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Aims Treatment with sodium-glucose co-transporter 2 (SGLT2)-inhibitors reduces the risk of cardiovascular disease and mortality, but the mechanism is unclear. We hypothesized that a functional genetic variant in solute carrier family 5 member 2 (SLC5A2), known to be associated with familial renal glucosuria, would mimic pharmacological SGLT2-inhibition, and thus provide an opportunity to examine potential mediators of the effects on lower risk of cardiovascular disease and mortality. Methods and results We examined 112 712 individuals from the Copenhagen City Heart Study and Copenhagen General Population Study (CCHS + CGPS), 488 687 from the UK Biobank, and 342 499 from FinnGen, genotyped for SLC5A2 rs61742739, c.1961A > G; p.(Asn654Ser). The 2.0% heterozygotes and 0.01% homozygotes were pooled as carriers and compared with the 98% non-carriers. First, we examined the risk of cardiovascular disease and mortality; second, whether carrying the variant was associated with potential mediators of the effect; and third, whether identified potential mediators could explain the observed reduced risk of cardiovascular disease and mortality. In the CCHS + CGPS, carriers vs. non-carries had a 31% lower risk of heart failure, 21% lower risk of myocardial infarction, 16% lower risk of ischaemic heart disease, and 22% lower risk of all-cause mortality. Corresponding values in meta-analyses of the three studies combined were lower risk by 10%, 6%, 6%, and 10%, respectively. The SLC5A2 rs61742739 variant was not associated with a risk of ischaemic stroke or cardiovascular mortality. Of the lower risks observed in CCHS + CGPS, lower plasma glucose mediated 2.0%(P = 0.004) on heart failure, 3.1%(P = 0.09) on myocardial infarction, 4.1%(P = 0.02) on ischaemic heart disease, and 6.0%(P = 0.39) on all-cause mortality; corresponding values in the UK Biobank were 2.9%(P = 0.70), 1.5%(P = 0.77), 4.1%(P = 0.23), and 3.1%(P = 0.21), respectively. Conclusion A functional genetic variant in SLC5A2 , mimicking SGLT2-inhibition, was associated with a lower risk of heart failure, myocardial infarction, ischaemic heart disease, and all-cause mortality. These effects were at most minimally mediated through lower plasma glucose. [ABSTRACT FROM AUTHOR]

We tested the hypothesis that low plasma adiponectin is associated observationally and causally with increased risk of type 2 diabetes. Observational analyses are prone to confounding and reverse causation, while genetic Mendelian randomization (MR) analyses are much less influenced by these biases. We examined 30,045 individuals from the Copenhagen General Population Study observationally (plasma adiponectin [1,751 individuals with type 2 diabetes]), 96,903 Copenhagen individuals using one-sample MR (5 genetic variants [5,012 individuals with type 2 diabetes]), and 659,316 Europeans (ADIPOGen, GERA, DIAGRAM, UK Biobank) using two-sample MR (10 genetic variants [62,892 individuals type 2 diabetes]). Observationally, and in comparisons with individuals with median plasma adiponectin of 28.9 μg/mL (4th quartile), multivariable adjusted hazard ratios (HRs) for type 2 diabetes were 1.42 (95% CI 1.18-1.72) for 19.2 μg/mL (3rd quartile), 2.21 (1.84-2.66) for 13.9 μg/mL (2nd quartile), and 4.05 (3.38-4.86) for 9.2 μg/mL (1st quartile). Corresponding cumulative incidence for type 2 diabetes at age 70 years was 3%, 7%, 11%, and 20%, respectively. A 1 μg/mL lower plasma adiponectin conferred an HR for type 2 diabetes of 1.07 (1.06-1.09), while genetic, causal risk ratio per 1 unit log-transformed lower plasma adiponectin was 1.13 (95% CI 0.83-1.53) in one-sample MR and 1.26 (1.01-1.57) in two-sample MR. In conclusion, low plasma adiponectin is associated with increased risk of type 2 diabetes, an association that could represent a causal relationship. [ABSTRACT FROM AUTHOR]

Objective: To evaluate whether high glucose levels in the normoglycemic range and higher have a causal genetic effect on risk of retinopathy, neuropathy, nephropathy, chronic kidney disease (CKD), peripheral arterial disease (PAD), and myocardial infarction (MI; positive control) in the general population.Research Design and Methods: This study applied observational and one-sample Mendelian randomization (MR) analyses to individual-level data from 117,193 Danish individuals, and validation by two-sample MR analyses on summary-level data from 133,010 individuals from the Meta-Analyses of Glucose and Insulin-Related Traits Consortium (MAGIC), 117,165 from the CKDGen Consortium, and 452,264 from the UK Biobank.Results: Observationally, glucose levels in the normoglycemic range and higher were associated with high risks of retinopathy, neuropathy, diabetic nephropathy, PAD, and MI (all P for trend <0.001). In genetic causal analyses, the risk ratio for a 1 mmol/L higher glucose level was 2.01 (95% CI 1.18-3.41) for retinopathy, 2.15 (1.38-3.35) for neuropathy, 1.58 (1.04-2.40) for diabetic nephropathy, 0.97 (0.84-1.12) for estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2, 1.19 (0.90-1.58) for PAD, and 1.49 (1.02-2.17) for MI. Summary-level data from the MAGIC, the CKDGen Consortium, and the UK Biobank gave a genetic risk ratio of 4.55 (95% CI 2.26-9.15) for retinopathy, 1.48 (0.83-2.66) for peripheral neuropathy, 0.98 (0.94-1.01) for eGFR <60 mL/min/1.73 m2, and 1.23 (0.57-2.67) for PAD per 1 mmol/L higher glucose level.Conclusions: Glucose levels in the normoglycemic range and higher were prospectively associated with a high risk of retinopathy, neuropathy, diabetic nephropathy, eGFR <60 mL/min/1.73 m2, PAD, and MI. These associations were confirmed in genetic causal analyses for retinopathy, neuropathy, diabetic nephropathy, and MI, but they could not be confirmed for PAD and seemed to be refuted for eGFR <60 mL/min/1.73 m2. [ABSTRACT FROM AUTHOR]

Background: Low-density lipoprotein cholesterol (LDL-C) is causally associated with a high risk of coronary artery disease. Whether this also holds for a spectrum of peripheral vascular diseases is unknown.Objectives: The purpose of this study was to determine whether high LDL-C causally relates to risk of retinopathy, neuropathy, chronic kidney disease (CKD), and peripheral arterial disease (PAD) in the general population.Methods: One-sample Mendelian randomization (MR) of 116,419 Danish individuals, 2-sample MR on summary-level data from the Global Lipid Genetics Consortium (GLGC) (n = 94,595) and the UK Biobank (n = 408,455), and meta-analysis of randomized statin trials (n = 64,134) were performed.Results: Observationally, high LDL-C did not associate with high risk of retinopathy or neuropathy. There were stepwise increases in risk of CKD and PAD with higher LDL-C (both p for trend <0.001), with hazard ratios of 1.05 (95% confidence interval [CI]: 0.97 to 1.13) for CKD, and 1.41 (95% CI: 1.23 to 1.62) for PAD in individuals with LDL-C above the 95th percentile versus below the 50th percentile. In genetic, causal analyses in the Copenhagen studies, the risk ratio of disease for a 1 mmol/l higher LDL-C was 1.06 (95% CI: 0.24 to 4.58) for retinopathy, 1.05 (95% CI: 0.64 to 1.72) for neuropathy, 3.83 (95% CI: 2.00 to 7.34) for CKD, and 2.09 (95% CI: 1.30 to 2.38) for PAD. Summary-level data from the GLGC and the UK Biobank for retinopathy, neuropathy, and PAD gave similar results. For CKD, a 1-mmol/l lower LDL-C conferred a higher eGFR of 1.95 ml/min/1.73 m2 (95% CI: 1.88 to 2.02 ml/min/1.73 m2) observationally, 5.92 ml/min/1.73 m2 (95% CI: 4.97 to 6.86 ml/min/1.73 m2) genetically, and 2.69 ml/min/1.73 m2 (95% CI: 1.48 to 3.94 ml/min/1.73 m2) through statin therapy.Conclusions: High LDL-C was not causally associated with risk of retinopathy and neuropathy; however, high LDL-C was observationally and genetically associated with high risks of PAD and CKD, suggesting that LDL-C is causally involved in the pathogenesis of these diseases. [ABSTRACT FROM AUTHOR]

Background: Epidemiological studies have observed a positive association between an earlier age at sexual development and prostate cancer, but markers of sexual maturation in boys are imprecise and observational estimates are likely to suffer from a degree of uncontrolled confounding. To obtain causal estimates, we examined the role of pubertal development in prostate cancer using genetic polymorphisms associated with Tanner stage in adolescent boys in a Mendelian randomization (MR) approach.Methods: We derived a weighted genetic risk score for pubertal development, combining 13 SNPs associated with male Tanner stage. A higher score indicated a later puberty onset. We examined the association of this score with prostate cancer risk, stage and grade in the UK-based ProtecT case-control study (n = 2,927), and used the PRACTICAL consortium (n = 43,737) as a replication sample.Results: In ProtecT, the puberty genetic score was inversely associated with prostate cancer grade (odds ratio (OR) of high- vs. low-grade cancer, per tertile of the score: 0.76; 95 % CI, 0.64-0.89). In an instrumental variable estimation of the causal OR, later physical development in adolescence (equivalent to a difference of one Tanner stage between pubertal boys of the same age) was associated with a 77 % (95 % CI, 43-91 %) reduced odds of high Gleason prostate cancer. In PRACTICAL, the puberty genetic score was associated with prostate cancer stage (OR of advanced vs. localized cancer, per tertile: 0.95; 95 % CI, 0.91-1.00) and prostate cancer-specific mortality (hazard ratio amongst cases, per tertile: 0.94; 95 % CI, 0.90-0.98), but not with disease grade.Conclusions: Older age at sexual maturation is causally linked to a reduced risk of later prostate cancer, especially aggressive disease. [ABSTRACT FROM AUTHOR]

Genome-wide polygenic risk scores (GW-PRSs) have been reported to have better predictive ability than PRSs based on genome-wide significance thresholds across numerous traits. We compared the predictive ability of several GW-PRS approaches to a recently developed PRS of 269 established prostate cancer-risk variants from multi-ancestry GWASs and fine-mapping studies (PRS 269). GW-PRS models were trained with a large and diverse prostate cancer GWAS of 107,247 cases and 127,006 controls that we previously used to develop the multi-ancestry PRS 269. Resulting models were independently tested in 1,586 cases and 1,047 controls of African ancestry from the California Uganda Study and 8,046 cases and 191,825 controls of European ancestry from the UK Biobank and further validated in 13,643 cases and 210,214 controls of European ancestry and 6,353 cases and 53,362 controls of African ancestry from the Million Veteran Program. In the testing data, the best performing GW-PRS approach had AUCs of 0.656 (95% CI = 0.635–0.677) in African and 0.844 (95% CI = 0.840–0.848) in European ancestry men and corresponding prostate cancer ORs of 1.83 (95% CI = 1.67–2.00) and 2.19 (95% CI = 2.14–2.25), respectively, for each SD unit increase in the GW-PRS. Compared to the GW-PRS, in African and European ancestry men, the PRS 269 had larger or similar AUCs (AUC = 0.679, 95% CI = 0.659–0.700 and AUC = 0.845, 95% CI = 0.841–0.849, respectively) and comparable prostate cancer ORs (OR = 2.05, 95% CI = 1.87–2.26 and OR = 2.21, 95% CI = 2.16–2.26, respectively). Findings were similar in the validation studies. This investigation suggests that current GW-PRS approaches may not improve the ability to predict prostate cancer risk compared to the PRS 269 developed from multi-ancestry GWASs and fine-mapping. Our findings suggest that in men of African and European ancestry, genome-wide polygenic risk scores including >1 million variants are not more predictive of prostate cancer risk than a carefully constructed polygenic risk score limited to variants with statistical evidence of an association with prostate cancer risk. [ABSTRACT FROM AUTHOR]

Background: The high-density lipoprotein hypothesis of atherosclerosis has been challenged by clinical trials of cholesteryl ester transfer protein (CETP) inhibitors, which failed to show significant reductions in cardiovascular events. Plasma levels of high-density lipoprotein cholesterol (HDL-C) decline drastically during sepsis, and this phenomenon is explained, in part, by the activity of CETP, a major determinant of plasma HDL-C levels. We tested the hypothesis that genetic or pharmacological inhibition of CETP would preserve high-density lipoprotein levels and decrease mortality in clinical cohorts and animal models of sepsis.Methods: We examined the effect of a gain-of-function variant in CETP (rs1800777, p.Arg468Gln) and a genetic score for decreased CETP function on 28-day sepsis survival using Cox proportional hazard models adjusted for age and sex in the UK Biobank (n=5949), iSPAAR (Identification of SNPs Predisposing to Altered Acute Lung Injury Risk; n=882), Copenhagen General Population Study (n=2068), Copenhagen City Heart Study (n=493), Early Infection (n=200), St Paul's Intensive Care Unit 2 (n=203), and Vasopressin Versus Norepinephrine Infusion in Patients With Septic Shock studies (n=632). We then studied the effect of the CETP inhibitor, anacetrapib, in adult female APOE*3-Leiden mice with or without human CETP expression using the cecal-ligation and puncture model of sepsis.Results: A fixed-effect meta-analysis of all 7 cohorts found that the CETP gain-of-function variant was significantly associated with increased risk of acute sepsis mortality (hazard ratio, 1.44 [95% CI, 1.22-1.70]; P<0.0001). In addition, a genetic score for decreased CETP function was associated with significantly decreased sepsis mortality in the UK Biobank (hazard ratio, 0.77 [95% CI, 0.59-1.00] per 1 mmol/L increase in HDL-C) and iSPAAR cohorts (hazard ratio, 0.60 [95% CI, 0.37-0.98] per 1 mmol/L increase in HDL-C). APOE*3-Leiden.CETP mice treated with anacetrapib had preserved levels of HDL-C and apolipoprotein-AI and increased survival relative to placebo treatment (70.6% versus 35.3%, Log-rank P=0.03), whereas there was no effect of anacetrapib on the survival of APOE*3-Leiden mice that did not express CETP (50.0% versus 42.9%, Log-rank P=0.87).Conclusions: Clinical genetics and humanized mouse models suggest that inhibiting CETP may preserve high-density lipoprotein levels and improve outcomes for individuals with sepsis. [ABSTRACT FROM AUTHOR]

Background: Whether associations between circulating metabolites and prostate cancer are causal is unknown. We report on the largest study of metabolites and prostate cancer (2,291 cases and 2,661 controls) and appraise causality for a subset of the prostate cancer-metabolite associations using two-sample Mendelian randomization (MR)., Methods: The case-control portion of the study was conducted in nine UK centers with men ages 50-69 years who underwent prostate-specific antigen screening for prostate cancer within the Prostate Testing for Cancer and Treatment (ProtecT) trial. Two data sources were used to appraise causality: a genome-wide association study (GWAS) of metabolites in 24,925 participants and a GWAS of prostate cancer in 44,825 cases and 27,904 controls within the Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium., Results: Thirty-five metabolites were strongly associated with prostate cancer ( P < 0.0014, multiple-testing threshold). These fell into four classes: (i) lipids and lipoprotein subclass characteristics (total cholesterol and ratios, cholesterol esters and ratios, free cholesterol and ratios, phospholipids and ratios, and triglyceride ratios); (ii) fatty acids and ratios; (iii) amino acids; (iv) and fluid balance. Fourteen top metabolites were proxied by genetic variables, but MR indicated these were not causal., Conclusions: We identified 35 circulating metabolites associated with prostate cancer presence, but found no evidence of causality for those 14 testable with MR. Thus, the 14 MR-tested metabolites are unlikely to be mechanistically important in prostate cancer risk., Impact: The metabolome provides a promising set of biomarkers that may aid prostate cancer classification., (©2018 American Association for Cancer Research.)

Context: Vitamin D may be a modifiable risk factor for inflammatory bowel disease (IBD)., Objectives: We tested the hypothesis that plasma 25-hydroxyvitamin D levels are causally associated with risk of Crohn disease (CD) and ulcerative colitis (UC)., Design, Setting, Patients, and Interventions: We used a Mendelian randomization design to study 120,013 individuals from the Copenhagen City Heart Study, the Copenhagen General Population Study, and a Copenhagen-based cohort of patients with IBD. Of these, 35,558 individuals had plasma 25-hydroxyvitamin D measurements available, and 115,110 were genotyped for rs7944926 and rs11234027 in DHCR7 and rs10741657 and rs12794714 in CYP2R1, all variants associated with plasma 25-hydroxyvitamin D levels. We identified 653 cases of CD and 1265 cases of UC, of which 58 and 113, respectively, had 25-hydroxyvitamin D measurements available. We also included genetic data from 408,455 individuals from the UK Biobank, including 1707 CD cases and 3147 UC cases., Main Outcome Measure: Hazard ratios for higher plasma 25-hydroxyvitamin D levels., Results: The multivariable-adjusted hazard ratios for 10 nmol/L higher 25-hydroxyvitamin D level were 1.04 (95% CI: 0.93 to 1.16) for CD and 1.13 (95% CI: 1.06 to 1.21) for UC. A combined 25-hydroxyvitamin D allele score was associated with a 1.4-nmol/L increase in plasma 25-hydroxyvitamin D level and hazard ratios of 0.98 (95% CI: 0.94 to 1.03) for CD and 1.01 (95% CI: 0.97 to 1.05) for UC. Combining genetic data from the Copenhagen studies and the UK Biobank, genetically determined vitamin D did not appear to influence the risk of CD or UC., Conclusions: Our results do not support a major role for vitamin D deficiency in the development of IBD.