Previous fracture and subsequent fracture risk: a meta-analysis to update FRAX.

A large international meta-analysis using primary data from 64 cohorts has quantified the increased risk of fracture associated with a previous history of fracture for future use in FRAX. INTRODUCTION: The aim of this study was to quantify the fracture risk associated with a prior fracture on an international basis and to explore the relationship of this risk with age, sex, time since baseline and bone mineral density (BMD). METHODS: We studied 665,971 men and 1,438,535 women from 64 cohorts in 32 countries followed for a total of 19.5 million person-years. The effect of a prior history of fracture on the risk of any clinical fracture, any osteoporotic fracture, major osteoporotic fracture, and hip fracture alone was examined using an extended Poisson model in each cohort. Covariates examined were age, sex, BMD, and duration of follow-up. The results of the different studies were merged by using the weighted ß-coefficients. RESULTS: A previous fracture history, compared with individuals without a prior fracture, was associated with a significantly increased risk of any clinical fracture (hazard ratio, HR = 1.88; 95% CI = 1.72-2.07). The risk ratio was similar for the outcome of osteoporotic fracture (HR = 1.87; 95% CI = 1.69-2.07), major osteoporotic fracture (HR = 1.83; 95% CI = 1.63-2.06), or for hip fracture (HR = 1.82; 95% CI = 1.62-2.06). There was no significant difference in risk ratio between men and women. Subsequent fracture risk was marginally downward adjusted when account was taken of BMD. Low BMD explained a minority of the risk for any clinical fracture (14%), osteoporotic fracture (17%), and for hip fracture (33%). The risk ratio for all fracture outcomes related to prior fracture decreased significantly with adjustment for age and time since baseline examination. CONCLUSION: A previous history of fracture confers an increased risk of fracture of substantial importance beyond that explained by BMD. The effect is similar in men and women. Its quantitation on an international basis permits the more accurate use of this risk factor in case finding strategies.

Update of the fracture risk prediction tool FRAX: a systematic review of potential cohorts and analysis plan.

We describe the collection of cohorts together with the analysis plan for an update of the fracture risk prediction tool FRAX with respect to current and novel risk factors. The resource comprises 2,138,428 participants with a follow-up of approximately 20 million person-years and 116,117 documented incident major osteoporotic fractures. INTRODUCTION: The availability of the fracture risk assessment tool FRAX® has substantially enhanced the targeting of treatment to those at high risk of fracture with FRAX now incorporated into more than 100 clinical osteoporosis guidelines worldwide. The aim of this study is to determine whether the current algorithms can be further optimised with respect to current and novel risk factors. METHODS: A computerised literature search was performed in PubMed from inception until May 17, 2019, to identify eligible cohorts for updating the FRAX coefficients. Additionally, we searched the abstracts of conference proceedings of the American Society for Bone and Mineral Research, European Calcified Tissue Society and World Congress of Osteoporosis. Prospective cohort studies with data on baseline clinical risk factors and incident fractures were eligible. RESULTS: Of the 836 records retrieved, 53 were selected for full-text assessment after screening on title and abstract. Twelve cohorts were deemed eligible and of these, 4 novel cohorts were identified. These cohorts, together with 60 previously identified cohorts, will provide the resource for constructing an updated version of FRAX comprising 2,138,428 participants with a follow-up of approximately 20 million person-years and 116,117 documented incident major osteoporotic fractures. For each known and candidate risk factor, multivariate hazard functions for hip fracture, major osteoporotic fracture and death will be tested using extended Poisson regression. Sex- and/or ethnicity-specific differences in the weights of the risk factors will be investigated. After meta-analyses of the cohort-specific beta coefficients for each risk factor, models comprising 10-year probability of hip and major osteoporotic fracture, with or without femoral neck bone mineral density, will be computed. CONCLUSIONS: These assembled cohorts and described models will provide the framework for an updated FRAX tool enabling enhanced assessment of fracture risk (PROSPERO (CRD42021227266)).

Reproductive factors and risk of total knee replacement due to severe knee osteoarthritis in women, the Singapore Chinese Health Study.

OBJECTIVES: Knee osteoarthritis (OA) is more common in women, and may be related to reproductive or hormonal factors. We evaluated these factors with the risk of total knee replacement (TKR) for severe knee OA among women. METHODS: The Singapore Chinese Health Study recruited 63,257 Chinese aged 45-74 years from 1993 to 1998, and among them, 35,298 were women. Information on height, weight, lifestyle factors, number of biological children, ages at menarche and menopause, and use of hormonal therapies was collected through interviews. Incident cases of TKR were identified via linkage with nationwide database. RESULTS: There were 1,645 women with TKR after mean follow-up of 14.8 years. Higher parity was associated with increased TKR risk in a stepwise manner (P for trend <0.001). Compared to nulliparous women, those with ≥5 children had the highest risk [hazard ratio (HR) 2.01, 95% confidence intervals (CIs) 1.50-2.70]. The effect of parity on TKR risk was significantly stronger among lean women compared to heavier women; HRs (95% CIs) for highest parity was 4.86 (2.22-10.63) for women with body mass index (BMI) <23 kg/m2 and 1.57 (1.14-2.14) for those ≥23 kg/m2 (P for interaction = 0.001). Earlier age at menarche and use of oral contraceptives were significantly associated with TKR in a stepwise manner (P for trend ≤0.002). Age at menopause and use of hormonal therapy were not associated with TKR risk. CONCLUSION: Higher parity, earlier age of menarche and use of oral contraceptives were associated with increased risk of TKR for severe knee OA among women.

No association between circulating concentrations of vitamin D and risk of lung cancer: an analysis in 20 prospective studies in the Lung Cancer Cohort Consortium (LC3).

Background: There is observational evidence suggesting that high vitamin D concentrations may protect against lung cancer. To investigate this hypothesis in detail, we measured circulating vitamin D concentrations in prediagnostic blood from 20 cohorts participating in the Lung Cancer Cohort Consortium (LC3). Patients and methods: The study included 5313 lung cancer cases and 5313 controls. Blood samples for the cases were collected, on average, 5 years before lung cancer diagnosis. Controls were individually matched to the cases by cohort, sex, age, race/ethnicity, date of blood collection, and smoking status in five categories. Liquid chromatography coupled with tandem mass spectrometry was used to separately analyze 25-hydroxyvitamin D2 [25(OH)D2] and 25-hydroxyvitamin D3 [25(OH)D3] and their concentrations were combined to give an overall measure of 25(OH)D. We used conditional logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for 25(OH)D as both continuous and categorical variables. Results: Overall, no apparent association between 25(OH)D and risk of lung cancer was observed (multivariable adjusted OR for a doubling in concentration: 0.98, 95% CI: 0.91, 1.06). Similarly, we found no clear evidence of interaction by cohort, sex, age, smoking status, or histology. Conclusion: This study did not support an association between vitamin D concentrations and lung cancer risk.

Gout and risk of knee replacement for severe knee osteoarthritis in the Singapore Chinese Health Study.

OBJECTIVE: While cross-sectional and retrospective case-control studies suggest that gout is associated with knee osteoarthritis (KOA), no prospective study has evaluated the risk of total knee replacement (TKR) for KOA in association with gout. We prospectively evaluated the association between gout and the risk of TKR due to severe KOA. DESIGN: We used data from the Singapore Chinese Health Study (SCHS), a prospective cohort with 63,257 Chinese adults aged 45-74 years at recruitment (1993-1998). Self-report of physician-diagnosed gout was enquired at follow-up I interview (1999-2004) from 52,322 subjects. TKR cases for KOA after follow-up I were identified via linkage with nationwide hospital discharge database through 31 December 2011. Multivariable Cox proportional hazards regression model was applied with adjustment for potential risk factors of KOA. RESULTS: Among 51,858 subjects (22,180 men and 29,678 women) included in this analysis, after average 9.7 follow-up years, there were 1,435 cases of TKR. Gout was associated with 39% higher risk of TKR in women [hazard ratio (HR) 1.39; 95% confidence interval (CI) 1.08-1.79] but not in men (HR 0.78; 95% CI 0.49-1.23). The positive gout-TKR association in women remained after excluding participants with self-reported history of arthritis (HR 1.57; 95% CI 1.04-2.37). This association was stronger in women who were lean (body mass index [BMI] < 23 kg/m2) (HR 2.17; 95% CI 1.30-3.64) compared to their heavier counterparts (Pinteraction = 0.016). CONCLUSION: Gout is associated with risk of severe KOA, especially in lean women, suggesting the crystal arthritis may play a role in the pathogenesis or progression of OA.

Association between body mass index and risk of total knee replacement, the Singapore Chinese Health Study.

PURPOSE: Data on the association between body mass index (BMI) and risk of knee osteoarthritis (KOA) are sparse for Asian populations who are leaner than Western populations. We evaluated the association between BMI and risk of total knee replacement (TKR) due to severe KOA among Chinese in Singapore. METHODS: We used data from the Singapore Chinese Health Study (SCHS), a population-based prospective cohort of 63,257 Chinese men and women, aged 45-74 years at enrollment from 1993 to 1998. Information on height, weight, diet and lifestyle factors were obtained via in-person interviews. TKR cases for severe KOA were identified via linkage with the nationwide hospital discharge database through 2011. Cox regression and weighted least squares regression were used in the analysis. RESULTS: The mean BMI among cohort participants was 23.1 kg/m(2), and more than two-thirds had BMI below 25 kg/m(2). A total of 1649 had TKR attributable to severe KOA. Risk of TKR increased in a strong dose-dependent manner with increasing BMI throughout the 15-32 kg/m(2) range and became less clear at BMI >32 kg/m(2). In the BMI range 16-27 kg/m(2), there was a 27% increase in TKR risk for each unit increase in BMI (P for trend < 0.001). Compared to BMI 19-20 kg/m(2), the risk estimates of TKR were all statistically significant with increasing unit of BMI ≥21 kg/m(2). Results were similar for men and women. CONCLUSION: Our results provided evidence for a constant mechanical mechanism underlying BMI and KOA initiation and/or progression.

Association between change in body weight after midlife and risk of hip fracture-the Singapore Chinese Health Study.

UNLABELLED: The relationship between change in body weight and risk of fractures is inconsistent in epidemiologic studies. In this cohort of middle-aged to elderly Chinese in Singapore, compared to stable weight, weight loss ≥10 % over an average of 6 years is associated with nearly 40 % increase in risk of hip fracture. INTRODUCTION: Findings on the relationship between change in body weight and risk of hip fracture are inconsistent. In this study, we examined this association among middle-aged and elderly Chinese in Singapore. METHODS: We used prospective data from the Singapore Chinese Health Study, a population-based cohort of 63,257 Chinese men and women aged 45-74 years at recruitment in 1993-1998. Body weight and height were self-reported at recruitment and reassessed during follow-up interview in 1999-2004. Percent in weight change was computed based on the weight difference over an average of 6 years, and categorized as loss ≥10 %, loss 5 to <10 %, loss or gain <5 % (stable weight), gain 5 to <10 %, and gain ≥10 %. Multivariable Cox proportional hazards regression model was applied with adjustment for risk factors for hip fracture and body mass index (BMI) reported at follow-up interview. RESULTS: About 12 % experienced weight loss ≥10 %, and another 12 % had weight gain ≥10 %. After a mean follow-up of 9.0 years, we identified 775 incident hip fractures among 42,149 eligible participants. Compared to stable weight, weight loss ≥10 % was associated with 39 % increased risk (hazard ratio 1.39; 95 % confidence interval 1.14, 1.69). Such elevated risk with weight loss ≥10 % was observed in both genders and age groups at follow-up (≤65 and >65 years) and in those with baseline BMI ≥20 kg/m(2).There was no significant association with weight gain. CONCLUSIONS: Our findings provide evidence that substantial weight loss is an important risk factor for osteoporotic hip fractures among the middle-aged to elderly Chinese.

Cigarette smoking and risk of total knee replacement for severe osteoarthritis among Chinese in Singapore--the Singapore Chinese health study.

PURPOSE: Data on the effects of cigarette smoking with osteoarthritis (OA) are inconsistent and no study has examined the effect of smoking cessation. We examined smoking status, duration, dosage and cessation in association with risk of total knee replacement (TKR) for severe knee OA among elderly Chinese in Singapore. METHODS: We used data from the Singapore Chinese Health Study, a population-based prospective cohort of 63,257 Chinese men and women aged 45-74 years during enrollment between 1993 and 1998. Detailed information on smoking, current diet and lifestyle factors were obtained through in person interviews. As of 31 December 2011, 1,973 incident TKR cases for severe knee OA had been identified via linkage with nationwide hospital discharge database. We used Cox regression methods to examine smoking in relation to TKR risk with adjustment for age, gender, education, body mass index (BMI), comorbidities and physical activity level. RESULTS: Compared to never smokers, current smokers had a 51% decrease in risk of TKR [Hazards ratio (HR) = 0.49; 95% confidence interval (CI) = 0.40-0.60]. Among current smokers, there was a very strong dose-dependent association between increasing duration and dosage of smoking with decreasing risk of TKR (P for trend <0.0001). Among former smokers, there was a dose-dependent response between decrease in duration of smoking cessation and reduction in TKR risk (P for trend = 0.034). CONCLUSION: Our findings strongly implicate smoking as a protective factor for TKR indicated for severe knee OA. This concurs with experimental data that nicotine promotes proliferation and collagen synthesis in chondrocytes.

Diabetes mellitus and risk of hepatocellular carcinoma: findings from the Singapore Chinese Health Study.

BACKGROUND: The increasing prevalence of diabetes may contribute to the rising incidence of hepatocellular carcinoma (HCC) in the US and other developed countries where HCC incidence is relatively low. Data from prospective studies on diabetes and risk of HCC in at-risk populations due to high prevalence of viral hepatitis in southeast Asia are sparse. METHODS: The Singapore Chinese Health Study is a prospective cohort of 63, 257 middle-aged and older Chinese men and women enrolled in 1993-1998. Besides an in-person interview administered to all participants at baseline, testing of serologic markers of hepatitis B or C infections were performed on a subset of cohort subjects. After a mean follow-up of 14 years, 499 cohort participants developed HCC. RESULTS: A history of diabetes at baseline was associated with a hazard ratio of 2.14 (95% confidence interval, 1.69-2.71). This statistically significant association was comparable in magnitude between men and women, and remained equally strong across strata of subjects defined by the number of years between their first clinical diagnosis of diabetes and time of enrollment in this cohort. Within a nested case-control set of cohort subjects tested for serological markers of hepatitis B or C infections, the diabetes-HCC association was found to be present mainly among those devoid of any markers. CONCLUSION: A history of diabetes at baseline is highly associated with non-viral HCC. Future studies are warranted to elucidate the biological mechanism underpinning the role of diabetes in nonviral-related hepatocarcinogenesis.

Dietary B vitamin intake and risk of hip fracture: the Singapore Chinese Health Study.

UNLABELLED: This prospective cohort study that comprehensively examined effects of different B vitamins in an Asian population showed an inverse relationship between dietary intake of pyridoxine and hip fracture risk in elderly women. These findings suggest that maintaining sufficient pyridoxine intake may be beneficial in preserving bone health in postmenopausal women. INTRODUCTION: B vitamins have recently been investigated for their possible roles in maintaining bone health. Incidence of osteoporotic hip fracture has been rising in Asia, but epidemiological data on dietary B vitamins and risk of osteoporotic fractures are sparse. We aimed to examine the association between dietary intakes of B vitamins (thiamin, riboflavin, niacin, pyridoxine, folate, and cobalamin) and hip fracture risk among elderly Chinese in Singapore. METHODS: The current study was conducted in the Singapore Chinese Health Study, which is a population-based cohort prospective study that enrolled a total of 63,257 men and women aged 45-74 years between 1993 and 1998. Dietary intakes of B vitamins were derived from a validated food frequency questionnaire and the Singapore Food Composition Database. RESULTS: After a mean follow-up period of 13.8 years, 1,630 hip fracture incident cases were identified. A statistically significant inverse relationship between dietary pyridoxine intake and hip fracture risk was observed among women (p for trend = 0.002) but not among men. Compared to women in the lowest quartile intake (0.37-0.61 mg/1,000 kcal/day), women in the highest quartile intake (0.78-1.76 mg/1,000 kcal/day) had a 22 % reduction in hip fracture risk (hazard ratio 0.78, 95 % confidence interval 0.66-0.93). Dietary intakes of the other B vitamins of interest were not related to hip fracture risk. CONCLUSIONS: Our findings suggest that maintaining adequate intake of pyridoxine may prevent osteoporotic fractures among elderly women.

All-cause and cause-specific mortality after hip fracture among Chinese women and men: the Singapore Chinese Health Study.

UNLABELLED: All-cause mortality risk persisted for 5 years after hip fractures in both men and women. There may be gender-specific differences in effect and duration of excess risk for cause-specific mortality after hip fracture. INTRODUCTION: To determine all-cause and cause-specific mortality risk in the first 5 years after hip fracture in an Asian Chinese population. METHODS: The Singapore Chinese Health Study is a population-based cohort of 63,257 middle-aged and elderly Chinese men and women in Singapore recruited between 1993 and 1998. This cohort was followed up for hip fracture and death via linkage with nationwide hospital discharge database and death registry. As of 31 December 2008, we identified 1,166 hip fracture cases and matched five non-fracture cohort subjects by age and gender for each fracture case. Cox proportional hazards and competing risks regression models with hip fracture as a time-dependent covariate were used to determine all-cause and cause-specific mortality risk, respectively. RESULTS: Increase in all-cause mortality risk persisted till 5 years after hip fracture (adjusted hazard ratio, aHR = 1.58 [95 % CI, 1.35-1.86] for females and aHR = 1.64 [95 % CI, 1.30-2.06] for males). Men had higher mortality risk after hip fracture than women for deaths from stroke and cancer up to 1 year post-fracture but women with hip fracture had higher coronary artery mortality risk than men for 5 years post-fracture. Men had higher risk of death from pneumonia while women had increased risk of death from urinary tract infections. There was no difference in mortality risk by types of hip fracture surgery. CONCLUSIONS: All-cause mortality risk persisted for 5 years after hip fractures in men and women. There are gender-specific differences in effect size and duration of excess mortality risk from hip fractures between specific causes of death.

Higher parity is associated with an increased risk of type-II diabetes in Chinese women: the Singapore Chinese Health Study.

OBJECTIVE: The association between parity and type-II diabetes has been studied primarily in Western populations, and the findings have been inconsistent. Here, we examine whether parity was positively associated with incident type-II diabetes in Singaporean Chinese women. DESIGN: Prospective cohort study. SETTING: Singapore. POPULATION: A total of 25,021 Singaporean Chinese women aged 45-74 years from the Singapore Chinese Health Study who were free of cancer, heart disease, stroke, and diabetes at baseline (1993-1998). METHODS: Women were followed through 2004 for incident diabetes. Hazard ratios for type-II diabetes were computed across parity (of live births) categories and adjusted for baseline age, interview year, dialect, education, smoking, dietary pattern, physical activity, age at menarche, oral contraceptive use, menopausal status, hormone therapy use, and body mass index (BMI). MAIN OUTCOME MEASURE: Self-reported diabetes, as diagnosed by a doctor. RESULTS: Over an average of 5.7 person-years of follow-up, 1294 women were diagnosed with diabetes. Before and after multivariable adjustment there was a positive graded association between parity and type-II diabetes risk (P < 0.001). In the fully adjusted model, which included adult BMI, the risk of type-II diabetes increased by 31% (from -2 to 76%), 62% (from 22 to 116%), and 74% (from 29 to 133%) for women with one or two, three or four, and five or more live births, respectively, compared with women with no live births. Moreover, in a supplementary multivariate analysis in non-diabetic women we found a positive monotonic association between parity and glycated haemoglobin (HbA1c) (P = 0.01). CONCLUSIONS: Increased parity may be a risk factor for type-II diabetes in Chinese women. More research is needed on lifestyle and physiologic factors that may explain this association.

Body mass, tobacco smoking, alcohol drinking and risk of cancer of the small intestine--a pooled analysis of over 500,000 subjects in the Asia Cohort Consortium.

BACKGROUND: The evidence for a role of tobacco smoking, alcohol drinking, and body mass index (BMI) in the etiology of small intestine cancer is based mainly on case-control studies from Europe and United States. SUBJECTS AND METHODS: We harmonized the data across 12 cohort studies from mainland China, Japan, Korea, Singapore, and Taiwan, comprising over 500,000 subjects followed for an average of 10.6 years. We calculated hazard ratios (HRs) for BMI and (only among men) tobacco smoking and alcohol drinking. RESULTS: A total of 134 incident cases were observed (49 adenocarcinoma, 11 carcinoid, 46 other histologic types, and 28 of unknown histology). There was a statistically non-significant trend toward increased HR in subjects with high BMI [HR for BMI>27.5 kg/m2, compared with 22.6-25.0, 1.50; 95% confidence interval (CI) 0.76-2.96]. No association was suggested for tobacco smoking; men drinking>400 g of ethanol per week had an HR of 1.57 (95% CI 0.66-3.70), compared with abstainers. CONCLUSIONS: Our study supports the hypothesis that elevated BMI may be a risk factor for small intestine cancer. An etiologic role of alcohol drinking was suggested. Our results reinforce the existing evidence that the epidemiology of small intestine cancer resembles that of colorectal cancer.

Predictors of decrease in ankle-brachial index among patients with diabetes mellitus.

AIM: Screening for peripheral arterial disease, a complication among patients with diabetes, is performed by periodic assessment of ankle-brachial index. We aimed to study the degree of ankle-brachial index change over time and factors associated with significant change. METHOD: We assessed difference between two ankle-brachial index measurements over time in a consecutive series of 82 patients with Type 2 diabetes. All patients had ankle-brachial index > 0.9 but ≤ 1.3 for the first measurement, and significant ankle-brachial index decrease was defined as a decrease of > 0.1 in the follow-up measurement compared with the baseline. RESULTS: The mean follow-up duration was 27.6 (median 30.0) months. Significant ankle-brachial index decrease was seen in 20.7% of patients, including 5% with follow-up ankle-brachial index of ≤ 0.9, consistent with the diagnosis of peripheral arterial disease. After adjusting for age and gender, higher baseline HbA(1c) and serum creatinine levels, increase in follow-up serum LDL cholesterol levels compared with baseline and history of retinopathy were predictors of significant ankle-brachial index decrease. CONCLUSIONS: Our study suggests that, within two years, one in five patients with diabetes and a normal ankle-brachial index may have significant progression of peripheral arterial disease. Annual ankle-brachial index assessment and better control of hyperlipidaemia may thus be required for at-risk patients with poor glycaemic control, renal impairment and retinopathy.

Filaggrin mutations are associated with recurrent skin infection in Singaporean Chinese patients with atopic dermatitis.

BACKGROUND: Loss-of-function (null) mutations within the filaggrin (FLG) gene are a strong risk factor for atopic dermatitis (AD). We hypothesized that the absence or reduction of the filaggrin protein could compromise skin barrier and increase patients' susceptibility to recurrent skin infection. OBJECTIVES: To investigate the association between FLG-null mutations and the risk of recurrent skin infection among a series of patients with AD in Singapore. METHODS: This study included 228 Singaporean Chinese patients with AD with at least 1year of follow-up at the time of recruitment between January 2008 and December 2009 at the National Skin Centre in Singapore. Each patient had their medical records reviewed for history of skin infection in the preceding year and was genotyped for 22 FLG-null mutations. RESULTS: Compared with those without the FLG-null mutations, patients with AD who had FLG mutation(s) had approximately a seven times increased risk of more than four episodes of skin infection requiring antibiotics in the past year (odds ratio 6·74; 95% confidence interval 2·29-19·79). This risk was much greater in those with mild or moderate disease, and was present in both users and nonusers of oral steroids. CONCLUSION: This study highlights a novel association between FLG-null mutations and an increased susceptibility to recurrent bacterial skin infection among patients with AD.

Smoking as an independent risk factor for hepatocellular carcinoma: the Singapore Chinese Health Study.

BACKGROUND: Given the close correlation between smoking and alcohol intake in most epidemiologic studies, it is difficult to exclude the residual confounding effect of alcohol in the association between smoking and hepatocellular carcinoma (HCC). METHOD: We evaluated the association between smoking and risk of HCC in the Singapore Chinese Health Study, a prospective cohort with a low prevalence of alcohol intake. Information on cigarette smoking and alcohol consumption was obtained through in-person interviews conducted at enrolment. RESULTS: After a mean of 11.5 years of follow-up, there were 394 incident cases of HCC. Participants who consumed more than two alcoholic drinks per day showed an increased risk for HCC (hazard ratio (HR)=2.24; 95% confidence interval (CI)=1.46-3.41). After adjusting for alcohol consumption and other potential confounders, current vs never smokers had a statistically significant, increased risk of HCC (HR=1.63; 95% CI=1.27-2.10) that was dose-dependent (number of cigarettes per day, P for trend<0.001). The observed tobacco-HCC association also was duration-dependent (years of smoking in ever smokers, P for trend=0.002). When we excluded daily drinkers from the analysis, all risk estimates remained essentially the same and statistically significant. CONCLUSION: Our findings strongly implicate tobacco smoke as a causal factor of HCC development.

Plasma carotenoids and risk of acute myocardial infarction in the Singapore Chinese Health Study.

BACKGROUND AND AIM: Modification of low-density lipoprotein due to oxidative stress is essential in the development of coronary atherosclerosis. Data of specific carotenoids except ß-carotene on cardioprotective effects in humans are limited. METHODS AND RESULTS: This study examined the associations between plasma concentrations of specific carotenoids and incidence of acute myocardial infarction. The study included 280 incident cases of acute myocardial infarction and 560 matched controls nested within the Singapore Chinese Health Study, a prospective cohort of 63,257 Chinese men and women aged 45-74 years old enrolled in 1993-1998 in Singapore. Retinol and carotenoids in prediagnostic plasma were quantified using high-performance liquid chromatography. High levels of plasma ß-cryptoxanthin and lutein were associated with decreased risk of acute myocardial infarction after adjustment for multiple risk factors for coronary heart disease. For ß-cryptoxanthin, the odds ratio (95% confidence interval) for the highest (Q5) versus the lowest (Q1) quintile was 0.67 (0.37-1.21) (P for trend=0.03). For lutein, the odds ratios (95% confidence intervals) for the combined Q2-Q3 and the combined Q4-Q5 versus Q1 were 0.71 (0.45-1.12) and 0.58 (0.35-0.94) respectively (P for trend=0.03). There was no statistically significant association between other carotenoids or retinol and risk of acute myocardial infarction. CONCLUSIONS: High plasma levels of ß-cryptoxanthin and lutein were associated with decreased risk of acute myocardial infarction. The findings of this study support a cardioprotective role of these two carotenoids in humans.

Adipokines and the risk of active TB: a nested case-control study.

BACKGROUND: Adipokines are emerging mediators of immune response, and may affect susceptibility to active TB.OBJECTIVE: To examine the associations between adipokines and the risk of active TB.METHODS: In a case-control study nested within a prospective cohort of middle-aged and older adults in Singapore, 280 incident active TB cases who donated blood for research before diagnosis were matched with 280 controls. Serum levels of adiponectin, resistin, leptin and ghrelin were measured. Multivariable logistic regression models were used to compute the adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between adipokines and the risk of active TB.RESULTS: Higher levels of leptin and resistin were associated with reduced risk of TB in a dose-dependent manner. Compared to those in the lowest quartile of leptin levels, those in the highest quartile had an OR of 0.46 (95%CI 0.26-0.82; P for trend = 0.009). Similarly, compared to those in the lowest quartile of resistin levels, those in the highest quartile had an OR of 0.46 (95%CI 0.24-0.90; P for trend = 0.03). Adiponectin and ghrelin levels were not associated with TB risk.CONCLUSION: Increased serum levels of leptin and resistin may be associated with reduced susceptibility to active TB infection.

Body mass index and smoking-related lung cancer risk in the Singapore Chinese Health Study.

BACKGROUND: Smokers with low body mass index (BMI) may be more susceptible to lung cancer. METHODS: We prospectively examined the association between baseline BMI and lung cancer risk in the Singapore Chinese Health Study, a cohort of 63 257 Chinese enrolled between 1993 and 1998. RESULTS: After adjustment for smoking intensity and duration, BMI was inversely associated with risk of lung cancer among current smokers (P for trend=0.0004). Current smokers at different dosage of smoking with low BMI had significantly higher risk for lung cancer than those with high BMI. Hazard ratios (95% confidence intervals) of lung cancer for heavy smokers with BMI of > or =28, 24-<28, 20-<24, and <20 kg m(-2) were 6.37 (2.10-19.30), 9.01 (5.04-16.10), 8.53 (6.35-11.5), and 11.12 (6.60-18.70), respectively, as compared with nonsmokers. BMI had no modifying effects on lung cancer risk among nonsmokers and former smokers. CONCLUSION: Smokers with lower BMI may experience an enhanced risk of lung cancer. The findings have significant public-health implication given the increase in smoking prevalence in developing countries, where people still have relatively low BMI.