Sun Ha Jee

Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis.

BACKGROUND Substantial controversy surrounds the use of estimated glomerular filtration rate (eGFR) and albuminuria to define chronic kidney disease and assign its stages. We undertook a meta-analysis to assess the independent and combined associations of eGFR and albuminuria with mortality. METHODS In this collaborative meta-analysis of general population cohorts, we pooled standardised data for all-cause and cardiovascular mortality from studies containing at least 1000 participants and baseline information about eGFR and urine albumin concentrations. Cox proportional hazards models were used to estimate hazard ratios (HRs) for all-cause and cardiovascular mortality associated with eGFR and albuminuria, adjusted for potential confounders. FINDINGS The analysis included 105,872 participants (730,577 person-years) from 14 studies with urine albumin-to-creatinine ratio (ACR) measurements and 1,128,310 participants (4,732,110 person-years) from seven studies with urine protein dipstick measurements. In studies with ACR measurements, risk of mortality was unrelated to eGFR between 75 mL/min/1.73 m(2) and 105 mL/min/1.73 m(2) and increased at lower eGFRs. Compared with eGFR 95 mL/min/1.73 m(2), adjusted HRs for all-cause mortality were 1.18 (95% CI 1.05-1.32) for eGFR 60 mL/min/1.73 m(2), 1.57 (1.39-1.78) for 45 mL/min/1.73 m(2), and 3.14 (2.39-4.13) for 15 mL/min/1.73 m(2). ACR was associated with risk of mortality linearly on the log-log scale without threshold effects. Compared with ACR 0.6 mg/mmol, adjusted HRs for all-cause mortality were 1.20 (1.15-1.26) for ACR 1.1 mg/mmol, 1.63 (1.50-1.77) for 3.4 mg/mmol, and 2.22 (1.97-2.51) for 33.9 mg/mmol. eGFR and ACR were multiplicatively associated with risk of mortality without evidence of interaction. Similar findings were recorded for cardiovascular mortality and in studies with dipstick measurements. INTERPRETATION eGFR less than 60 mL/min/1.73 m(2) and ACR 1.1 mg/mmol (10 mg/g) or more are independent predictors of mortality risk in the general population. This study provides quantitative data for use of both kidney measures for risk assessment and definition and staging of chronic kidney disease. FUNDING Kidney Disease: Improving Global Outcomes (KDIGO), US National Kidney Foundation, and Dutch Kidney Foundation.Background A comprehensive evaluation of the independent and combined associations of estimated glomerular filtration rate (eGFR) and albuminuria with mortality is required for assessment of the impact of kidney function on risk in the general population, with implications for improving the definition and staging of chronic kidney disease (CKD).

Smoking cessation and risk of type 2 diabetes mellitus: Korea Medical Insurance Corporation Study

Background To investigate the independent effects of smoking cessation on the risk for developing type 2 diabetes mellitus (DM) in the general population. Design An 8-year prospective study. Methods This prospective study started with baseline examinations in 1990 and 1992, and continued with follow-up examinations every 2 years up to 1998 and 2000. A total of 27635 nondiabetic men, aged 35–44 years were classified as 5701 nonsmokers, 7477 ex-smokers and 14457 sustained smokers, based on repeated self-reported questionnaires in 1992, 1994 and 1996. Baseline fasting serum glucose level and other risk factors were measured in 1990 and 1992. The outcome was newly developed DM, defined as a fasting glucose level ≥7.0mmol/l in 1998 and 2000 (averaged). Results Over the 8 years, 1170 men (4.2%) developed DM. When compared with nonsmokers, the fully adjusted risk ratio of ex-smokers and sustained smokers for diabetes was 1.22 [95% confidence interval (CI), 0.96–1.55] and 1.60 (95% CI, 1.29–1.97), respectively. Among the ex-smokers, the risk for diabetes differed according to the quit-smoking period. Compared with nonsmokers, the fully adjusted risk ratio for DM in men who quit smoking before 1992, during 1992–1993 and during 1994–1995 was 0.95 (0.72–1.25), 1.44 (0.96–2.15) and 2.13 (1.51–3.00), respectively, after adjustment for age, baseline fasting serum glucose, weight change, baseline body mass index, family history of DM, alcohol consumption and exercise status. Conclusions Our results support cigarette smoking as an independent and modifiable risk factor for DM. Early smoking cessation could decrease the risk for developing DM to that of nonsmokers in the long term.

Comparison of risk prediction using the CKD-EPI equation and the MDRD Study equation for estimated glomerular filtration rate

CONTEXT The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation more accurately estimates glomerular filtration rate (GFR) than the Modification of Diet in Renal Disease (MDRD) Study equation using the same variables, especially at higher GFR, but definitive evidence of its risk implications in diverse settings is lacking. OBJECTIVE To evaluate risk implications of estimated GFR using the CKD-EPI equation compared with the MDRD Study equation in populations with a broad range of demographic and clinical characteristics. DESIGN, SETTING, AND PARTICIPANTS A meta-analysis of data from 1.1 million adults (aged ≥ 18 years) from 25 general population cohorts, 7 high-risk cohorts (of vascular disease), and 13 CKD cohorts. Data transfer and analyses were conducted between March 2011 and March 2012. MAIN OUTCOME MEASURES All-cause mortality (84,482 deaths from 40 cohorts), cardiovascular mortality (22,176 events from 28 cohorts), and end-stage renal disease (ESRD) (7644 events from 21 cohorts) during 9.4 million person-years of follow-up; the median of mean follow-up time across cohorts was 7.4 years (interquartile range, 4.2-10.5 years). RESULTS Estimated GFR was classified into 6 categories (≥90, 60-89, 45-59, 30-44, 15-29, and <15 mL/min/1.73 m(2)) by both equations. Compared with the MDRD Study equation, 24.4% and 0.6% of participants from general population cohorts were reclassified to a higher and lower estimated GFR category, respectively, by the CKD-EPI equation, and the prevalence of CKD stages 3 to 5 (estimated GFR <60 mL/min/1.73 m(2)) was reduced from 8.7% to 6.3%. In estimated GFR of 45 to 59 mL/min/1.73 m(2) by the MDRD Study equation, 34.7% of participants were reclassified to estimated GFR of 60 to 89 mL/min/1.73 m(2) by the CKD-EPI equation and had lower incidence rates (per 1000 person-years) for the outcomes of interest (9.9 vs 34.5 for all-cause mortality, 2.7 vs 13.0 for cardiovascular mortality, and 0.5 vs 0.8 for ESRD) compared with those not reclassified. The corresponding adjusted hazard ratios were 0.80 (95% CI, 0.74-0.86) for all-cause mortality, 0.73 (95% CI, 0.65-0.82) for cardiovascular mortality, and 0.49 (95% CI, 0.27-0.88) for ESRD. Similar findings were observed in other estimated GFR categories by the MDRD Study equation. Net reclassification improvement based on estimated GFR categories was significantly positive for all outcomes (range, 0.06-0.13; all P < .001). Net reclassification improvement was similarly positive in most subgroups defined by age (<65 years and ≥65 years), sex, race/ethnicity (white, Asian, and black), and presence or absence of diabetes and hypertension. The results in the high-risk and CKD cohorts were largely consistent with the general population cohorts. CONCLUSION The CKD-EPI equation classified fewer individuals as having CKD and more accurately categorized the risk for mortality and ESRD than did the MDRD Study equation across a broad range of populations.

Body-mass index and all-cause mortality: Individual-participant-data meta-analysis of 239 prospective studies in four continents.

Summary Background Overweight and obesity are increasing worldwide. To help assess their relevance to mortality in different populations we conducted individual-participant data meta-analyses of prospective studies of body-mass index (BMI), limiting confounding and reverse causality by restricting analyses to never-smokers and excluding pre-existing disease and the first 5 years of follow-up. Methods Of 10 625 411 participants in Asia, Australia and New Zealand, Europe, and North America from 239 prospective studies (median follow-up 13·7 years, IQR 11·4–14·7), 3 951 455 people in 189 studies were never-smokers without chronic diseases at recruitment who survived 5 years, of whom 385 879 died. The primary analyses are of these deaths, and study, age, and sex adjusted hazard ratios (HRs), relative to BMI 22·5–<25·0 kg/m2. Findings All-cause mortality was minimal at 20·0–25·0 kg/m2 (HR 1·00, 95% CI 0·98–1·02 for BMI 20·0–<22·5 kg/m2; 1·00, 0·99–1·01 for BMI 22·5–<25·0 kg/m2), and increased significantly both just below this range (1·13, 1·09–1·17 for BMI 18·5–<20·0 kg/m2; 1·51, 1·43–1·59 for BMI 15·0–<18·5) and throughout the overweight range (1·07, 1·07–1·08 for BMI 25·0–<27·5 kg/m2; 1·20, 1·18–1·22 for BMI 27·5–<30·0 kg/m2). The HR for obesity grade 1 (BMI 30·0–<35·0 kg/m2) was 1·45, 95% CI 1·41–1·48; the HR for obesity grade 2 (35·0–<40·0 kg/m2) was 1·94, 1·87–2·01; and the HR for obesity grade 3 (40·0–<60·0 kg/m2) was 2·76, 2·60–2·92. For BMI over 25·0 kg/m2, mortality increased approximately log-linearly with BMI; the HR per 5 kg/m2 units higher BMI was 1·39 (1·34–1·43) in Europe, 1·29 (1·26–1·32) in North America, 1·39 (1·34–1·44) in east Asia, and 1·31 (1·27–1·35) in Australia and New Zealand. This HR per 5 kg/m2 units higher BMI (for BMI over 25 kg/m2) was greater in younger than older people (1·52, 95% CI 1·47–1·56, for BMI measured at 35–49 years vs 1·21, 1·17–1·25, for BMI measured at 70–89 years; pheterogeneity<0·0001), greater in men than women (1·51, 1·46–1·56, vs 1·30, 1·26–1·33; pheterogeneity<0·0001), but similar in studies with self-reported and measured BMI. Interpretation The associations of both overweight and obesity with higher all-cause mortality were broadly consistent in four continents. This finding supports strategies to combat the entire spectrum of excess adiposity in many populations. Funding UK Medical Research Council, British Heart Foundation, National Institute for Health Research, US National Institutes of Health.

A genome-wide association study of cleft lip with and without cleft palate identifies risk variants near MAFB and ABCA4

Case-parent trios were used in a genome-wide association study of cleft lip with and without cleft palate. SNPs near two genes not previously associated with cleft lip with and without cleft palate (MAFB, most significant SNP rs13041247, with odds ratio (OR) per minor allele = 0.704, 95% CI 0.635–0.778, P = 1.44 × 10−11; and ABCA4, most significant SNP rs560426, with OR = 1.432, 95% CI 1.292–1.587, P = 5.01 × 10−12) and two previously identified regions (at chromosome 8q24 and IRF6) attained genome-wide significance. Stratifying trios into European and Asian ancestry groups revealed differences in statistical significance, although estimated effect sizes remained similar. Replication studies from several populations showed confirming evidence, with families of European ancestry giving stronger evidence for markers in 8q24, whereas Asian families showed stronger evidence for association with MAFB and ABCA4. Expression studies support a role for MAFB in palatal development.

Lung cancer occurrence in never-smokers: an analysis of 13 cohorts and 22 cancer registry studies.

Background Better information on lung cancer occurrence in lifelong nonsmokers is needed to understand gender and racial disparities and to examine how factors other than active smoking influence risk in different time periods and geographic regions. Methods and Findings We pooled information on lung cancer incidence and/or death rates among self-reported never-smokers from 13 large cohort studies, representing over 630,000 and 1.8 million persons for incidence and mortality, respectively. We also abstracted population-based data for women from 22 cancer registries and ten countries in time periods and geographic regions where few women smoked. Our main findings were: (1) Men had higher death rates from lung cancer than women in all age and racial groups studied; (2) male and female incidence rates were similar when standardized across all ages 40+ y, albeit with some variation by age; (3) African Americans and Asians living in Korea and Japan (but not in the US) had higher death rates from lung cancer than individuals of European descent; (4) no temporal trends were seen when comparing incidence and death rates among US women age 40–69 y during the 1930s to contemporary populations where few women smoke, or in temporal comparisons of never-smokers in two large American Cancer Society cohorts from 1959 to 2004; and (5) lung cancer incidence rates were higher and more variable among women in East Asia than in other geographic areas with low female smoking. Conclusions These comprehensive analyses support claims that the death rate from lung cancer among never-smokers is higher in men than in women, and in African Americans and Asians residing in Asia than in individuals of European descent, but contradict assertions that risk is increasing or that women have a higher incidence rate than men. Further research is needed on the high and variable lung cancer rates among women in Pacific Rim countries.

The Effect of Chronic Coffee Drinking on Blood Pressure: A Meta-Analysis of Controlled Clinical Trials

We sought to assess the effect of coffee consumption on blood pressure in humans. Our data sources included a MEDLINE search of the literature published before December 1997, bibliography review, and expert consultation. We selected controlled trials in which coffee consumption was the only difference between the intervention and control groups, mean blood pressure change was reported for each group or period, and treatment lasted for >24 hours. Of 36 studies initially identified, 11 (522 participants) met these inclusion criteria. Information on sample size, study design, participant characteristics (gender, race, age, baseline blood pressure, and antihypertensive medications), and treatment results were abstracted by 3 reviewers using a standardized protocol. Treatment effect of coffee consumption on blood pressure was estimated with the use of a random-effects model. In the 11 trials, median duration was 56 days (range, 14 to 79 days), and median dose of coffee was 5 cups/d. Systolic and diastolic blood pressure increased by 2.4 (range, 1.0 to 3.7) mm Hg and 1.2 (range, 0.4 to 2.1) mm Hg, respectively, with coffee treatment compared with control. Multiple linear regression analysis identified an independent, positive relationship between cups of coffee consumed and subsequent change in systolic blood pressure, independent of age of study participants and study design characteristics. The effect of coffee drinking on systolic and diastolic blood pressure was greater in trials with younger participants. Our findings provide support for a relationship between coffee consumption and higher blood pressure. Trials of coffee cessation of longer duration and in persons with hypertension should be performed.

Identification of genetic susceptibility loci for colorectal tumors in a genome-wide meta-analysis

BACKGROUND & AIMS Heritable factors contribute to the development of colorectal cancer. Identifying the genetic loci associated with colorectal tumor formation could elucidate the mechanisms of pathogenesis. METHODS We conducted a genome-wide association study that included 14 studies, 12,696 cases of colorectal tumors (11,870 cancer, 826 adenoma), and 15,113 controls of European descent. The 10 most statistically significant, previously unreported findings were followed up in 6 studies; these included 3056 colorectal tumor cases (2098 cancer, 958 adenoma) and 6658 controls of European and Asian descent. RESULTS Based on the combined analysis, we identified a locus that reached the conventional genome-wide significance level at less than 5.0 × 10(-8): an intergenic region on chromosome 2q32.3, close to nucleic acid binding protein 1 (most significant single nucleotide polymorphism: rs11903757; odds ratio [OR], 1.15 per risk allele; P = 3.7 × 10(-8)). We also found evidence for 3 additional loci with P values less than 5.0 × 10(-7): a locus within the laminin gamma 1 gene on chromosome 1q25.3 (rs10911251; OR, 1.10 per risk allele; P = 9.5 × 10(-8)), a locus within the cyclin D2 gene on chromosome 12p13.32 (rs3217810 per risk allele; OR, 0.84; P = 5.9 × 10(-8)), and a locus in the T-box 3 gene on chromosome 12q24.21 (rs59336; OR, 0.91 per risk allele; P = 3.7 × 10(-7)). CONCLUSIONS In a large genome-wide association study, we associated polymorphisms close to nucleic acid binding protein 1 (which encodes a DNA-binding protein involved in DNA repair) with colorectal tumor risk. We also provided evidence for an association between colorectal tumor risk and polymorphisms in laminin gamma 1 (this is the second gene in the laminin family to be associated with colorectal cancers), cyclin D2 (which encodes for cyclin D2), and T-box 3 (which encodes a T-box transcription factor and is a target of Wnt signaling to β-catenin). The roles of these genes and their products in cancer pathogenesis warrant further investigation.

Smoking and cancer risk in Korean men and women.

AbstractObjective: In Korea, male smoking prevalence is among the worlds highest, and mortality rates from smoking-caused cancers, particularly lung cancer, are escalating. This cohort study examined the effects of cigarette smoking on the risk of cancer mortality and incidence, and characterized the relationship of cancer risk with the amount and duration of cigarette smoking. Method: A nine-year prospective cohort study was carried out on 1,212,906 Koreans, 30–95 years of age. The study population includes participants in a national insurance program, who completed a questionnaire on smoking and other risk factors. The main outcome measures were death from cancer and cancer incidence, obtained through record linkage. At baseline, 472,970 men (57.0%) and 20,548 (5.4%) women were current cigarette smokers. Results: In multivariate Cox proportional hazards models, controlling for age, current smoking among men increased the risks of mortality for cancer of the lung (relative risk (RR), 4.6; 95% confidence interval (CI), 4.0–5.3) and other cancers, including larynx, bile duct, esophagus, liver, stomach, pancreas, bladder, and also leukemia. Current smoking among women increased the risk of lung cancer mortality (RR = 2.5, 95% CI = 2.0–3.1). Similar results were found for incidence among men and women. Conclusion: In Korea, smoking is an independent risk factor for a number of major cancers. The findings affirm the need for aggressive tobacco control in Korea in order to minimize the epidemic of smoking-caused disease.

Body-mass index and cancer mortality in the Asia-Pacific Cohort Studies Collaboration: pooled analyses of 424 519 participants

BACKGROUND Excess bodyweight is an established risk factor for several types of cancer, but there are sparse data from Asian populations, where the proportion of overweight and obese individuals is increasing rapidly and adiposity can be substantially greater for the same body-mass index (BMI) compared with people from Western populations. METHODS We examined associations of adult BMI with cancer mortality (overall and for 20 cancer sites) in geographic populations from Asia and from Australia and New Zealand (ANZ), within the Asia-Pacific Cohort Studies Collaboration, by use of Cox regression analysis. Pooled data from 39 cohorts (recruitment 1961-99, median follow-up 4 years) were analysed for 424,519 participants (77% Asian; 41% female; mean recruitment age 48 years) with individual data on BMI. FINDINGS After excluding those with follow-up of less than 3 years, 4872 cancer deaths occurred in 401,215 participants. Hazard ratios for cancer sites with increased mortality risk in obese (BMI > or = 30 kg/m(2)) compared with normal weight participants (BMI 18.5-24.9 kg/m(2)) were: 1.21 (95% CI 1.09-1.36) for all-cause cancer (excluding lung and upper aerodigestive tract), 1.50 (1.13-1.99) for colon, 1.68 (1.06-2.67) for rectum, 1.63 (1.13-2.35) for breast in women 60 years or older, 2.62 (1.57-4.37) for ovary, 4.21 (1.89-9.39) for cervix, 1.45 (0.97-2.19) for prostate, and 1.66 (1.03-2.68) for leukaemia (all after left censoring at 3 years). The increased risk associated with a 5-unit increase in BMI for those with BMI of 18.5 kg/m(2) or higher was 1.09 (95% CI 1.04-1.14) for all cancers (excluding lung and upper aerodigestive tract). There was little evidence of regional differences in relative risk of cancer with higher BMI, apart from cancers of the oropharynx and larynx, where the association was inverse in ANZ and absent in Asia. INTERPRETATION Overweight and obese individuals in populations across the Asia-Pacific region have a significantly increased risk of mortality from cancer. Strategies to prevent individuals from becoming overweight and obese in Asia are needed to reduce the burden of cancer that is expected if the obesity epidemic continues. FUNDING National Health and Medical Research Council of Australia, Health Research Council of New Zealand, and Pfizer Inc.