T2DM appears to be heritable in South East Asians with excess maternal transmission of obesity, IR and dyslipidemia.

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.

Background: The objective of this study is to assess the risk of second primary cancers following a first primary esophageal cancer as well as the risk of esophageal cancer as a second primary, following first primary cancers of other sites. Methods: The present investigation is a multicenter study of 13 population-based cancer registries in Europe, Australia, Canada, and Singapore. To assess excess occurrence of second cancers after esophageal cancers, we calculated standardized incidence ratios (SIR) by dividing the observed numbers of second cancers by the expected number of cancers calculated from the accumulated person-years and the age-, sex-, calendar period-, and registry-specific first primary cancer incidence rates. Results: During the study period, 959 cases of second primary cancers occurred after an initial esophageal cancer, resulting in a SIR of 1.15 (95% confidence interval, 1.08-1.22). Second primary stomach cancers were associated with first primary esophageal adenocarcinomas (SIR, 2.13; 95% confidence interval, 1.26-3.37) and second primary cancers of the oral cavity and pharynx (6.68; 5.33-8.26), stomach (1.53; 1.14-2.01), larynx (3.24; 1.88-5.18), lung (1.55; 1.28-1.87), kidney (1.88; 1.18-2.85), and thyroid (2.92; 1.18-6.02) were associated with first primary squamous cell carcinomas of the esophagus. An excess of esophageal cancer as a second primary were observed following first primary cancers of the aerodigestive tract, female breast, cervix, testis, bladder, Hodgkin's lymphoma, and non–Hodgkin lymphoma. Conclusion: We observed associations of esophageal cancer with second primary head and neck cancers and lung cancer regardless of years of follow-up, which may suggest that common risk factors play a role in multiple tumor development. (Cancer Epidemiol Biomarkers Prev 2008;17(6):1543–9)

Inconsistent seasonal patterns in peak presentation of acute lymphoblastic leukemia have been reported but no formal synthesis of published reports has been attempted to date. We extracted monthly tabulations of cases from publications and reanalysed using an angular methodology and the von Mises distribution. Twenty-four articles from 11 countries in locations ranging from 35.05 degrees S to 65.01 degrees N were identified. Formal synthesis established weak evidence for seasonality in adults and children. Were seasonality present, and arising from a climatic determinant, one might anticipate peaks of an increasing magnitude as the associated latitude moved away from the equator. No such pattern was apparent.

Bioinformatics is the use of informatics tools and techniques in the study of molecular biology, genetic, or clinical data. The field of bioinformatics has expanded tremendously to cope with the large expansion of information generated by the mouse and human genome projects, as newer generations of computers that are much more powerful have emerged in the commercial market. It is now possible to employ the computing hardware and software at hand to generate novel methodologies in order to link data across the different databanks generated by these international projects and derive clinical and biological relevance from all of the information gathered. The ultimate goal would be to develop a computer program that can provide information correlating genes, their single nucleotide polymorphisms (SNPs), and the possible structural and functional effects on the encoded proteins with relation to known information on complex diseases with great ease and speed. Here, the recent developments of available software methods to analyze SNPs in relation to complex diseases are reviewed with emphasis on the type of predictions on protein structure and functions that can be made. The need for further development of comprehensive bioinformatics tools that can cope with information generated by the genomics communities is emphasized.

Background: Skin cancers are known to be associated with sun exposure, whereas sunlight through the production of vitamin D may protect against some cancers. The aim of this study was to assess whether patients with skin cancer have an altered risk of developing other cancers. Methods: The study cohort consisted of 416,134 cases of skin cancer and 3,776,501 cases of non-skin cancer as a first cancer extracted from 13 cancer registries. 10,886 melanoma and 35,620 non-melanoma skin cancer cases had second cancers. The observed numbers (O) of 46 types of second primary cancer after skin melanoma, basal cell carcinoma or non-basal cell carcinoma, and of skin cancers following non-skin cancers were compared to the expected numbers (E) derived from the age, sex and calendar period specific cancer incidence rates in each of the cancer registries (O/E = SIR, standardised incidence ratios). Rates from cancer registries classified to sunny countries (Australia, Singapore and Spain) and less sunny countries (Canada, Denmark, Finland, Iceland, Norway, Scotland, Slovenia and Sweden) were compared to each other. Results: SIR of all second solid primary cancers (except skin and lip) after skin melanoma were significantly lower for the sunny countries (SIR(S) = 1.03; 95% CI 0.99-1.08) than in the less sunny countries (SIR(L) = 1.14; 95%CI 1.11-1.17). The difference was more obvious after non-melanoma skin cancers: after basal cell carcinoma SIR(S)/SIR(L) = 0.65 (95%CI = 0.58-0.72); after non-basal cell carcinoma SIR(S)/SIR(L) = 0.58 (95%CI = 0.50-0.67). In sunny countries, the risk of second primary cancer after non-melanoma skin cancers was lower for most of the cancers except for lip, mouth and non-Hodgkin lymphoma. Conclusions: Vitamin D production in the skin seems to decrease the risk of several solid cancers (especially stomach, colorectal, liver and gallbladder, pancreas, lung, female breast, prostate, bladder and kidney cancers). The apparently protective effect of sun exposure against second primary cancer is more pronounced after non-melanoma skin cancers than melanoma, which is consistent with earlier reports that non-melanoma skin cancers reflect cumulative sun exposure, whereas melanoma is more related to sunburn. © 2007 Elsevier Ltd. All rights reserved.

Background: Survivors of childhood leukemia and lymphoma experience high risks of second malignant neoplasms. We quantified such risk using a large dataset from 13 population-based cancer registries. Methods: The registries provided individual data on cases of leukemia, Hodgkin lymphoma, and non-Hodgkin lymphoma occurring in children aged 0-14 years and on subsequent second malignant neoplasms for different time periods from 1943 to 2000. Risks of second malignant neoplasms were assessed through standardized incidence ratios (SIRs) and corresponding 95% confidence intervals (CIs), using the incidence rates in the general populations covered by the registries as a reference. Cumulative absolute risks were also calculated. Results: A total of 133 second malignant neoplasms were observed in 16 540 patients (12 731 leukemias, 1246 Hodgkin lymphomas, and 2563 non-Hodgkin lymphomas) after an average follow-up of 6.5 years. The most frequent second malignancies after leukemia were brain cancer (19 cases, SIR = 8.52, 95% CI = 5.13 to 13.3), non-Hodgkin lymphoma (nine cases, SIR = 9.41, 95% CI = 4.30 to 17.9), and thyroid cancer (nine cases, SIR = 18.8, 95% CI = 8.60 to 35.7); the most frequent after Hodgkin lymphoma were thyroid cancer (nine cases, SIR = 52.5, 95% CI = 24.0 to 99.6), breast cancer (six cases, SIR = 20.9, 95% CI = 7.66 to 45.4), and neoplasms of skin (non-melanoma) (six cases, SIR = 34.0, 95% CI = 12.5 to 74.0); and the most frequent after non-Hodgkin lymphoma were thyroid cancer (six cases, SIR = 40.4, 95% CI = 14.8 to 88.0) and brain cancer (four cases, SIR = 6.97, 95% CI = 1.90 to 17.9). Cumulative incidence of any second malignant neoplasm was 2.43% (95% CI = 1.09 to 3.78), 12.7% (95% CI = 8.29 to 17.2), and 2.50% (95% CI = 1.04 to 3.96) within 30 years from diagnosis of leukemia, Hodgkin lymphoma, and non-Hodgkin lymphoma, respectively. Conclusions: This population-based study provides, to our knowledge, the most precise and up-to-date estimates for relative and absolute risks of second malignant neoplasms after childhood leukemia and lymphoma. © The Author 2007. Published by Oxford University Press. All rights reserved.

Lead and homocysteine are both linked to cardiovascular disease. With this in mind, the authors evaluated the relation between blood lead and homocysteine in people aged 19-66 years in two Asian populations.This cross-sectional study comprised 183 workers from a lead stabiliser factory in Singapore and 323 workers from a battery factory in Vietnam. Workers were occupationally exposed to lead. Blood lead was analysed using atomic absorption spectrophotometry while plasma homocysteine was measured using high performance liquid chromatography.Chinese subjects had the lowest blood lead levels while the Indians had the highest. Controlling for age, sex and race, an increase of 1 microg/dl in blood lead was associated with an increase of 0.04 micromol/l of homocysteine on the log scale. Gender and ethnicity seemed to be strongly associated with the relation between lead and homocysteine. The positive relation between lead and homocysteine among the Vietnamese subjects was significant (Pearson's r = 0.254, p0.01). When blood lead levels were divided by quartiles, the correlation coefficient between blood lead levels in the 4th quartile and homocysteine among the Vietnamese was higher (r = 0.405, p0.01). Overall, an increase of 1 microg/dl in blood lead in all the Vietnamese subjects was associated with an increase of 0.05 micromol/l increase in homocysteine on the log scale. However, in the 4th quartile, the same increase was associated with an increase of 0.41 micromol/l of homocysteine on the log scale.Blood lead was found to be associated with homocysteine levels in this Asian sample. Although we cannot determine causality from cross-sectional data, it is sensible to consider the probability that this relation could explain one of the mechanisms of the impact of lead on the cardiovascular system. More studies would be needed to confirm this inference.

Previous reports suggested that female breast cancer is associated with earlier ages at onset among Asian than Western populations. However, most studies utilized cross-sectional analyses that may be confounded by calendar-period and/or birth cohort effects. We, therefore, considered a longitudinal (forward-looking) approach adjusted for calendar-period changes and conditioned upon birth cohort.Invasive female breast cancer data (1988-2009) were obtained from cancer registries in China, Hong Kong, South Korea, Taiwan, Singapore, and the United States. Age-period-cohort models were used to extrapolate longitudinal age-specific incidence rates for the 1920, 1944, and 1970 birth cohorts.Cross-sectional age-specific incidence rates rose continuously until age 80 years among US white women, but plateaued or decreased after age 50 years among Asian women. In contrast, longitudinal age-specific rates were proportional (similar) among all Asian countries and the United States with incidence rates rising continuously until age 80 years. The extrapolated estimates for the most recent cohorts in some Asian countries actually showed later ages at onset than in the United States. Additionally, over successive birth cohorts, the incidence rate ratios (IRRs) for the longitudinal curves converged (narrowed) between Asian and US white women.Similar longitudinal age-specific incidence rates along with converging IRRs indicate that the age effects for invasive breast cancer are more similar among Asian and Western populations than might be expected from a solely cross-sectional analysis. Indeed, the Asian breast cancer rates in recent generations are even surpassing the historically high rates in the United States, highlighting an urgent need for efficient prevention and treatment strategies among Asian populations.

Family history of endometrial cancer increases the risk of developing the disease, but it is still largely unknown which germ-line genetic factors are involved in the aetiology of endometrial cancer. In a Swedish population-based case-control study including 705 cases and 1565 controls, we examined common variation in the ATM, CHEK2 and ERBB2 genes in relation to endometrial cancer risk overall, restricted to tumours of certain characteristics or stratified by various endometrial cancer risk factors. We genotyped a large number of single-nucleotide polymorphisms (SNPs) in the genes and selected seven haplotype-tagging SNPs (tagSNPs) in ATM, six tagSNPs in CHEK2 and seven tagSNPs in ERBB2 that could predict common variants and haplotypes (frequency > or =0.03) in each gene with R(2) > or = 0.8. We included the tagSNPs or their haplotypes as explanatory variables in unconditional logistic regression models adjusted for age. Our results indicated an increased risk of developing endometroid endometrial cancer for homozygous carriers of the rare allele (AA) of a tagSNP (rs4987886) in CHEK2 (P = 0.005) when contrasted with GG carriers. We also found a decreased endometrial cancer risk among non-smoking carriers of a haplotype in ATM (P = 0.0007) and among carriers of a haplotype in CHEK2, who had experienced menopause below 49 years of age (P = 0.0009) compared with non-carriers of these haplotypes. We found no effect of genetic variation in ERBB2 on endometrial cancer risk. In conclusion, it is possible that common variants in the ATM and CHEK2 genes, in interaction with oestrogen-related exposures, are involved in endometrial cancer aetiology.

The aim of the study was to determine whether the risk of ischaemic heart disease (IHD) associated with diabetes mellitus differs between ethnic groups.Registry linkage was used to identify IHD events in 5707 Chinese, Malay and Asian Indian participants from three cross-sectional studies conducted in Singapore between the years 1984 and 1995. The study provided a median of 10.2 years of follow-up with 240 IHD events experienced. We assessed the interaction between diabetes mellitus and ethnicity in relation to the risk of IHD events using Cox proportional hazards regression.Diabetes mellitus was more common in Asian Indians. Furthermore, diabetes mellitus was associated with a greater risk of IHD in Asian Indians. The hazard ratio when comparing diabetes mellitus with non-diabetes mellitus was 6.41 (95% CI 5.77-7.12) in Asian Indians and 3.07 (95% CI 1.86-5.06) in Chinese (p = 0.009 for interaction). Differences in the levels of established IHD risk factors among diabetics from the three ethnic groups did not appear to explain the differences in IHD risk.Asian Indians are more susceptible to the development of diabetes mellitus than Chinese and Malays. When Asian Indians do develop diabetes mellitus, the risk of IHD is higher than for Chinese and Malays. Consequently, the prevention of diabetes mellitus amongst this ethnic group is particularly important for the prevention of IHD in Asia, especially given the size of the population at risk. Elucidation of the reasons for these ethnic differences may help us understand the pathogenesis of IHD in those with diabetes mellitus.

Previous investigations of the ACE gene as a susceptibility factor for diabetic nephropathy have primarily focused on its insertion/deletion (Ins/Del) polymorphism. In a departure from these earlier studies, we used three tagging markers (A-5466C, T-3892C, and Ins/Del) at the ACE locus to test for disease haplotype associations. A case-control study design was used where case subjects were type 2 diabetic patients with advanced diabetic nephropathy, as indicated by the presence of proteinuria or chronic renal failure/end-stage renal disease, while control subjects were normoalbuminuric, despite >6 years of diabetes. None of the individual markers showed significant disease association when considered on their own. However, haplotype analyses revealed a near doubling in the prevalence of the A.T.D risk haplotype in case subjects (0.136) compared with control subjects (0.075) (P = 0.009), thus providing first evidence for a disease haplotype for advanced diabetic nephropathy at the ACE locus.

Peroxisome proliferators activated receptor alpha (PPARalpha) regulates the transcription of several proteins involved in human lipoprotein metabolism. We screened the PPARA locus for polymorphisms in 20 unrelated subjects from each of three ethnic groups (Chinese, Malays and Asian Indians). Only the V227A polymorphism was observed. We genotyped 4248 subjects (2899 Chinese, 761 Malay and 588 Asian Indians) and found allele frequencies for the A227 allele of 0.04 in Chinese, 0.006 in Malays and 0.003 in Asian Indians. We examined the associations between this polymorphism and serum lipid concentrations in Chinese. In women, but not in men, the presence of the A227 allele was associated with lower serum concentrations of total cholesterol [5.38mmol/l (95%CI: 5.22-5.54) versus 5.21mmol/l (95%CI: 4.99-5.43), p=0.047] and triglycerides [1.19mmol/l (95%CI: 1.10-1.28) versus 1.09mmol/l (95%CI: 0.98-1.21), p=0.048]. We also found that the V227A polymorphism modulates the association between dietary polyunsaturated fatty acid intake and serum high density lipoprotein concentration (p-value for interaction=0.049). Our findings implicate PPARalpha in the lipid lowering associated with diets high in PUFA and suggests that genetic variation at the PPARA locus may determine the lipid response to changes in PUFA intake.

Background Saliva is a potentially useful but untapped source of genomic DNA for genetic epidemiological studies. However, current commercial methods are mainly concerned with DNA extraction and do not address important issues concerning saliva preservation and storage. As such, we evaluated how various saliva storage conditions affected DNA yield and quality obtained using a new commercially available method that proposes to integrate these aspects in a single kit. Methods The conditions involved the extraction of the DNA immediately after saliva collection (condition 1) or when stored at air-conditioned room temperature (20 °C) for 1 month (condition 2) and 6 months (condition 3) as well as at − 80 °C for 6 months (condition 4). The effect of incorporating an additional incubation of saliva samples at 30 °C for 2 weeks was also examined. Results Overall average DNA yield from 2 ml of saliva was 35.5 μg (8.5–85.2 μg). DNA yield was unaffected by incubation of saliva at 30 °C but DNA yield under condition 3 was significantly higher compared to conditions 1 and 2. OD 260 / 280 values were acceptable and comparable across all conditions. Differences in storage conditions did not impact DNA quality in real time PCR experiments and genotyping fidelity remained undiminished. Conclusion Saliva is a viable alternative source of human genomic DNA for genetic epidemiological studies and that this new commercial method and possibly other related techniques can be effective means towards this end.

Studies of pancreatic cancer in the setting of second primary malignant neoplasms can provide etiologic clues. An international multicenter study was carried out using data from 13 cancer registries with a registration period up to year 2000. Cancer patients were followed up from the initial cancer diagnosis, and the occurrence of second primary malignant neoplasms was compared with expected values derived from local rates, adjusting for age, sex, and period of diagnosis. Results from individual registries were pooled by use of a fixed-effects model. People were at higher risk of developing pancreatic cancer within 10 years of a diagnosis of cancers of the pharynx, stomach, gallbladder, larynx, lung, cervix, corpus uteri, bladder, and eye and 10 years or later following a diagnosis of cancers of the stomach, colon, gallbladder, breast, cervix, placenta, corpus uteri, ovary, testis, bladder, kidney, and eye, as well as Hodgkin's and non-Hodgkin's lymphomas. Pancreatic cancer was connected with smoking-related cancers, confirming the etiologic role of tobacco. The associations with uterine and ovarian cancers suggest that reproductive factors might be implicated in pancreatic carcinogenesis. The elevated pancreatic cancer risk in young patients observed among several types of cancer implies a role of genetic factors. Radiotherapy is also suggested as a risk factor. Copyright © 2006 by the Johns Hopkins Bloomberg School of Public Health All rights reserved.

// Prashant Kumar 1,* , Sayantani Nandi 1,* , Tuan Zea Tan 2,* , Siok Ghee Ler 3 , Kee Seng Chia 4 , Wei-Yen Lim 5 , Zentia Butow 6 , Dimitrios Vordos 6 , Alexandre De laTaille 6 , Muthafar Al-Haddawi 1 , Manfred Raida 7 , Burkhard Beyer 8 , Estelle Ricci 9 , Marc Colombel 9 , Tsung Wen Chong 10 , Edmund Chiong 11 , Ross Soo 12 , Mi Kyoung Park 13 , Hong Koo Ha 14,** , Jayantha Gunaratne 3,4,** and Jean Paul Thiery 1,2,7,** 1 Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore 2 Cancer Science Institute, National University of Singapore, Singapore 3 Quantitative Proteomics Group, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore 4 Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 5 Saw Swee Hock School of Public Health, National University of Singapore, Singapore 6 CHU Hopital Henri Mondor, Department of Urology, Creteil, France 7 Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 8 Department of Urology, Section for Translational Prostate Cancer Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany 9 Service d’Urologie et Chirurgie de la Transplantation, Hopital Edouard Herriot, Lyon, France 10 Department of Urology, Singapore General Hospital, Singapore 11 Department of Urology, University Surgical Cluster, National University Health System (NUHS), Singapore 12 Haematology-Oncology Research Group, Department of Haematology-Oncology, National University Cancer Institute (NCIS), National University Hospital, Singapore 13 Institute of Microelectronics (IME), A*STAR, Singapore 14 Department of Urology, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea * These authors are co-first authors ** These authors are co-senior authors Correspondence to: Jean Paul Thiery, email: // Keywords : transitional bladder carcinoma, urine biomarkers, receiving operating characteristics, combination model Received : December 08, 2014 Accepted : March 19, 2015 Published : April 15, 2015 Abstract Transitional bladder carcinoma (BCa) is prevalent in developed countries, particularly among men. Given that these tumors frequently recur or progress, the early detection and subsequent monitoring of BCa at different stages is critical. Current BCa diagnostic biomarkers are not sufficiently sensitive for substituting or complementing invasive cystoscopy. Here, we sought to identify a robust set of urine biomarkers for BCa detection. Using a high-resolution, mass spectrometry-based, quantitative proteomics approach, we measured, compared and validated protein variations in 451 voided urine samples from healthy subjects, non-bladder cancer patients and patients with non-invasive and invasive BCa. We identified five robust biomarkers: Coronin-1A, Apolipoprotein A4, Semenogelin-2, Gamma synuclein and DJ-1/PARK7. In diagnosing Ta/T1 BCa, these biomarkers achieved an AUC of 0.92 and 0.98, respectively, using ELISA and western blot data (sensitivity, 79.2% and 93.9%; specificity, 100% and 96.7%, respectively). In diagnosing T2/T3 BCa, an AUC of 0.94 and 1.0 was attained (sensitivity, 86.4% and 100%; specificity, 100%) using the same methods. Thus, our multiplex biomarker panel offers unprecedented accuracy for the diagnosis of BCa patients and provides the prospect for a non-invasive way to detect bladder cancer.

We examined six newly identified polymorphisms in the delta-aminolevulinic acid dehydratase (ALAD) single-nucleotide polymorphisms (SNPs) to determine if these SNPs could modify the relationship between blood lead (PbB) and some renal parameters. This is a cross-sectional study of 276 lead-exposed workers in Vietnam. All workers were measured for PbB, urinary retinol-binding protein (URBP), urinary alpha1-microglobulin (Ualpha1m), urinary beta2-microglobulin (Ubeta 2m), urinary N-acetyl-beta -d-glucosaminidase (NAG), urinary aminolevulinic acid (ALAU), serum alpha1-microglobulin (Salpha1m), serum beta2-microglobulin (Sbeta 2m), and urinary albumin (Ualb). The six SNPs were Msp and Rsa in exon 4, Rsa39488 in exon 5, HpyIV and HpyCH4 in intron 6, and Sau3A in intron 12. Analysis of covariance (ANCOVA) with interaction of PbB times SNPs were applied to examine modifying effect of the SNPs on the association of renal parameters and PbB, adjusting for potential confounders of age, gender, body mass index, and exposure duration. HpyCH4 was found to be associated with certain renal parameters. For HpyCH4 1-1, an increase of 1 microg/dL PbB caused an increase of 1.042 mg/g creatinine (Cr) U alpha1m, 1.069 mg/g Cr Ubeta 2m, 1.038 mg/g Cr URBP, and 1.033 mg/g Cr Ualb, whereas in HpyCH4 1-2, an increase of 1 microg/dL PbB resulted in an increase of only 1.009 mg/g Cr Ualpha1m, 1.012 mg/g Cr Ubeta 2m, 1.009 mg/g Cr URBP, and 1.007 mg/g Cr Ualb. HpyCH4 SNP appeared to modify the lead toxicity to kidney with wild-type allele being more susceptible than variants. The mechanism for this effect is not clear. Further studies are needed to confirm this observation.

The ACE insertion/deletion polymorphism has been examined for association with diabetic nephropathy over the past decade with conflicting results. To clarify this situation, we conducted a comprehensive meta-analysis encompassing all relevant studies that were published between 1994 and 2004 and investigated this potential genetic association.A total of 14,727 subjects from 47 studies was included in this meta-analysis. Cases (n=8,663) were type 1 or 2 diabetic subjects with incipient (microalbuminuria) or advanced diabetic nephropathy (proteinuria, chronic renal failure, end-stage renal disease). Control subjects (n=6,064) were predominantly normoalbuminuric.No obvious publication bias was detected. Using a minimal-case definition based on incipient diabetic nephropathy, subjects with the II genotype had a 22% lower risk of diabetic nephropathy than carriers of the D allele (pooled odds ratio [OR]=0.78, 95% CI=0.69-0.88). While there was a reduced risk of diabetic nephropathy associated with the II genotype among Caucasians with either type 1 or type 2 diabetes, the association was most marked among type 2 diabetic Asians (Chinese, Japanese, Koreans) (OR=0.65, 95% CI=0. 51-0.83). This OR is significantly different from the OR of 0.90 (95% CI= 0.78-1.04) that was obtained for type 2 diabetic Caucasians (p=0.019). Using a stricter case definition based on advanced diabetic nephropathy, a comparable risk reduction of 24-32% was observed among the three subgroups, although statistical significance was reached only among Asians.The results of our meta-analysis support a genetic association of the ACE Ins/Del polymorphism with diabetic nephropathy. These findings may have implications for the management of diabetic nephropathy using ACE inhibitors especially among type 2 diabetic Asians.

Cancer of the small intestine is a rare neoplasm, and its etiology remains poorly understood. Analysis of other primary cancers in individuals with small intestine cancer may help elucidate the causes of this neoplasm and the underlying mechanisms. We included 10,946 cases of first primary small intestine cancer from 13 cancer registries in a pooled analysis. The observed numbers of 44 types of second primary cancer were compared to the expected numbers derived from the age-, gender- and calendar period-specific cancer incidence rates in each registry. We also calculated the standardized incidence ratios (SIR) for small intestine cancer as a second primary after other cancers. There was a 68% overall increase in the risk of a new primary cancer after small intestine carcinoma (SIR = 1.68, 95% confidence interval [CI] = 1.47-1.71), that remained constant over time. The overall SIR was 1.18 (95% CI = 1.05-1.32) after carcinoid, 1.29 (1.01-1.63) after sarcoma, and 1.27 (0.78-1.94) after lymphoma. Significant (p < 0.05) increases were observed for cancers of the oropharynx, colon, rectum, ampulla of Vater, pancreas, corpus uteri, ovary, prostate, kidney, thyroid gland, skin and soft tissue sarcomas. Small intestine cancer as a second primary was increased significantly after all these cancers, except after oropharyngeal and kidney cancers. Although some of the excess may be attributable to overdiagnosis, it is plausible that most additional cases of second primary cancers were clinically relevant and were due to common genetic (e.g., defects in mismatch or other DNA repair pathways) and environmental (e.g., dietary) factors. © 2005 Wiley-Liss, Inc.

We carried out a cross-sectional study on a group of male workers to determine the frequency of delta-aminolevulinic acid dehydratase (ALAD) polymorphisms among Chinese, Malays and Indians workers who were exposed to low to medium levels of inorganic lead. Also, the association between ALAD1 and ALAD2 genotypes and neurobehavioral functions among these workers were investigated. A total of 120 male workers were studied. Blood and urine were collected for each worker to determine the ALAD genotypes, blood lead levels, ALAD, and urinary delta-aminolevulinic acid (ALAU). ALAD1-1 was the predominant genotype for all three ethnic groups while ALAD2-2 was the rarest. The distribution of ALAD1-2 was higher among Malays (16.7%) and Indians (14.3%), compared to Chinese (3.6%). Selected tests from the World Health Organization Neurobehavioral Core Test Battery (WHO-NCTB) were used. Although workers in the ALAD1-1 and ALAD1-2/2-2 groups had comparable blood lead levels, the 106 workers with ALAD1-1 genotypes have significantly higher urinary ALA and significantly poorer neurobehavioral scores involving motor dexterity compared with those who have ALAD1-2/2-2 genotypes (13 workers). It is postulated that the ALAD2 allele may exert protective measures against the neurotoxic effects of lead. Further study involving a larger cohort of workers with the ALAD2 allele would be needed to confirm this hypothesis.

OBJECTIVE—To determine the effect of lowering the fasting plasma glucose (FPG) criterion for impaired fasting glucose (IFG) on the prevalence of IFG, the risks of diabetes, and cardiovascular disease (CVD) associated with IFG. RESEARCH DESIGN AND METHODS—Three studies were used: 1) the 1998 National Health Survey (NHS98), a randomly selected cross-sectional sample of 4,723 subjects; 2) the Singapore Impaired Glucose Tolerance (IGT) Follow-up Study, a cohort study comprising 295 IGT and 292 normal glucose tolerance subjects (frequency matched for age, sex, and ethnic group) followed up from 1992 to 2000; and 3) the Singapore CVD Cohort Study, comprising 5,920 subjects from three cross-sectional studies in whom the first ischemic heart disease (IHD) event was identified through linkage to registry databases. Risk of diabetes (Singapore IGT Follow-up study) was estimated using logistic regression adjusted for age, sex, and ethnicity. Risk of IHD (Singapore CVD cohort) was estimated using stratified (by study, from which data were derived) Cox’s proportional hazards models adjusted for age, sex, and ethnicity. RESULTS—Lowering the criterion for diagnosing IFG to 5.6 mmol/l increased the prevalence of IFG from 9.5 to 32.3% in the NHS98. The lower cutoff identified more subjects at risk of diabetes and IHD, but the relative risk was lower than that for IGT. CONCLUSIONS—Greater efforts to identify those with IGT, or a group at similar risk of diabetes and CVD, may be a more efficient public health measure than lowering the FPG criterion for diagnosing IFG.

Background: Ethnic differences in coronary mortality have been documented, and South Asians from the Indian subcontinent are particularly vulnerable. Hypothesis: This study sought to determine whether there was a difference in the utilization of invasive cardiac procedures and long-term mortality in survivors of myocardial infarction (MI) among Chinese, Malays, and South Asians in Singapore. Methods: All MI events in the country were identified and defined by the Singapore Myocardial Infarction Register, which uses modified procedures of the World Health Organization MONICA Project. Information on utilization of coronary angiography, coronary angioplasty, coronary artery bypass graft, and survival was obtained by data linkage with national billing and death registries. Hazard ratios (HR) were calculated using the Cox proportional hazards model with adjustment for baseline characteristics. Results: From 1991 to 1999, there were 10,294 patients who survived ≥3 days of MI. Of these, 40.6% underwent coronary angiography and 16.5% a revascularization procedure ≤28 days. Malays received substantially less angiography (34.0%) and revascularization (11.4%) than Chinese (41.9%, 17.9%) and South Asians (40.0%, 16.3%). The ethnic disparity increased during the 1990s, particularly in the performance of coronary angiography (p = 0.038). While fatality declined during the study period for Chinese and South Asians, the rate remained stable for Malays. After a median follow-up period of 4.1 years, survival was lowest among Malays (adjusted HR, 1.28; 95% confidence interval, 1.15--1.42, compared with Chinese). Conclusion: Ethnic inequalities in invasive cardiac procedures exist in Singapore and were exacerbated in the 1990s. Inequalities in medical care may contribute to the poorer long-term survival among Malays.

Aim: To examine the association of birth parameters with biometry and refraction in Singapore Chinese schoolchildren. Methods: Chinese children aged 7–9 years (n = 1413) from three schools in Singapore were recruited. Birth parameter information on birth weight, head circumference, length at birth, and gestational age were obtained from standard hospital records. Cycloplegic autorefraction, keratometry and biometry measures (axial length, vitreous chamber depth, lens thickness, and anterior chamber depth) were obtained. Results: Across the normal birthweight range (2.0–4.9 kg), children with birth weights ⩾4.0 kg had longer axial lengths (adjusted mean 23.65 mm versus 23.16 mm), compared with children with birth weights Conclusions: Children who were born heavier, had larger head sizes or lengths at birth, or who were born more mature had longer axial lengths, and deeper vitreous chambers; but there were no differences in refraction at ages 7–9 years, possibly because of the observed compensatory flattening of the cornea.

Objectives : To study the association between parental occupation and low birth weight (LBW) in infants born in Singapore between 1994 and 1998. Other factors that may be related to LBW were also investigated. Methods : A retrospective study. Information was obtained from the Singapore National Registry of Births and Deaths on parental occupations for live births between 1 January 1994 to 31 December 1998. Parental date of birth, ethnic group, and highest educational qualification were also obtained. The associations between these factors and the occurrence of LBW was assessed using descriptive statistics and logistic regression analysis. Results : A total 208,360 live births were studied. Analyses were restricted to singleton births ≥37th week gestation (total of 189,064). No significant differences in LBW risk were found for the different maternal occupational groups, compared with a referent group (“legislators, senior officers, and managers”). However, fathers who were “not working” (OR=2.04; 1.57–2.65), “not classifiable by occupation” (OR=1.34; 1.09–1.65), and “cleaners, laborers, and related workers” (OR=1.32; 1.12–1.55) had the highest risk of LBW infants when compared with “legislators, senior officers, and managers,” after adjustment for maternal occupation, ethnic group, educational level and age, paternal educational level, infant gestational age, sex, and birth order. Conclusion : Certain paternal occupational groups appear to be associated with a higher risk of having LBW infants. This may be linked to socioeconomic status and possible work-related factors. Future studies of pregnancy outcomes should not ignore the potential contributions of fathers.

Previous studies have shown conflicting results on the prognosis of mucinous adenocarcinoma of the colorectum. This could be because of heavy bias on patient selection. Furthermore, little data are available from Asian populations. This study was designed to examine incident and prognostic characteristics of mucinous adenocarcinoma of the colorectum based on data obtained from a population-based, Asian, cancer registry.A total of 627 of 15,762 were mucinous adenocarcinoma cases from invasive colorectal cancer patients registered in the Singapore Registry from 1968 to 1997. Age-standardized incidence rate was used to describe the incident pattern of mucinous adenocarcinoma of colon and rectum during a period of time. Survival of patients with mucinous adenocarcinoma or ordinary adenocarcinoma was compared using relative survival and proportional hazards model.Age-standardized incidence rate of mucinous adenocarcinoma of the colon and rectum were almost unchanged in males, rising slightly in females during the study periods from 1968 to 1972 to 1993 to 1997. The proportion of mucinous adenocarcinoma cases was similar among genders and calendar-year periods but was higher in younger age groups, Malays and Indians, in advanced stages of the disease, and proximal colon. Five-year relative survival rate of patients with mucinous adenocarcinoma were similar in the colon but were lower in the rectum.Colorectal mucinous adenocarcinoma as a different etiologic entity from other histologic types of colorectal cancer was suggested. Possibly greater aggressiveness of mucinous adenocarcinoma occurring in the rectum requires confirmation but suggests that mucin is important in the pathogenesis of mucinous adenocarcinoma.

Breast cancer incidence in Sweden has always been approximately twice as high as in Singapore. In recent years, this difference is limited to postmenopausal women. The aim of this study was to explore the reasons behind these differences through the use of age-period-cohort modeling. This population-based study included all breast cancer cases reported to the Swedish and the Singapore cancer registries from 1968 to 1997, with a total of 135,581 Swedish and 10,716 Singaporean women. Poisson regression using age-period and age-cohort models was used to determine the effects of age at diagnosis, calendar period and birth cohort. Incidence rate ratios were used to summarize these effects. An age-cohort model provided the best fit to the data in both countries, indicating that changes over lifetime, rather than recent differences in medical surveillance, might account for the observed differences in these 2 populations. The changes over birth cohort were much greater among Singaporean women. The relative effect of age was very similar in the 2 countries. Analyses show that age and cohort effects may explain the differences in trends of female breast cancer incidence between Sweden and Singapore. The larger cohort effect seen in Singaporean women may be attributed to more rapid changes in reproduction and lifestyle patterns than that of Swedish women during the period studied. The incidence of breast cancer in postmenopausal women in Singapore will probably continue to rise in the coming decades to match the current Swedish rates.

Serum lipid concentrations are modulated by environmental factors such as exercise, alcohol intake, smoking, obesity and dietary intake and genetic factors. Polymorphisms at the Apolipoprotein E (APOE) locus have consistently shown a significant association with total and LDL-cholesterol (LDL-C). However, their impact on HDL-cholesterol (HDL-C) may be population dependent. Having three major ethnic groups within a similar social environment allows us to study the role of genetics and their interactions with lifestyle factors on the serum lipid profile and coronary risk in Asians.This study included 1740 males (1146 Chinese, 327 Malays and 267 Asian Indians) and 1950 females (1329 Chinese, 360 Malays and 261 Asian Indians) with complete data on anthropometric indices, fasting lipids, smoking status, alcohol consumption, exercise frequency and genotype at the APOE locus.Malays and Asian Indians were more obese compared with the Chinese. Smoking was uncommon in all females but Malay males had significantly higher prevalence of smokers. Malays had the highest LDL-C whilst Indians had the lowest HDL-C, The epsilon 3 allele was the most frequent allele in all three ethnic groups. Malays had the highest frequency of epsilon 4 (0.180 and 0.152) compared with Chinese (0.085 and 0.087) and Indians (0.108 and 0.075) in males and females, respectively. The epsilon 2 allele was the least common in Asian Indians. Total cholesterol (TC) and LDL-C was highest in epsilon 4 carriers and lowest in epsilon 2 carriers. The reverse was seen in HDL-C with the highest levels seen in epsilon 2 subjects. The association between ethnic group and HDL-C differed according to APOE genotype and gender. Asian Indians had the lowest HDL-C for each APOE genotype except in Asian Indian males with epsilon 2, where HDL-C concentrations were intermediate between Chinese and Malays.Ethnic differences in lipid profile could be explained in part by the higher prevalence of epsilon 4 in the Malays. Ethnicity may influence the association between APOE genotypes and HDL-C. APOE genotype showed no correlation with HDL-C in Malay males whereas the association in Asian Indians was particularly marked. Further studies of interactions between genes and environmental factors will contribute to the understanding of differences of coronary risk amongst ethnic groups.

SummaryBackground There has been an alarming recent increase in skin cancer incidence among fair-skinned populations. Information from Asian populations is less readily available. Objectives This study examines time trends and ethnic differences of skin cancers among Asians in Singapore. Methods Data from 1968 to 1997 was obtained from the Singapore Cancer Registry, a population-based registry. Age-standardized incidence rates (ASRs) and age-adjusted average annual percentage change, using the Poisson regression model, were calculated. Results A total of 2650 basal cell carcinomas (BCCs), 1407 squamous cell carcinomas (SCCs) and 281 melanomas were reported. There was an overall increase of skin cancer from 6·0 per 100 000 person years (1968–72) to 8·9 per 100 000 person years (1993–97). BCC incidence increased 3% annually, melanoma remained constant, and SCC decreased 0·9% annually. BCC ASRs were highest among Chinese, then Malays and Indians. A similar pattern was noted for SCC and melanomas. Conclusions The incidence rates of skin cancer increased in Singapore during the period 1968–97. Fairer-skinned Chinese had a higher incidence of skin cancer.

Younger women who develop breast cancer are hypothesized to have poorer survival rates than women who develop it at a later stage in life. Several studies have suggested that differences in biologic characteristics of breast cancer in younger (premenopausal) and older (postmenopausal) women may account for the prognostic variation. This population-based cohort study reports on survival rates of breast cancer in Singapore and examines the hypothesis that younger breast cancer patients have a poorer prognosis. A total of 6,397 breast cancer patients diagnosed from 1968 to 1992 were identified from the population-based cancer registry and followed up through 1997. Outcome measures were relative survival rates (RSRs) calculated using Hakulinen's method and excess hazards ratios (HRs) derived from a regression model based on relative survival. The 2-, 5- and 10-year RSRs were worse among those aged > 75 (65%, 48% and 39%, respectively). The best survival rates were seen among those aged 40–44 (84%, 67% and 56%). Patients younger than 35 years faired reasonably well (79%, 60% and 50%). When the data were stratified according to clinical stage and calendar year, the highest risk of excess deaths was found in women ≥ 75 years old. In patients with localized cancer and/or regional metastases, those in the 35–39 age group had the lowest excess risk. In patients with distant metastases, those younger than 35 years of age had the lowest excess risk of death. At the population level, younger women (< 45 years) with breast cancer in Singapore have higher relative survival rates. © 2003 Wiley-Liss, Inc.

Objective To examine the risk factors for variations in ocular biometry parameters in Singapore Chinese children, a population with a known high prevalence rate of myopia at an early age. Design Cross-sectional study. Participants Children aged 7 to 9 years (n = 1453) from three schools in Singapore. Methods The children underwent A scan biometry and cycloplegic autorefraction measurements. Questions were asked regarding number of books read per week, night lighting, and parental myopia. Main outcome measures Axial length, vitreous chamber depth, lens thickness, anterior chamber depth, refraction, and corneal curvature radius measurements were made. Results After controlling for several factors, the axial lengths were found to be longer and vitreous chambers deeper in children who were older, male, read more than two books per week, or taller, and those who had at least one parent who was myopic. In these models, children who read more than two books per week had axial lengths that were 0.17 mm longer and vitreous chambers that were 0.15 mm deeper compared with children who read two or fewer books per week. Anterior chambers were deeper in males and taller children, whereas corneal curvature was steeper in female, older, and shorter children. Conclusions Increases of axial length and vitreous cavity depth were associated with older age, being male, reading more than two books per week, increased height, and parental history of myopia. Of these risk factors, however, neither reading nor parental myopia history were associated with values for anterior chamber depth, corneal curvature, or lens thickness. These findings confirm that conventional risk factors for myopia associated with the vitreous cavity, but suggest that anterior segment parameters such as corneal curvature and lens thickness may be subject to unrelated postnatal growth control mechanisms.

PURPOSE: To examine the optimal cutoff point for the use of the visual acuity test to screen for refractive errors in schoolchildren. METHODS: In a sample of schoolchildren between 7 and 9 years old, visual acuity testing was performed using modified ETDRS charts monocularly without optical aids by trained personnel. Cycloplegic autorefraction was performed in each eye. The screening efficacy of using various cutoff points for referring children for further optometric/ ophthalmic assessment was studied. Myopia was defined as a spherical equivalent of at least -0.5 D, hyperopia a spherical equivalent of at least +2.0 D, and astigmatism a cylinder of at least -1.0 D in at least one eye. The sensitivity, specificity, and predictive values were calculated using each patient as a case; a receiver operator curve was plotted. RESULTS: A total of 1,028 children were tested. A satisfactory sensitivity/specificity profile was obtained using a referral criterion of visual acuity worse than or equal to 0.28 logarithm of the minimum angle of resolution in at least one eye. In this scenario, the sensitivity and specificity of this screening test were 72% (95% confidence interval [CI], 68 to 76) and 97% (95%CI, 95 to 98), respectively. The positive and negative predictive values were 96% (95%CI, 93 to 98) and 78% (95%CI, 75 to 82), respectively. CONCLUSIONS: The modified ETDRS visual acuity chart can be used to predict refractive errors in schoolchildren in Singapore in a sensitive and specific manner using a referral criterion of worse than or equal to 0.28 logarithm of the minimum angle of resolution.

Since the 1980s, colorectal cancer incidence in Singapore has ranked second to lung in males and females. We describe a population-based analysis of survival of colorectal cancer patients diagnosed from 1968 to 1992 in Singapore. Data of colorectal cancer patients diagnosed during 1968–1992 were retrieved from the Singapore Cancer Registry. Patients were passively followed up for death to the end of 1997. The final dataset consisted of 10,114 subjects. Observed and relative survival rates were calculated by stage (localized, regional metastases and distant metastases), age, ethnicity and calendar period for both genders. Over the study period, a significant progress in survival of colorectal cancer patients was observed. For localized cancer of the colon, the 5-year age-standardized relative survival (ASRS) increased from 36% in 1968–1972 to 66% in 1988–1992 for males and from 32 to 71% for females. For localized rectal cancer, the 5-year ASRS improved from 25 to 66% for males and from 23 to 66% in females. Similarly, improvement was observed in colorectal cancer patients with regional metastases, but not in those with distant metastases. Calendar year period and clinical stage of disease were identified as major significant prognostic factors of survival for colorectal cancer. The substantially improved colorectal cancer survival rates reflected the interplay of cancer control activities in various areas, such as health promotion, early diagnosis and treatment. Our study shows a unique changing pattern of survival experience for colorectal patients from a country undergoing rapid economic development. © 2002 Wiley-Liss, Inc.

Effects of CYP4F2 and GGCX genetic variants on maintenance warfarin dose in a multi-ethnic Asian population

ObjectiveSingapore is a microcosm of Asia as a whole, and its rapidly ageing, increasingly sedentary population heralds the chronic health problems other Asian countries are starting to face and will likely face in the decades ahead. Forecasting the changing burden of chronic diseases such as type 2 diabetes in Singapore is vital to plan the resources needed and motivate preventive efforts.MethodsThis paper describes an individual-level simulation model that uses evidence synthesis from multiple data streams—national statistics, national health surveys, and four cohort studies, and known risk factors—aging, obesity, ethnicity, and genetics—to forecast the prevalence of type 2 diabetes in Singapore. This comprises submodels for mortality, fertility, migration, body mass index trajectories, genetics, and workforce participation, parameterized using Markov chain Monte Carlo methods, and permits forecasts by ethnicity and employment status.ResultsWe forecast that the obesity prevalence will quadruple from 4.3% in 1990 to 15.9% in 2050, while the prevalence of type 2 diabetes (diagnosed and undiagnosed) among Singapore adults aged 18–69 will double from 7.3% in 1990 to 15% in 2050, that ethnic Indians and Malays will bear a disproportionate burden compared with the Chinese majority, and that the number of patients with diabetes in the workforce will grow markedly.ConclusionsIf the recent rise in obesity prevalence continues, the lifetime risk of type 2 diabetes in Singapore will be one in two by 2050 with concomitant implications for greater healthcare expenditure, productivity losses, and the targeting of health promotion programmes.

South Asia possesses a significant amount of genetic diversity due to considerable intergroup differences in culture and language. There have been numerous reports on the genetic structure of Asian Indians, although these have mostly relied on genotyping microarrays or targeted sequencing of the mitochondria and Y chromosomes. Asian Indians in Singapore are primarily descendants of immigrants from Dravidian-language–speaking states in south India, and 38 individuals from the general population underwent deep whole-genome sequencing with a target coverage of 30X as part of the Singapore Sequencing Indian Project (SSIP). The genetic structure and diversity of these samples were compared against samples from the Singapore Sequencing Malay Project and populations in Phase 1 of the 1,000 Genomes Project (1 KGP). SSIP samples exhibited greater intra-population genetic diversity and possessed higher heterozygous-to-homozygous genotype ratio than other Asian populations. When compared against a panel of well-defined Asian Indians, the genetic makeup of the SSIP samples was closely related to South Indians. However, even though the SSIP samples clustered distinctly from the Europeans in the global population structure analysis with autosomal SNPs, eight samples were assigned to mitochondrial haplogroups that were predominantly present in Europeans and possessed higher European admixture than the remaining samples. An analysis of the relative relatedness between SSIP with two archaic hominins (Denisovan, Neanderthal) identified higher ancient admixture in East Asian populations than in SSIP. The data resource for these samples is publicly available and is expected to serve as a valuable complement to the South Asian samples in Phase 3 of 1 KGP., Author Summary Indians of South Asia has long been a population of interest to a wide audience, due to its unique diversity. We have deep-sequenced 38 individuals of Indian descent residing in Singapore (SSIP) in an effort to illustrate their diversity from a whole-genome standpoint. Indeed, among Asians in our population panel, SSIP was most diverse, followed by the Malays in Singapore (SSMP). Their diversity is further observed in the population's chromosome Y haplogroup and mitochondria haplogroup profiles; individuals with European-dominant haplogroups had greater proportion of European admixture. Among variants (single nucleotide polymorphism and small insertions/deletions) discovered in SSIP, 21.69% were novel with respect to previous sequencing projects. In addition, some 14 loss-of-function variants (LOFs) were associated to cancer, Type II diabetes, and cholesterol levels. Finally, D statistic test with ancient hominids concurred that there was gene flow to East Asians compared to South Asians.