Genome-wide association studies (GWAS) have laid the foundation for investigations into the biology of complex traits, drug development and clinical guidelines. However, the majority of discovery efforts are based on data from populations of European ancestry 1-3. In light of the differential genetic architecture that is known to exist between populations, bias in representation can exacerbate existing disease and healthcare disparities. Critical variants may be missed if they have a low frequency or are completely absent in European populations, especially as the field shifts its attention towards rare variants, which are more likely to be population-specific 4-10. Additionally, effect sizes and their derived risk prediction scores derived in one population may Reprints and permissions information is available at http://www.nature.com/reprints.

Diabetic kidney disease is the leading cause of ESRD, but few biomarkers of diabetic kidney disease are available. This study used gas chromatography-mass spectrometry to quantify 94 urine metabolites in screening and validation cohorts of patients with diabetes mellitus (DM) and CKD(DM+CKD), in patients with DM without CKD (DM-CKD), and in healthy controls. Compared with levels in healthy controls, 13 metabolites were significantly reduced in the DM+CKD cohorts (P#0.001), and 12 of the 13 remained significant when compared with the DM-CKD cohort. Many of the differentially expressed metabolites were water-soluble organic anions. Notably, organic anion transporter-1 (OAT1) knockout mice expressed a similar pattern of reduced levels of urinary organic acids, and human kidney tissue from patients with diabetic nephropathy demonstrated lower gene expression of OAT1 and OAT3. Analysis of bioinformatics data indicated that 12 of the 13 differentially expressed metabolites are linked to mitochondrial metabolism and suggested global suppression of mitochondrial activity in diabetic kidney disease. Supporting this analysis, human diabetic kidney sections expressed less mitochondrial protein, urine exosomes from patients with diabetes and CKD had less mitochondrial DNA, and kidney tissues from patients with diabetic kidney disease had lower gene expression of PGC1a (a master regulator of mitochondrial biogenesis). We conclude that urine metabolomics is a reliable source for biomarkers of diabetic complications, and our data suggest that renal organic ion transport and mitochondrial function are dysregulated in diabetic kidney disease.

SummaryBackgroundA high circulating concentration of interleukin 6 is associated with increased risk of coronary heart disease. Blockade of the interleukin-6 receptor (IL6R) with a monoclonal antibody (tocilizumab) licensed for treatment of rheumatoid arthritis reduces systemic and articular inflammation. However, whether IL6R blockade also reduces risk of coronary heart disease is unknown.MethodsApplying the mendelian randomisation principle, we used single nucleotide polymorphisms (SNPs) in the gene IL6R to evaluate the likely efficacy and safety of IL6R inhibition for primary prevention of coronary heart disease. We compared genetic findings with the effects of tocilizumab reported in randomised trials in patients with rheumatoid arthritis.FindingsIn 40 studies including up to 133 449 individuals, an IL6R SNP (rs7529229) marking a non-synonymous IL6R variant (rs8192284; p.Asp358Ala) was associated with increased circulating log interleukin-6 concentration (increase per allele 9·45%, 95% CI 8·34–10·57) as well as reduced C-reactive protein (decrease per allele 8·35%, 95% CI 7·31–9·38) and fibrinogen concentrations (decrease per allele 0·85%, 95% CI 0·60–1·10). This pattern of effects was consistent with IL6R blockade from infusions of tocilizumab (4–8 mg/kg every 4 weeks) in patients with rheumatoid arthritis studied in randomised trials. In 25 458 coronary heart disease cases and 100 740 controls, the IL6R rs7529229 SNP was associated with a decreased odds of coronary heart disease events (per allele odds ratio 0·95, 95% CI 0·93–0·97, p=1·53×10−5).InterpretationOn the basis of genetic evidence in human beings, IL6R signalling seems to have a causal role in development of coronary heart disease. IL6R blockade could provide a novel therapeutic approach to prevention of coronary heart disease that warrants testing in suitably powered randomised trials. Genetic studies in populations could be used more widely to help to validate and prioritise novel drug targets or to repurpose existing agents and targets for new therapeutic uses.FundingUK Medical Research Council; British Heart Foundation; Rosetrees Trust; US National Heart, Lung, and Blood Institute; Du Pont Pharma; Chest, Heart and Stroke Scotland; Wellcome Trust; Coronary Thrombosis Trust; Northwick Park Institute for Medical Research; UCLH/UCL Comprehensive Medical Research Centre; US National Institute on Aging; Academy of Finland; Netherlands Organisation for Health Research and Development; SANCO; Dutch Ministry of Public Health, Welfare and Sports; World Cancer Research Fund; Agentschap NL; European Commission; Swedish Heart-Lung Foundation; Swedish Research Council; Strategic Cardiovascular Programme of the Karolinska Institutet; Stockholm County Council; US National Institute of Neurological Disorders and Stroke; MedStar Health Research Institute; GlaxoSmithKline; Dutch Kidney Foundation; US National Institutes of Health; Netherlands Interuniversity Cardiology Institute of the Netherlands; Diabetes UK; European Union Seventh Framework Programme; Nationa...

IMPORTANCE Coronary artery calcium (CAC), measured by computed tomography (CT), has strong predictive value for incident cardiovascular disease (CVD) events. The standard CAC score is the Agatston, which is weighted upward for greater calcium density. However, some data suggest increased plaque calcium density may be protective for CVD.OBJECTIVE To determine the independent associations of CAC volume and CAC density with incident CVD events. DESIGN, SETTING, AND PARTICIPANTS Multicenter, prospective observational MESA study (Multi-Ethnic Study of Atherosclerosis), conducted at 6 US field centers of 3398 men and women from 4 race/ethnicity groups; non-Hispanic white, African American, Hispanic, and Chinese. Participants were aged 45-84 years, free of known CVD at baseline, had CAC greater than 0 on their baseline CT, and were followed up through October 2010.MAIN OUTCOMES AND MEASURES Incident coronary heart disease (CHD) and all CVD events RESULTS During a median of 7.6 years of follow-up, there were 175 CHD events and an additional 90 other CVD events for a total of 265 CVD events. With both lnCAC volume and CAC density scores in the same multivariable model, the lnCAC volume score showed an independent association with incident CHD, with a hazard ratio (HR) of 1.81 (95% CI, 1.47-2.23) per standard deviation (SD = 1.6) increase, absolute risk increase 6.1 per 1000 person-years, and for CVD an HR of 1.68 (95% CI, 1.42-1.98) per SD increase, absolute risk increase 7.9 per 1000 person-years. Conversely, the CAC density score showed an independent inverse association, with an HR of 0.73 (95% CI, 0.58-0.91) per SD (SD = 0.7) increase for CHD, absolute risk decrease 2.0 per 1000 person-years, and an HR of 0.71 (95% CI, 0.60-0.85) per SD increase for CVD, absolute risk decrease 3.4 per 1000 person years. Area under the receiver operating characteristic curve analyses showed significantly improved risk prediction with the addition of the density score to a model containing the volume score for both CHD and CVD. In the intermediate CVD risk group, the area under the curve for CVD increased from 0.53 (95% CI, 0.48-0.59) to 0.59 (95% CI, 0.54-0.64), P = .02.CONCLUSIONS AND RELEVANCE CAC volume was positively and independently associated with CHD and CVD risk. At any level of CAC volume, CAC density was inversely and significantly associated with CHD and CVD risk. The role of CAC density should be considered when evaluating current CAC scoring systems.

SummaryBackground and objectives Creatinine excretion rate (CER) indicates timed urine collection accuracy. Although equations to estimate CER exist, their bias and precision are untested and none simultaneously include age, sex, race, and weight.Design, setting, participants, & measurements Participants (n ϭ 2466) from three kidney disease trials were randomly allocated into equation development (2/3) and internal validation (1/3) data sets. CER served as the dependent variable in linear regression to develop new equations. Their stability was assessed within the internal validation data set. Among 987 individuals from three additional studies the equations were externally validated and compared with existing equations.Results Mean age was 46 years, 42% were women, and 9% were black. Age, sex, race, weight, and serum phosphorus improved model fit. Two equations were developed, with or without serum phosphorus. In external validation, the new equations showed little bias (mean difference [measured Ϫ estimated CER] Ϫ0.7% [95% confidence interval Ϫ2.5% to 1.0%] and 0.3% [95% confidence interval Ϫ2.6% to 3.1%], respectively) and moderate precision (estimated CER within 30% of measured CER among 79% [76% to 81%] and 81% [77% to 85%], respectively). Corresponding numbers within 15% were 51% [48% to 54%] and 54% [50% to 59%]). Compared with existing equations, the new equations had similar accuracy but showed less bias in individuals with high measured CER.Conclusions CER can be estimated with commonly available variables with little bias and moderate precision, which may facilitate assessment of accuracy of timed urine collections.