Jeannette Lee

Dietary effects on breast-cancer risk in Singapore

It is suspected that diet influences the risk of getting breast cancer. A study of diet and breast cancer was done among 200 Singapore Chinese women with histologically confirmed disease and 420 matched controls. A quantitative food-frequency questionnaire was used to assess intakes of selected nutrients and foods 1 year before interview. Daily intakes were computed and risk analysed after adjustment for concomitant risk factors. In premenopausal women, high intakes of animal proteins and red meat were associated with increased risk. Decreased risk was associated with high intakes of polyunsaturated fatty acids (PUFA), beta-carotene, soya proteins, total soya products, a high PUFA to saturated fatty acid ratio, and a high proportion of soya to total protein. In multiple analysis, the variables which were significant after adjustment for each other were red meat (p less than 0.001) as a predisposing factor, and PUFA (p = 0.02), beta-carotene (p = 0.003), and soya protein (p = 0.02) as protective factors. The analysis of dietary variables in postmenopausal women gave uniformly non-significant results. Our finding that soya products may protect against breast cancer in younger women is of interest since these foods are rich in phyto-oestrogens.

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

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

Low copy number of the salivary amylase gene predisposes to obesity

Common multi-allelic copy number variants (CNVs) appear enriched for phenotypic associations compared to their biallelic counterparts. Here we investigated the influence of gene dosage effects on adiposity through a CNV association study of gene expression levels in adipose tissue. We identified significant association of a multi-allelic CNV encompassing the salivary amylase gene (AMY1) with body mass index (BMI) and obesity, and we replicated this finding in 6,200 subjects. Increased AMY1 copy number was positively associated with both amylase gene expression (P = 2.31 × 10−14) and serum enzyme levels (P < 2.20 × 10−16), whereas reduced AMY1 copy number was associated with increased BMI (change in BMI per estimated copy = −0.15 (0.02) kg/m2; P = 6.93 × 10−10) and obesity risk (odds ratio (OR) per estimated copy = 1.19, 95% confidence interval (CI) = 1.13–1.26; P = 1.46 × 10−10). The OR value of 1.19 per copy of AMY1 translates into about an eightfold difference in risk of obesity between subjects in the top (copy number > 9) and bottom (copy number < 4) 10% of the copy number distribution. Our study provides a first genetic link between carbohydrate metabolism and BMI and demonstrates the power of integrated genomic approaches beyond genome-wide association studies.

Profound changes in breast cancer incidence may reflect changes into a Westernized lifestyle: a comparative population-based study in Singapore and Sweden.

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.

incidence and Survival of Mucinous Adenocarcinoma of the Colorectum: A Population-based Study From an Asian Country

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Polymorphisms Identified through Genome-Wide Association Studies and Their Associations with Type 2 Diabetes in Chinese, Malays, and Asian-Indians in Singapore

CONTEXT Novel type 2 diabetes mellitus (T2DM) susceptibility loci, identified through genome-wide association studies (GWAS), have been replicated in many European and Japanese populations. However, the association in other East Asian populations is less well characterized. OBJECTIVE To examine the effects of SNPs in CDKAL1, CDKN2A/B, IGF2BP2, HHEX, SLC30A8, PKN2, LOC387761, and KCNQ1 on risk of T2DM in Chinese, Malays, and Asian-Indians in Singapore. DESIGN We genotyped these candidate single-nucleotide polymorphisms (SNPs) in subjects from three major ethnic groups in Asia, namely, the Chinese (2196 controls and 1541 cases), Malays (2257 controls and 1076 cases), and Asian-Indians (364 controls and 246 cases). We also performed a metaanalysis of our results with published studies in East Asians. RESULTS In Chinese, SNPs in CDKAL1 [odds ratio (OR) = 1.19; P = 2 x 10(-4)], HHEX (OR = 1.15; P = 0.013), and KCNQ1 (OR = 1.21; P = 3 x 10(-4)) were significantly associated with T2DM. Among Malays, SNPs in CDKN2A/B (OR = 1.22; P = 3.7 x 10(-4)), HHEX (OR = 1.12; P = 0.044), SLC30A8 (OR = 1.12; P = 0.037), and KCNQ1 (OR = 1.19-1.25; P = 0.003-2.5 x 10(-4)) showed significant association with T2DM. The combined analysis of the three ethnic groups revealed significant associations between SNPs in CDKAL1 (OR = 1.13; P = 3 x 10(-4)), CDKN2A/B (OR = 1.16; P = 9 x 10(-5)), HHEX (OR = 1.14; P = 6 x 10(-4)), and KCNQ1 (OR = 1.16-1.20; P = 3 x 10(-4) to 3 x 10(-6)) with T2DM. SLC30A8 (OR = 1.06; P = 0.039) showed association only after adjustment for gender and body mass index. Metaanalysis with data from other East Asian populations showed similar effect sizes to those observed in populations of European ancestry. CONCLUSIONS SNPs at T2DM susceptibility loci identified through GWAS in populations of European ancestry show similar effects in Asian populations. Failure to detect these effects across different populations may be due to issues of power owing to limited sample size, lower minor allele frequency, or differences in genetic effect sizes.

Risk factors associated with hypertension awareness, treatment, and control in a multi-ethnic Asian population.

Objectives To investigate demographic and cardiovascular disease risk factors associated with awareness, treatment and control of hypertension in a multi-ethnic Asian population. Methods Participants from four previous cross-sectional studies were invited for a repeat examination (2004–2007). Information of demographic details and cardiovascular disease risk factors was obtained using questionnaire, physical examination and blood tests. Odds ratios and 95% confidence intervals were calculated using multiple logistic regression models. Results The final number of respondents was 5022 (response rate 49.7%). Although hypertension treatment (84.4% of those aware of hypertension) was high, awareness (51.8% of those having hypertension) and control (27.1% of hypertension on treatment) were low. Reduced awareness and treatment were associated with being younger, never married, and working adults with a higher education level. Low socioeconomic status individuals were more likely to be treated but had poorer control. A similar relationship was found for treatment and control for individuals with coexisting cardiovascular disease risk factors. The use of multiple drug classes was not associated with better control. Diuretic use for treatment of hypertension, as recommended by local and international guidelines, was not common (15.0% of all hypertension medications used). Conclusions The awareness, treatment, and control of hypertension in Singapore can be improved. There is a need to improve awareness through education and target screening and treatment in younger, working adults with higher levels of education and higher economic status, as well as Malays. Control of hypertension could be improved among older or diabetic hypertensive individuals.

Ethnicity Modifies the Relationships of Insulin Resistance, Inflammation, and Adiponectin With Obesity in a Multiethnic Asian Population

OBJECTIVE The development of obesity-related metabolic disorders varies with ethnicity. We examined whether ethnicity modifies the relationship between BMI and three metabolic pathways (insulin resistance, inflammation, and adiponectin) that are involved in the pathogenesis of diabetes and cardiovascular disease (CVD). RESEARCH DESIGN AND METHODS We analyzed data from 4,804 Chinese, Malay, and Asian-Indian residents of Singapore with complete data on insulin resistance (IR), C-reactive protein (CRP), and total adiponectin levels. Linear regression models with an interaction term ethnicity*BMI were used to evaluate whether ethnicity modifies the association between BMI and IR, CRP, and adiponectin. RESULTS In both uni- and multivariate analyses, BMI was directly associated with IR and CRP and inversely with adiponectin across all ethnic groups. When compared with Chinese and Malays, Asian-Indians had higher IR and CRP and lower adiponectin levels. The associations between BMI and its metabolic pathways were significantly stronger in Chinese than in other ethnic groups. The increase in IR and CRP and the decrease in adiponectin for each unit increase in BMI were greater in Chinese than in other ethnic groups. The findings were similar when waist circumference was used in the analyses instead of BMI. CONCLUSIONS The impact of BMI on IR, CRP, and adiponectin appears greater in Chinese as compared with other major Asian ethnic groups. This may partly explain the rapid increase in the prevalence of diabetes and CVD in Chinese populations and highlights the importance of weight management in Asian ethnic groups despite the apparently low levels of obesity.

Should central obesity be an optional or essential component of the metabolic syndrome? : Ischemic heart disease risk in the singapore cardiovascular cohort study

OBJECTIVE—The International Diabetes Federation (IDF) proposes that central obesity is an “essential” component of the metabolic syndrome, while the American Heart Association/National Heart, Lung, and Blood Institute (AHA/NHLBI) proposes that central obesity is an “optional” component. This study examines the effect of the metabolic syndrome with and without central obesity in an Asian population with ischemic heart disease (IHD). RESEARCH DESIGN AND METHODS—From the population-based cohort study (baseline 1992–1995), 4,334 healthy individuals were grouped by the presence or absence of the metabolic syndrome and central obesity and followed up for an average of 9.6 years by linkage with three national registries. Cox’s proportional hazards model was used to obtain adjusted hazard ratios (HRs) for risk of a first IHD event. RESULTS—The prevalence of metabolic syndrome was 17.7% by IDF criteria and 26.2% by AHA/NHLBI criteria using Asian waist circumference cutoff points for central obesity. Asian Indians had higher rates than Chinese and Malays. There were 135 first IHD events. Compared with individuals without metabolic syndrome, those with central obesity/metabolic syndrome and no central obesity/metabolic syndrome were at significantly increased risk of IHD, with adjusted HRs of 2.8 (95% CI 1.8–4.2) and 2.5 (1.5–4.0), respectively. CONCLUSIONS—Having metabolic syndrome either with or without central obesity confers IHD risk. However, having central obesity as an “optional” rather than “essential” criterion identifies more individuals at risk of IHD in this Asian cohort.

Is There a Clear Threshold for Fasting Plasma Glucose That Differentiates Between Those With and Without Neuropathy and Chronic Kidney Disease? The Singapore Prospective Study Program

Recent studies suggest that no distinct glycemic threshold consistently differentiates individuals with or without retinopathy. The authors sought to determine whether the same was true for other microvascular complications. They studied 5,094 participants with fasting plasma glucose values and concurrent microvascular complications from 4 previous cross-sectional surveys carried out in Singapore (1982-1998) who attended a follow-up examination in 2004-2007. Peripheral neuropathy was diagnosed based on abnormal responses to a 10-g monofilament or neurothesiometer test. Chronic kidney disease was defined in various ways by using albuminuria (urine albumin:creatinine ratio >30 microg/mg) and estimated glomerular filtration rate, alone and in combination. Prevalence of peripheral neuropathy was 7.5%. For chronic kidney disease, prevalence of albuminuria only was 10.5%, estimated glomerular filtration rate of <60 mL/minute per 1.73 m(2) only was 4.1%, and both was 2.1%. Prevalence of peripheral neuropathy and chronic kidney disease gradually increased in relation to fasting plasma glucose, beginning at levels below the existing diagnostic threshold for diabetes mellitus of 7.0 mmol/L (126 mg/dL). For chronic kidney disease, these associations persisted after adjustment for age, gender, ethnic group, and hypertension. Current diagnostic thresholds for diabetes mellitus have limited sensitivity for identifying individuals with these microvascular complications. Ascertaining these individuals may require development and application of novel screening strategies.