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Background - The obesity-lung cancer association remains controversial. Concerns over confounding by smoking and reverse causation persist. The influence of obesity type and effect modifications by race/ethnicity and tumor histology are largely unexplored.
Methods - We examined associations of body mass index (BMI), waist circumference (WC), and waist-hip ratio (WHR) with lung cancer risk among 1.6 million Americans, Europeans, and Asians. Cox proportional hazard regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) with adjustment for potential confounders. Analyses for WC/WHR were further adjusted for BMI. The joint effect of BMI and WC/WHR was also evaluated.
Results - During an average 12-year follow-up, 23 732 incident lung cancer cases were identified. While BMI was generally associated with a decreased risk, WC and WHR were associated with increased risk after controlling for BMI. These associations were seen 10 years before diagnosis in smokers and never smokers, were strongest among blacks, and varied by histological type. After excluding the first five years of follow-up, hazard ratios per 5 kg/m2 increase in BMI were 0.95 (95% CI = 0.90 to 1.00), 0.92 (95% CI = 0.89 to 0.95), and 0.89 (95% CI = 0.86 to 0.91) in never, former, and current smokers, and 0.86 (95% CI = 0.84 to 0.89), 0.94 (95% CI = 0.90 to 0.99), and 1.09 (95% CI = 1.03 to 1.15) for adenocarcinoma, squamous cell, and small cell carcinoma, respectively. Hazard ratios per 10 cm increase in WC were 1.09 (95% CI = 1.00 to 1.18), 1.12 (95% CI = 1.07 to 1.17), and 1.11 (95% CI = 1.07 to 1.16) in never, former, and current smokers, and 1.06 (95% CI = 1.01 to 1.12), 1.20 (95% CI = 1.12 to 1.29), and 1.13 (95% CI = 1.04 to 1.23) for adenocarcinoma, squamous cell, and small cell carcinoma, respectively. Participants with BMIs of less than 25 kg/m2 but high WC had a 40% higher risk (HR = 1.40, 95% CI = 1.26 to 1.56) than those with BMIs of 25 kg/m2 or greater but normal/moderate WC.
Conclusions - The inverse BMI-lung cancer association is not entirely due to smoking and reverse causation. Central obesity, particularly concurrent with low BMI, may help identify high-risk populations for lung cancer.
INTRODUCTION - Kidney stone risk factors are understudied among Asians. Our study objective was to investigate associations of obesity and other chronic diseases with incident kidney stones among the urban Chinese.
PATIENTS AND METHODS - Included in this study are two prospective cohorts: the Shanghai Women's Health Study (N = 69,166) and Shanghai Men's Health Study (N = 58,054). Incident kidney stones were determined by self-report in 2004 and 2008. Cox regression models were used to evaluate the associations of study variables with stone risk with adjustment of demographics, medical history, and dietary intakes.
RESULTS - There were 2653 incident stones over 1,007,958 person-years of follow-up. Overall incidence rates (per 1000 person-years, 95% confidence interval [CI]) were 2.10 (1.99, 2.21) among women and 3.80 (3.59, 4.02) among men. Higher body mass index (BMI) was associated with risk (BMI ≥25 vs 18.5-24.9 kg/m, women: hazard ratio [HR] = 1.14 [95% CI 1.01, 1.28]; men: HR = 1.17 [1.03, 1.32]). High waist-hip ratio (≥0.80 and ≥0.90 for women and men, respectively) was associated with risk (HR 1.13, 95% CI 1.01, 1.27 for women; HR 1.19, 95% CI 1.05, 1.35 for men). Coronary heart disease or stroke history was associated with risk in women only (HR 1.31, 95% CI 1.10, 1.56). Hypertension history was associated with risk in men only (HR 1.27, 95% CI 1.11, 1.45). No significant association with diabetes mellitus was observed.
CONCLUSIONS - Among the Chinese, kidney stone incidence in men is almost twice that of women. Obesity is a shared risk factor. Hypertension history is associated with risk in men, whereas history of coronary heart disease or stroke is associated with risk in women.
Genome-wide association studies (GWAS) have identified >300 loci associated with measures of adiposity including body mass index (BMI) and waist-to-hip ratio (adjusted for BMI, WHRadjBMI), but few have been identified through screening of the African ancestry genomes. We performed large scale meta-analyses and replications in up to 52,895 individuals for BMI and up to 23,095 individuals for WHRadjBMI from the African Ancestry Anthropometry Genetics Consortium (AAAGC) using 1000 Genomes phase 1 imputed GWAS to improve coverage of both common and low frequency variants in the low linkage disequilibrium African ancestry genomes. In the sex-combined analyses, we identified one novel locus (TCF7L2/HABP2) for WHRadjBMI and eight previously established loci at P < 5×10-8: seven for BMI, and one for WHRadjBMI in African ancestry individuals. An additional novel locus (SPRYD7/DLEU2) was identified for WHRadjBMI when combined with European GWAS. In the sex-stratified analyses, we identified three novel loci for BMI (INTS10/LPL and MLC1 in men, IRX4/IRX2 in women) and four for WHRadjBMI (SSX2IP, CASC8, PDE3B and ZDHHC1/HSD11B2 in women) in individuals of African ancestry or both African and European ancestry. For four of the novel variants, the minor allele frequency was low (<5%). In the trans-ethnic fine mapping of 47 BMI loci and 27 WHRadjBMI loci that were locus-wide significant (P < 0.05 adjusted for effective number of variants per locus) from the African ancestry sex-combined and sex-stratified analyses, 26 BMI loci and 17 WHRadjBMI loci contained ≤ 20 variants in the credible sets that jointly account for 99% posterior probability of driving the associations. The lead variants in 13 of these loci had a high probability of being causal. As compared to our previous HapMap imputed GWAS for BMI and WHRadjBMI including up to 71,412 and 27,350 African ancestry individuals, respectively, our results suggest that 1000 Genomes imputation showed modest improvement in identifying GWAS loci including low frequency variants. Trans-ethnic meta-analyses further improved fine mapping of putative causal variants in loci shared between the African and European ancestry populations.
OBJECTIVES - Arachidonic acid metabolites (eicosanoids) reflect oxidative stress and vascular health and have been associated with anthropometric measures and sex differences in cross-sectional analyses of HIV-infected (HIV+) persons. Telmisartan is an angiotensin receptor blocker and PPAR-γ agonist with potential anti-inflammatory and metabolic benefits. We assessed telmisartan's effects on urine eicosanoids among HIV+ adults with central adiposity on suppressive antiretroviral therapy enrolled in a prospective clinical trial.
METHODS - Thirty-five HIV+ adults (15 women; 20 men) completed 24 weeks of open-label oral telmisartan 40mg daily. Lumbar computed tomography quantified visceral (VAT) and subcutaneous (SAT) abdominal adipose tissue. Urine F2-isoprostane (F2-IsoP), prostaglandin E2 (PGE-M), prostacyclin (PGI-M), and thromboxane B2 (TxB-M) were quantified at baseline and 24 weeks using gas/liquid chromatography-mass spectroscopy. Mann-Whitney-U tests compared sub-group differences; Spearman's rho assessed correlations between clinical factors and eicosanoid levels.
RESULTS - Median PGE-M increased on telmisartan (p<0.01), with greater changes in men (+4.1 [p = 0.03] vs. +1.0 ng/mg cr in women; between-group p = 0.25) and participants losing >5% VAT (+3.7 ng/mg cr, p<0.01) and gaining >5% SAT (+1.7 ng/mg cr, p = 0.04). Median baseline F2-IsoP and TxB-M were slightly higher in women (both between-group p = 0.08) and did not change on telmisartan.
CONCLUSIONS - Urine PGE-M increased with 24 weeks of telmisartan in virally suppressed, HIV+ adults with central adiposity. Associations with favorable fat redistribution suggest increased PGE-M may reflect a beneficial response.
The association of obesity on survival among patients with colorectal cancer (CRC) has not been well characterized. We investigated the association of prediagnostic body mass index (BMI)/waist-hip ratio (WHR) and total/cause-specific mortality in CRC patients. Our study included 1,452 patients who participated in two large cohort studies and were diagnosed with CRC during follow-up period. Participants were measured for anthropometrics and interviewed to collect relevant information at baseline, prior to any cancer diagnosis. Data on site-specific cancer incidence and cause-specific mortality were obtained via in-person surveys and annual record linkage with cancer and vital statistics registries. Cox proportional hazard models were used to evaluate the associations of BMI and WHR with survival. A total of 547 participants died during the follow-up period, including 499 who died of CRC. Relative to normal BMI (18.5 to <25.0 kg/m ), obesity (BMI ≥ 30 kg/m ) was associated with increased mortality resulting from all causes [hazard ratio (HR) = 1.5, 95% confidence interval (CI): 1.1-2.1] and CRC (HR = 1.5, 95% CI: 1.1-2.1). Elevated risk of death was also found among underweight patients (BMI < 18.5 kg/m ), although not all risk estimates were statistically significant. Overweight BMI (25.0 to <30.0 kg/m ) was not associated with risk of death among CRC patients, nor was WHR. In conclusion, prediagnostic BMI was associated with survival among CRC patients following a U-shape pattern; obesity was associated with high mortality after CRC diagnosis. These findings provide support for maintaining healthy weight to improve the survival of CRC patients.
© 2016 UICC.
General obesity, typically measured using body mass index (BMI), has been associated with an increased risk of several cancers. However, few prospective studies have been conducted in Asian populations. Although central obesity, often measured using waist-hip ratio (WHR), is more predictive for type 2 diabetes and cardiovascular diseases (CVD) risk than BMI, knowledge of its association with cancer incidence is limited. In a cohort of 68,253 eligible Chinese women, we prospectively investigated the association of BMI, WHR and weight change during adulthood with risk of overall cancer and major site-specific cancers using multivariate Cox proportional hazard models. Compared to the BMI group of 18.5-22.9 kg/m(2) , obese (BMI ≥ 30 kg/m(2) ) women were at an increased risk of developing overall cancer (hazard ratio = 1.36, 95% confidence interval = 1.21-1.52), postmenopausal breast cancer (HR: 2.43, 95% CI: 1.73-3.40), endometrial cancer (HR: 5.34, 95% CI: 3.48-8.18), liver cancer (HR: 1.93, 95% CI: 1.14-3.27) and epithelial ovarian cancer (HR: 2.44, 95% CI: 1.37-4.35). Weight gain during adulthood (per 5 kg gain) was associated with increased risk of all cancers combined (HR: 1.05, 95% CI: 1.03-1.08), postmenopausal breast cancer (HR: 1.17, 95% CI: 1.10-1.24) and endometrial cancer (HR: 1.37, 95% CI: 1.27-1.48). On the other hand, WHR was not associated with cancer risk after adjustment for baseline BMI. These findings suggest that obesity may be associated with cancer risk through different mechanisms from those for type 2 diabetes and CVD and support measures of maintaining health body weight to reduce cancer risk in Chinese women.
© 2016 UICC.
Although the role of complete gene inactivation by two loss-of-function mutations inherited in trans is well-established in recessive Mendelian diseases, we have not yet explored how such gene knockouts (KOs) could influence complex human phenotypes. Here, we developed a statistical framework to test the association between gene KOs and quantitative human traits. Our method is flexible, publicly available, and compatible with common genotype format files (e.g. PLINK and vcf). We characterized gene KOs in 4498 participants from the NHLBI Exome Sequence Project (ESP) sequenced at high coverage (>100×), 1976 French Canadians from the Montreal Heart Institute Biobank sequenced at low coverage (5.7×), and >100 000 participants from the Genetic Investigation of ANthropometric Traits (GIANT) Consortium genotyped on an exome array. We tested associations between gene KOs and three anthropometric traits: body mass index (BMI), height and BMI-adjusted waist-to-hip ratio (WHR). Despite our large sample size and multiple datasets available, we could not detect robust associations between specific gene KOs and quantitative anthropometric traits. Our results highlight several limitations and challenges for future gene KO studies in humans, in particular when there is no prior knowledge on the phenotypes that might be affected by the tested gene KOs. They also suggest that gene KOs identified with current DNA sequencing methodologies probably do not strongly influence normal variation in BMI, height, and WHR in the general human population.
© The Author 2016. Published by Oxford University Press.
Sixty genetic loci associated with abdominal obesity, measured by waist circumference (WC) and waist-hip ratio (WHR), have been previously identified, primarily from studies conducted in European-ancestry populations. We conducted a meta-analysis of associations of abdominal obesity with approximately 2.5 million single nucleotide polymorphisms (SNPs) among 53,052 (for WC) and 48,312 (for WHR) individuals of Asian descent, and replicated 33 selected SNPs among 3,762 to 17,110 additional individuals. We identified four novel loci near the EFEMP1, ADAMTSL3 , CNPY2, and GNAS genes that were associated with WC after adjustment for body mass index (BMI); two loci near the NID2 and HLA-DRB5 genes associated with WHR after adjustment for BMI, and three loci near the CEP120, TSC22D2, and SLC22A2 genes associated with WC without adjustment for BMI. Functional enrichment analyses revealed enrichment of corticotropin-releasing hormone signaling, GNRH signaling, and/or CDK5 signaling pathways for those newly-identified loci. Our study provides additional insight on genetic contribution to abdominal obesity.
Asians have high prevalence of central obesity despite the low prevalence of general obesity. We evaluated associations between the central obesity measure, waist-hip ratio (WHR) with total and cause-specific mortality in middle-aged and elderly Chinese participants. Data arise from two prospective population-based cohort studies: the Shanghai Men's Health Study involves 53,425 men (participation rate = 74.0%), age 40-74 at baseline, and the Shanghai Women's Health Study involves 63,017 women (participation rate = 92.7%), age 40-70 at baseline. Information on lifestyle factors and anthropometric measurements were taken at baseline interview. Vital status and causes of death were obtained via surveys and annual linkages to relevant Shanghai registries through December 31, 2011. After median follow-up time of 7.5 years for the Shanghai Men's Health Study and 13.2 years for the Shanghai Women's Health Study, there were 2,058 and 3,167 deaths, respectively. In models adjusted for BMI and other potential confounders, WHR was associated with all-cause mortality; hazard ratios (HRs) (95% confidence intervals) across the first to fifth quintile increased from 1 (Reference), 1.10 (0.95,1.27), 1.21 (1.04,1.41), 1.11 (0.96,1.30), to 1.42 (1.22,1.65) in men and from 1 (Reference), 1.10 (0.96,1.27), 1.11 (0.97,1.27), 1.20 (1.05,1.37), to 1.48 (1.30,1.69) in women. WHR had a stronger association with cardiovascular disease, with multivariate-adjusted HRs of 1.5 to 1.7 observed for the highest versus lowest quintile of WHR. Dose-response associations were also seen for cancer and other-cause deaths. Stratified analyses suggested a stronger association with mortality among normal weight (BMI <25) than over-weight (BMI ≥25) individuals. Positive associations with mortality were observed in subgroups defined by follow-up duration, comorbidity, age, smoking, and physical activity. Greater central adiposity is associated with increased mortality in Chinese adults, even among individuals with low BMI. Physicians and the public should be aware of central adiposity's independent effects on health.
BACKGROUND - Associations between anthropometry and head and neck cancer (HNC) risk are inconsistent. We aimed to evaluate these associations while minimizing biases found in previous studies.
METHODS - We pooled data from 1,941,300 participants, including 3760 cases, in 20 cohort studies and used multivariable-adjusted Cox proportional hazard regression models to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association of anthropometric measures with HNC risk overall and stratified by smoking status.
RESULTS - Greater waist circumference (per 5 cm: HR = 1.04, 95% CI 1.03-1.05, P-value for trend = <0.0001) and waist-to-hip ratio (per 0.1 unit: HR = 1.07, 95% CI 1.05-1.09, P-value for trend = <0.0001), adjusted for body mass index (BMI), were associated with higher risk and did not vary by smoking status (P-value for heterogeneity = 0.85 and 0.44, respectively). Associations with BMI (P-value for interaction = <0.0001) varied by smoking status. Larger BMI was associated with higher HNC risk in never smokers (per 5 kg/m(2): HR = 1.15, 95% CI 1.06-1.24, P-value for trend = 0.0006), but not in former smokers (per 5 kg/m(2): HR = 0.99, 95% CI 0.93-1.06, P-value for trend = 0.79) or current smokers (per 5 kg/m(2): HR = 0.76, 95% CI 0.71-0.82, P-value for trend = <0.0001). Larger hip circumference was not associated with a higher HNC risk. Greater height (per 5 cm) was associated with higher risk of HNC in never and former smokers, but not in current smokers.
CONCLUSIONS - Waist circumference and waist-to-hip ratio were associated positively with HNC risk regardless of smoking status, whereas a positive association with BMI was only found in never smokers.
© The Author 2015; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.