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Background: Tobacco smoking is a major risk factor for many diseases. We sought to quantify the burden of tobacco-smoking-related deaths in Asia, in parts of which men's smoking prevalence is among the world's highest. Methods and Findings: We performed pooled analyses of data from 1,049,929 participants in 21 cohorts in Asia to quantify the risks of total and cause-specific mortality associated with tobacco smoking using adjusted hazard ratios and their 95% confidence intervals. We then estimated smoking-related deaths among adults aged [greater than or equal to]45 y in 2004 in Bangladesh, India, mainland China, Japan, Republic of Korea, Singapore, and Taiwan--accounting for ~71% of Asia's total population. An approximately 1.44-fold (95% CI = 1.37-1.51) and 1.48-fold (1.38-1.58) elevated risk of death from any cause was found in male and female ever-smokers, respectively. In 2004, active tobacco smoking accounted for approximately 15.8% (95% CI = 14.3%-17.2%) and 3.3% (2.6%-4.0%) of deaths, respectively, in men and women aged $45 y in the seven countries/ regions combined, with a total number of estimated deaths of ~1,575,500 (95% CI = 1,398,000-1,744,700). Among men, approximately 11.4%, 30.5%, and 19.8% of deaths due to cardiovascular diseases, cancer, and respiratory diseases, respectively, were attributable to tobacco smoking. Corresponding proportions for East Asian women were 3.7%, 4.6%, and 1.7%, respectively. The strongest association with tobacco smoking was found for lung cancer: a 3- to 4-fold elevated risk, accounting for 60.5% and 16.7% of lung cancer deaths, respectively, in Asian men and East Asian women aged [greater than or equal to]45 y. Conclusions: Tobacco smoking is associated with a substantially elevated risk of mortality, accounting for approximately 2 million deaths in adults aged $45 y throughout Asia in 2004. It is likely that smoking-related deaths in Asia will continue to rise over the next few decades if no effective smoking control programs are implemented. Please see later in the article for the Editors' Summary., Introduction Tobacco smoking is a major risk factor for many diseases, including cardiovascular disease (CVD), respiratory disease, and cancers of the lung and multiple other sites [1,2]. In the US [...]

Introduction: Telomeres and telomerase play important role in maintaining chromosome integrity and genomic stability. Recent epidemiologic data showed inconsistent findings which suggested that both short and long leukocyte telomeres could be associated with increased risk of pancreatic cancer. We prospectively examined the association between telomere length and pancreatic cancer risk in a population-based cohort study. Methods: The Singapore Chinese Health Study recruited 63,257 Chinese aged 45 to 74 years from 1993 to 1998 in Singapore. Relative telomere length in peripheral blood leukocytes was quantified using a validated monochrome multiplex quantitative polymerase chain reaction method in 26,540 participants, including 116 participants who later developed pancreatic cancer after an average of 13 years of follow-up. Cox proportional hazard regression method was used to calculate hazard ratio (HR) and its 95% confidence interval (CI) of pancreatic cancer risk associated with telomere length, with adjustment for confounding factors. Results: Longer telomeres were significantly associated with higher risk of pancreatic cancer (Ptrend = 0.02). Compared with lowest quartile, subjects with highest quartile of telomere length had an HR of 2.18 (95% CI: 1.25–3.80) for developing pancreatic cancer. In stratified analysis, this association remained among pancreatic adenocarcinoma patients but not among pancreatic non-adenocarcinoma patients. In continuous scale, the HRs and 95% CIs were 3.08 (1.17–8.11) for adenocarcinoma patients and 1.47 (0.43–5.06) for non-adenocarcinoma patients. The HRs and 95% CIs of the highest quartile of telomere length, compared with the lowest quartile, for adenocarcinoma and non-adenocarcinoma were 2.50 (1.22–5.13) and 1.63 (0.66–4.03), respectively. The length of follow-up from the collection of blood for the measurement of telomere length to the diagnosis of cancer (median = 8.0, range: from 5.0 months to 16.2 years) had no significant impact on the association between telomere length and pancreatic cancer risk. Conclusions: The present study demonstrates that longer telomeres are associated with increased risk of overall pancreatic cancer. [ABSTRACT FROM AUTHOR]

Background: Serum pyridoxal 5’-phosphate (PLP), the active form of vitamin B6, is associated with reduced risk of pancreatic cancer. Data on functional measures of vitamin B6 status and risk of pancreatic cancer is lacking. Methods: A nested case-control study involving 187 incident cases of pancreatic cancer and 362 individually matched controls were conducted within two prospective cohorts to evaluate the associations between kynurenine metabolites in pre-diagnostic serum samples and risk of pancreatic cancer. Results: Higher serum concentrations of 3-hydroxyanthranilic acid (HAA) and the HAA:3-hydroxykynurenine (HK) ratio (a measure for in vivo functional status of PLP) were significantly associated with reduced risk of pancreatic cancer. Compared with the lowest tertile, odds ratios (95% confidence intervals) of pancreatic cancer for the highest tertile was 0.62 (0.39, 1.01) for HAA, and 0.59 (0.35–0.98) for the HAA:HK ratio, after adjustment for potential confounders and serum PLP (both Ps for trend<0.05). The kynurenine:tryptophan ratio or neopterin was not significantly associated with pancreatic cancer risk. Conclusions: The inverse association between HAA or the HAA:HK ratio and risk of pancreatic cancer supports the notion that functional status of PLP may be a more important measure than circulating PLP alone for the development of pancreatic cancer. [ABSTRACT FROM AUTHOR]

ABO blood type is an inherited characteristic. The associations between ABO blood type and risk of all cancer and specific cancers were examined in a prospective cohort study of 18,244 Chinese men enrolled in 1986. During the 25 years of follow-up, 3,973 men developed cancer including 964 lung cancers, 624 colorectal cancers, 560 gastric cancers, 353 liver cancers, and 172 urinary bladder cancers. Hazard ratios (HR) for all cancer and specific cancers by ABO blood type were calculated using Cox proportional hazards models. Compared with blood type A, blood type B was associated with statistically significant reduced risk of all cancers (HR, 0.91, 95% CI:0.84, 0.99). Both blood types B and AB were associated with significantly lower risk of gastrointestinal cancer and colorectal cancer, respectively. Blood type B was also associated with significantly lower risk of stomach cancer and bladder cancer, while blood type AB was associated with significantly increased risk of liver cancer. By histological type, blood types B and AB were associated with lower risk of epidermoid carcinoma and adenocarcinoma, but were not associated with risk of sarcoma, lymphoma, leukemia or other cell types of cancer. The findings of this study support a role of genetic traits related to ABO blood type in the development of cancers in the gastrointestinal and urinary tracts. [ABSTRACT FROM AUTHOR]

Lung cancer is unusually common among non-smoking women in Southeastern Asia but the causes of this frequently fatal disease are not well understood. Several epidemiology studies indicate that inhalation of fumes from high temperature Chinese style cooking with a wok may be a cause. Only one previous study investigated uptake of potential toxicants and carcinogens by women who cook with a wok. We enrolled three-hundred twenty-eight non-smoking women from Singapore for this study. Each provided a spot urine sample and answered a questionnaire concerning their cooking habits and other factors. The urine samples were analyzed by liquid chromatography-tandem mass spectrometry for mercapturic acid metabolites of acrolein (3-hydroxypropylmercapturic acid), crotonaldehyde (3-hydroxy-1-methylpropylmercapturic acid), and benzene (S-phenylmercapturic acid), accepted biomarkers of uptake of these toxic and carcinogenic compounds. We observed statistically significant effects of wok cooking frequency on levels of 3-hydroxypropylmercapturic acid and 3-hydroxy-1-methylpropylmercapturic acid, but not S-phenylmercapturic acid. Women who cooked greater than 7 times per week had a geometric mean of 2600 (95% CI, 2189-3090) pmol/mg creatinine 3-hydroxypropylmercapturic acid compared to 1901 (95% CI, 1510-2395) pmol/mg creatinine when cooking less than once per week (P for trend 0.018). The corresponding values for 3-hydroxy-1-methylpropylmercapturic acid were 1167 (95% CI, 1022-1332) and 894 (95% CI, 749-1067) pmol/mg creatinine (P for trend 0.008). We conclude that frequent wok cooking leads to elevated exposure to the toxicants acrolein and crotonaldehyde, but not benzene. Kitchens should be properly ventilated to decrease exposure to potentially toxic and carcinogenic fumes produced during Chinese style wok cooking. [ABSTRACT FROM AUTHOR]

Background: N-Nitroso compounds are thought to play a significant role in the development of gastric cancer. Epidemiological data, however, are sparse in examining the associations between biomarkers of exposure to N-nitroso compounds and the risk of gastric cancer. Methods: A nested case-control study within a prospective cohort of 18,244 middle-aged and older men in Shanghai, China, was conducted to examine the association between urinary level of N-nitroso compounds and risk of gastric cancer. Information on demographics, usual dietary intake, and use of alcohol and tobacco was collected through in-person interviews at enrollment. Urinary levels of nitrate, nitrite, N-nitroso-2-methylthiazolidine-4-carboxylic acid (NMTCA), N-nitrosoproline (NPRO), N-nitrososarcosine (NSAR), N-nitrosothiazolidine-4-carboxylic acid (NTCA), as well as serum H. pylori antibodies were quantified in 191 gastric cancer cases and 569 individually matched controls. Logistic regression method was used to assess the association between urinary levels of N-nitroso compounds and risk of gastric cancer. Results: Compared with controls, gastric cancer patients had overall comparable levels of urinary nitrate, nitrite, and N-nitroso compounds. Among individuals seronegative for antibodies to H. pylori, elevated levels of urinary nitrate were associated with increased risk of gastric cancer. The multivariate-adjusted odds ratios for the second and third tertiles of nitrate were 3.27 (95% confidence interval = 0.76–14.04) and 4.82 (95% confidence interval = 1.05–22.17), respectively, compared with the lowest tertile (P for trend = 0.042). There was no statistically significant association between urinary levels of nitrite or N-nitroso compounds and risk of gastric cancer. Urinary NMTCA level was significantly associated with consumption of alcohol and preserved meat and fish food items. Conclusion: The present study demonstrates that exposure to nitrate, a precursor of N-nitroso compounds, may increase the risk of gastric cancer among individuals without a history of H. pylori infection. [ABSTRACT FROM AUTHOR]

Background: Genome-wide association studies (GWAS) have identified genetic factors in type 2 diabetes (T2D), mostly among individuals of European ancestry. We tested whether previously identified T2D-associated single nucleotide polymorphisms (SNPs) replicate and whether SNPs in regions near known T2D SNPs were associated with T2D within the Singapore Chinese Health Study. Methods: 2338 cases and 2339 T2D controls from the Singapore Chinese Health Study were genotyped for 507,509 SNPs. Imputation extended the genotyped SNPs to 7,514,461 with high estimated certainty (r2>0.8). Replication of known index SNP associations in T2D was attempted. Risk scores were computed as the sum of index risk alleles. SNPs in regions ±100 kb around each index were tested for associations with T2D in conditional fine-mapping analysis. Results: Of 69 index SNPs, 20 were genotyped directly and genotypes at 35 others were well imputed. Among the 55 SNPs with data, disease associations were replicated (at p<0.05) for 15 SNPs, while 32 more were directionally consistent with previous reports. Risk score was a significant predictor with a 2.03 fold higher risk CI (1.69–2.44) of T2D comparing the highest to lowest quintile of risk allele burden (p = 5.72×10−14). Two improved SNPs around index rs10923931 and 5 new candidate SNPs around indices rs10965250 and rs1111875 passed simple Bonferroni corrections for significance in conditional analysis. Nonetheless, only a small fraction (2.3% on the disease liability scale) of T2D burden in Singapore is explained by these SNPs. Conclusions: While diabetes risk in Singapore Chinese involves genetic variants, most disease risk remains unexplained. Further genetic work is ongoing in the Singapore Chinese population to identify unique common variants not already seen in earlier studies. However rapid increases in T2D risk have occurred in recent decades in this population, indicating that dynamic environmental influences and possibly gene by environment interactions complicate the genetic architecture of this disease. [ABSTRACT FROM AUTHOR]

Mitochondrial DNA (mtDNA) copy number in peripheral blood is associated with increased risk of several cancers. However, data from prospective studies on mtDNA copy number and breast cancer risk are lacking. We evaluated the association between mtDNA copy number in peripheral blood and breast cancer risk in a nested case-control study of 183 breast cancer cases with pre-diagnostic blood samples and 529 individually matched controls among participants of the Singapore Chinese Health Study. The mtDNA copy number was measured using real time PCR. Conditional logistic regression analyses showed that there was an overall positive association between mtDNA copy number and breast cancer risk (Ptrend = 0.01). The elevated risk for higher mtDNA copy numbers was primarily seen for women with <3 years between blood draw and cancer diagnosis; ORs (95% CIs) for 2nd, 3rd, 4th, and 5th quintile of mtDNA copy number were 1.52 (0.61, 3.82), 2.52 (1.03, 6.12), 3.12 (1.31, 7.43), and 3.06 (1.25, 7.47), respectively, compared with the 1st quintile (Ptrend = 0.004). There was no association between mtDNA copy number and breast cancer risk among women who donated a blood sample ≥3 years before breast cancer diagnosis (Ptrend = 0.41). This study supports a prospective association between increased mtDNA copy number and breast cancer risk that is dependent on the time interval between blood collection and breast cancer diagnosis. Future studies are warranted to confirm these findings and to elucidate the biological role of mtDNA copy number in breast cancer risk. [ABSTRACT FROM AUTHOR]

Background: The occurrence of diabetes has greatly increased in low- and middle-income countries, particularly in Asia, as has the prevalence of overweight and obesity; in European-derived populations, overweight and obesity are established causes of diabetes. The shape of the association of overweight and obesity with diabetes risk and its overall impact have not been adequately studied in Asia. Methods and Findings: A pooled cross-sectional analysis was conducted to evaluate the association between baseline body mass index (BMI, measured as weight in kg divided by the square of height in m) and self-reported diabetes status in over 900,000 individuals recruited in 18 cohorts from Bangladesh, China, India, Japan, Korea, Singapore and Taiwan. Logistic regression models were fitted to calculate cohort-specific odds ratios (OR) of diabetes for categories of increasing BMI, after adjustment for potential confounding factors. OR were pooled across cohorts using a random-effects meta-analysis. The sex- and age-adjusted prevalence of diabetes was 4.3% in the overall population, ranging from 0.5% to 8.2% across participating cohorts. Using the category 22.5-24.9 Kg/m2 as reference, the OR for diabetes spanned from 0.58 (95% confidence interval [CI] 0.31, 0.76) for BMI lower than 15.0 kg/m2 to 2.23 (95% CI 1.86, 2.67) for BMI higher than 34.9 kg/m2. The positive association between BMI and diabetes prevalence was present in all cohorts and in all subgroups of the study population, although the association was stronger in individuals below age 50 at baseline (p-value of interaction<0.001), in cohorts from India and Bangladesh (p<0.001), in individuals with low education (p-value 0.02), and in smokers (p-value 0.03); no differences were observed by gender, urban residence, or alcohol drinking. Conclusions: This study estimated the shape and the strength of the association between BMI and prevalence of diabetes in Asian populations and identified patterns of the association by age, country, and other risk factors for diabetes. [ABSTRACT FROM AUTHOR]

Background: Elevated serum homocysteine is associated with an increased risk of cardiovascular disease (CVD). This may reflect a reduced systemic remethylation capacity, which would be expected to cause decreased genomic DNA methylation in peripheral blood leukocytes (PBL)., Methodology/principal Findings: We examined the association between prevalence of CVD (myocardial infarction, stroke) and its predisposing conditions (hypertension, diabetes) and PBL global genomic DNA methylation as represented by ALU and Satellite 2 (AS) repetitive element DNA methylation in 286 participants of the Singapore Chinese Health Study, a population-based prospective investigation of 63,257 men and women aged 45-74 years recruited during 1993-1998. Men exhibited significantly higher global DNA methylation [geometric mean (95% confidence interval (CI)): 159 (143, 178)] than women [133 (121, 147)] (P = 0.01). Global DNA methylation was significantly elevated in men with a history of CVD or its predisposing conditions at baseline (P = 0.03) but not in women (P = 0.53). Fifty-two subjects (22 men, 30 women) who were negative for these CVD/predisposing conditions at baseline acquired one or more of these conditions by the time of their follow-up I interviews, which took place on average about 5.8 years post-enrollment. Global DNA methylation levels of the 22 incident cases in men were intermediate (AS, 177) relative to the 56 male subjects who remained free of CVD/predisposing conditions at follow-up (lowest AS, 132) and the 51 male subjects with a diagnosis of CVD or predisposing conditions reported at baseline (highest AS 184) (P for trend = 0.0008) No such association was observed in women (P = 0.91). Baseline body mass index was positively associated with AS in both men and women (P = 0.007)., Conclusions/significance: Our findings indicate that elevated, not decreased, PBL DNA methylation is positively associated with prevalence of CVD/predisposing conditions and obesity in Singapore Chinese.