Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, nineteen associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biologic pathways.

Glycemic traits are used to diagnose and monitor type 2 diabetes, and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here, we aggregated genome-wide association studies in up to 281,416 individuals without diabetes (30% non-European ancestry) with fasting glucose, 2h-glucose post-challenge, glycated hemoglobin, and fasting insulin data. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P <5x10 -8 ), 80% with no significant evidence of between-ancestry heterogeneity. Analyses restricted to European ancestry individuals with equivalent sample size would have led to 24 fewer new loci. Compared to single-ancestry, equivalent sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase understanding of diabetes pathophysiology by use of trans-ancestry studies for improved power and resolution.

Objective To use genetic variants as unconfounded proxies of C reactive protein concentration to study its causal role in coronary heart disease. Design Mendelian randomisation meta-analysis of individual participant data from 47 epidemiological studies in 15 countries. Participants 194 418 participants, including 46 557 patients with prevalent or incident coronary heart disease. Information was available on four CRP gene tagging single nucleotide polymorphisms (rs3093077, rs1205, rs1130864, rs1800947), concentration of C reactive protein, and levels of other risk factors. Main outcome measures Risk ratios for coronary heart disease associated with genetically raised C reactive protein versus risk ratios with equivalent differences in C reactive protein concentration itself, adjusted for conventional risk factors and variability in risk factor levels within individuals. Results CRP variants were each associated with up to 30% per allele difference in concentration of C reactive protein (P<10 −34) and were unrelated to other risk factors. Risk ratios for coronary heart disease per additional copy of an allele associated with raised C reactive protein were 0.93 (95% confidence interval 0.87 to 1.00) for rs3093077; 1.00 (0.98 to 1.02) for rs1205; 0.98 (0.96 to 1.00) for rs1130864; and 0.99 (0.94 to 1.03) for rs1800947. In a combined analysis, the risk ratio for coronary heart disease was 1.00 (0.90 to 1.13) per 1 SD higher genetically raised natural log (ln) concentration of C reactive protein. The genetic findings were discordant with the risk ratio observed for coronary heart disease of 1.33 (1.23 to 1.43) per 1 SD higher circulating ln concentration of C reactive protein in prospective studies (P=0.001 for difference). Conclusion Human genetic data indicate that C reactive protein concentration itself is unlikely to be even a modest causal factor in coronary heart disease.

To identify genetic factors contributing to type 2 diabetes (T2D), we performed large-scale meta-analyses by using a custom ∼50,000 SNP genotyping array (the ITMAT-Broad-CARe array) with ∼2000 candidate genes in 39 multiethnic population-based studies, case-control studies, and clinical trials totaling 17,418 cases and 70,298 controls. First, meta-analysis of 25 studies comprising 14,073 cases and 57,489 controls of European descent confirmed eight established T2D loci at genome-wide significance. In silico follow-up analysis of putative association signals found in independent genome-wide association studies (including 8,130 cases and 38,987 controls) performed by the DIAGRAM consortium identified a T2D locus at genome-wide significance (GATAD2A/CILP2/PBX4; p = 5.7 × 10(-9)) and two loci exceeding study-wide significance (SREBF1, and TH/INS; p < 2.4 × 10(-6)). Second, meta-analyses of 1,986 cases and 7,695 controls from eight African-American studies identified study-wide-significant (p = 2.4 × 10(-7)) variants in HMGA2 and replicated variants in TCF7L2 (p = 5.1 × 10(-15)). Third, conditional analysis revealed multiple known and novel independent signals within five T2D-associated genes in samples of European ancestry and within HMGA2 in African-American samples. Fourth, a multiethnic meta-analysis of all 39 studies identified T2D-associated variants in BCL2 (p = 2.1 × 10(-8)). Finally, a composite genetic score of SNPs from new and established T2D signals was significantly associated with increased risk of diabetes in African-American, Hispanic, and Asian populations. In summary, large-scale meta-analysis involving a dense gene-centric approach has uncovered additional loci and variants that contribute to T2D risk and suggests substantial overlap of T2D association signals across multiple ethnic groups.

Osteopenia has been ascribed to diabetics without residual insulin secretion and high insulin requirement. However, it is not known if this is partially due to disturbances in the IGF system, which is a key regulator of bone cell function.To address this question, we performed a cross-sectional study measuring serum levels of IGF-I, IGF-binding protein-1 (IGFBP-1), IGFBP-3, IGFBP-4 and IGFBP-5 by specific immunoassays in 52 adults with Type 1 (n=27) and Type 2 (n=25) diabetes mellitus and 100 age-and sex-matched healthy blood donors. In the diabetic patients, we further determined serum levels of proinsulin, intact parathyroid hormone (PTH), 25-hydroxyvitamin D 3 , 1,25-dihydroxyvitamin D 3 and several biochemical bone markers, including osteocalcin (OSC), bone alkaline phosphatase (B-ALP), carboxy-terminal propeptide of type I procollagen (PICP), and type I collagen cross-linked carboxy-terminal telopeptide (ICTP). Urinary albumin excretion was ascertained as a marker of diabetic nephropathy. Bone mineral density (BMD) of hip and lumbar spine was determined by dual-energy X-ray absorptiometry. Data are presented as means ... Differences between the experimental groups were determined by performing a one-way analysis of variance (ANOVA), followed by Newman-Keuls test. Correlations between variables were assessed using univariate linear regression analysis and partial correlation analysis.Type 1 diabetics showed significantly lower IGF-I (119 8 ng/ml) and IGFBP-3 (2590 104 ng/ml) but higher IGFBP-1 levels (38 10 ng/ml) compared with Type 2 patients (170 13, 2910 118, 11 3 respectively; P<0·05) or healthy controls (169 5, 4620 192, 3·5 0·4 respectively; P<0·01). IGFBP-5 levels were markedly lower in both diabetic groups (Type 1, 228 9; Type 2, 242 11 ng/ml) than in controls (460 7 ng/ml, P<0·01), whereas IGFBP-4 levels were similar in diabetics and controls. IGF-I correlated positively with IGFBP-3 and IGFBP-5 and negatively with IGFBP-1 and IGFBP-4 in all subjects. Type 1 patients showed a lower BMD of hip (83 2%, Z-score) and lumbar spine (93 2%) than Type 2 diabetics (93 5%, 101 5% respectively), reaching significance in the female subgroups (P<0·05). In Type 1 patients, BMD of hip correlated negatively with IGFBP-1 (r= 0·34, P<0·05) and IGFBP-4 (r= 0·3, P<0·05) but positively with IGFBP-5 (r=0·37, P<0·05), which was independent of age, diabetes duration, height, weight and body mass index, as assessed by partial correlation analysis. Furthermore, biochemical markers indicating bone loss (ICTP) and increased bone turnover (PTH, OSC) correlated positively with IGFBP-1 and IGFBP-4 but negatively with IGF-I, IGFBP-3 and IGFBP-5, while the opposite was observed with bone formation markers (PICP, B-ALP) and vitamin D 3 metabolites. In 20 Type 2 patients in whom immunoreactive proinsulin could be detected, significant positive correlations were found between proinsulin and BMD of hip (r=0·63, P<0·005), IGF-I (r=0·59, P<0·01) as well as IGFBP-3 (r=0·49, P<0·05). Type 1 and Type 2 patients with macroalbuminuria showe...

Background-Homoarginine is an amino acid derivative that may increase nitric oxide availability and enhance endothelial function. The effect of the level of homoarginine on cardiovascular outcome and mortality is unknown. Methods and Results-We assessed cardiovascular and all-cause mortality according to homoarginine levels in a cohort of 3305 subjects referred for coronary angiography from the LUdwigshafen RIsk and Cardiovascular Health (LURIC) Study. After investigating the relation of homoarginine with kidney function and markers of endothelial dysfunction, we explored its effects on adverse outcomes in a second high-risk cohort of 1244 patients with type 2 diabetes mellitus receiving maintenance hemodialysis (4D study [Die Deutsche Diabetes Dialyse Studie]). In the LURIC study, mean serum homoarginine levels were 2.6Ϯ1.1 mol/L. During a median follow-up of 7.7 years, 766 patients died. After adjustments for age and sex, patients in the lowest quartile (Ͻ1.85 mol/L) had a Ͼ4-fold higher rate of dying of cardiovascular disease (hazard ratio 4.1, 95% confidence interval 3.0 to 5.7) than patients in the highest quartile (Ͼ3.1 mol/L). Lower homoarginine levels were associated with lower estimated glomerular filtration rate and higher levels of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1. Hemodialysed patients had lower mean homoarginine levels of 1.2Ϯ0.5 mol/L and experienced a 5-fold increased mortality rate compared with LURIC patients (608 deaths during a median follow-up of 4 years). Homoarginine consistently affected mortality, which was 2-fold higher in 4D study patients in the lowest quartile (Ͻ0.87 mol/L) than in patients in the highest quartile (Ͼ1.4 mol/L). Conclusions-Homoarginine levels are independently associated with cardiovascular and all-cause mortality in patients referred for coronary angiography and in patients undergoing hemodialysis. Future studies are needed to elucidate the underlying pathomechanisms. (Circulation. 2010;122:967-975.)

IL-6 plasma levels are predictive of major cardiovascular events. Recently a G/C polymorphism at position -174 in the promoter of the IL-6 gene has been associated with differences in both the IL-6 transcription rate in vitro and IL-6 levels in vivo. We examined the association of this polymorphism with coronary artery disease (CAD) and previous myocardial infarction (MI) in 2559 patients with angiographically documented CAD with ( n=1365) and without ( n=1194) MI and in a control group of 729 individuals in whom CAD had been ruled out angiographically. Assuming dominant or recessive modes of inheritance, carriers of the G allele had odds ratios of 0.98 (95% CI 0.79 - 1.20) and 0.96 (95% CI 0.80 - 1.14), respectively, for CAD, and almost identical ones for previous MI. In subgroups stratified for low cardiovascular risk, the IL-6 promoter polymorphism was also not related to the risk of CAD or MI. In addition, the plasma concentration of IL-6 did not differ between groups with different IL-6 genotypes in 942 randomly selected individuals. We conclude that the IL-6 G(-174)C polymorphism is not associated with the risk of CAD or MI and does not contribute to cardiovascular risk stratification.

Background-Platelet-activating factor acetylhydrolase (PAF-AH), also denoted as lipoprotein-associated phospholipase A2, is a lipoprotein-bound enzyme that is possibly involved in inflammation and atherosclerosis. This study investigates the relationship of PAF-AH activity to angiographic coronary artery disease (CAD), the use of cardiovascular drugs, and other established risk factors. Methods and Results-PAF-AH activity, lipoproteins, sensitive C-reactive protein (sCRP), fibrinogen, serum amyloid A, and white blood cell count were determined in 2454 subjects with angiographically confirmed CAD and in 694 control subjects. PAF-AH activity was highly correlated with LDL cholesterol (rϭ0.517), apolipoprotein B (rϭ0.644), and non-HDL cholesterol (rϭ0.648) but not with sCRP or fibrinogen. PAF-AH activity was lower in women than in men and was affected by the intake of lipid-lowering drugs (Ϫ12%; PϽ0.001), aspirin (Ϫ6%; PϽ0.001), ␤-blockers (Ϫ6%; PϽ0.001), and digitalis (ϩ7%; PϽ0.001). Unlike sCRP, fibrinogen, and serum amyloid A, PAF-AH activity was not elevated in unstable angina, non-ST-elevation myocardial infarction, or ST-elevation myocardial infarction. When nonusers of lipid-lowering drugs were examined, PAF-AH activity was associated with the severity of CAD and the number of coronary vessels with significant stenoses. In individuals not taking lipid-lowering drugs and after adjustment for use of aspirin, ␤-blocker, and digitalis, the odds ratio for CAD associated with increasing PAF-AH activity was 1.39 (95% CI 1.26 to 1.54, PϽ0.001), a finding that was robust against further adjustments. Conclusions-PAF-AH activity is not an indicator of the systemic inflammation that accompanies acute coronary syndromes. PAF-AH activity is affected by a number of cardiovascular drugs; however, after such medication use was accounted for, PAF-AH activity was associated with angiographic CAD, complementary to sCRP and independently of established risk factors such as LDL cholesterol. (Circulation. 2005;111:980-987.)