Observational studies exploring whether there is a nonlinear effect of blood pressure on cardiovascular disease (CVD) risk are hindered by confounding. This limitation can be overcome by leveraging randomly allocated genetic variants in nonlinear Mendelian randomization analyses. Based on their association with blood pressure traits in a genome-wide association study of 299 024 European ancestry individuals, we selected 253 genetic variants to proxy the effect of modifying systolic and diastolic blood pressure. Considering the outcomes of incident coronary artery disease, stroke and the combined outcome of CVD, linear and nonlinear Mendelian randomization analyses were performed on 255 714 European ancestry participants without a history of CVD or antihypertensive medication use. There was no evidence favoring nonlinear relationships of genetically proxied systolic and diastolic blood pressure with the cardiovascular outcomes over linear relationships. For every 10-mm Hg increase in genetically proxied systolic blood pressure, risk of incident CVD increased by 49% (hazard ratio, 1.49 [95% CI, 1.38–1.61]), with similar estimates obtained for coronary artery disease (hazard ratio, 1.50 [95% CI, 1.38–1.63]) and stroke (hazard ratio, 1.44 [95% CI, 1.22–1.70]). Genetically proxied blood pressure had a similar relationship with CVD in men and women. These findings provide evidence to support that even for individuals who do not have elevated blood pressure, public health interventions achieving persistent blood pressure reduction will be of considerable benefit in the primary prevention of CVD.

b White-nose syndrome is a fungal disease that has decimated bat populations across eastern North America. Identification of the etiologic agent, Pseudogymnoascus destructans (formerly Geomyces destructans), in environmental samples is essential to proposed management plans. A major challenge is the presence of closely related species, which are ubiquitous in many soils and cave sediments and often present in high abundance. We present a dual-probe real-time quantitative PCR assay capable of detecting and differentiating P. destructans from closely related fungi in environmental samples from North America. The assay, based on a single nucleotide polymorphism (SNP) specific to P. destructans, is capable of rapid low-level detection from various sampling media, including sediment, fecal samples, wing biopsy specimens, and skin swabs. This method is a highly sensitive, high-throughput method for identifying P. destructans, other Pseudogymnoascus spp., and Geomyces spp. in the environment, providing a fundamental component of research and risk assessment for addressing this disease, as well as other ecological and mycological work on related fungi.

Epoxyeicosatrienoic acids (EETs) protect against the development of insulin resistance in rodents. EETs are hydrolyzed to less biologically active diols by soluble epoxide hydrolase (encoded for by EPHX2). Functional variants of EPHX2 encode for enzymes with increased (Lys55Arg) or decreased (Arg287Gln) hydrolase activity. This study tested the hypothesis that variants of EPHX2 are associated with insulin sensitivity or secretion in humans. Subjects participating in metabolic phenotyping studies were genotyped. Eighty-five subjects underwent hyperglycemic clamps. There was no relationship between the Lys55Arg genotype and insulin sensitivity or secretion. In contrast, the EPHX2 287Gln variant was associated with higher insulin sensitivity index (p=0.019 controlling for body mass index and metabolic syndrome). Also, there was an interactive effect of EPHX2 Arg287Gln genotype and body mass index on insulin sensitivity index (p=0.029). There was no relationship between EPHX2 Arg287Gln genotype and acute or late-phase glucose-stimulated insulin secretion, but disposition index was higher in 287Gln carriers compared with Arg/Arg (p=0.022). Plasma EETs correlated with insulin sensitivity index (r=0.64, p=0.015 for total EETs) and were decreased in the metabolic syndrome. A genetic variant that results in decreased soluble epoxide hydrolase activity is associated with increased insulin sensitivity, as are higher EETs.

Dipeptidyl peptidase‐4 (DPP‐4) inhibitors increase endogenous glucagon‐like peptide‐1 (GLP‐1). We hypothesized that genetic variation in the gene encoding the GLP‐1 receptor (GLP1R) could affect the metabolic response to DPP‐4 inhibition. To evaluate the relationship between the GLP1R rs6923761 variant (G‐to‐A nucleic acid substitution) and metabolic responses, we performed mixed meal studies in individuals with type 2 diabetes mellitus and hypertension after 7‐day treatment with placebo and the DPP‐4 inhibitor sitagliptin. This analysis is a substudy of NCT02130687. The genotype frequency was 13:12:7 GG:GA:AA among individuals of European ancestry. Postprandial glucose excursion was significantly decreased in individuals carrying the rs6923761 variant (GA or AA) as compared with GG individuals during both placebo (P = 0.001) and sitagliptin treatment (P = 0.045), while intact GLP‐1 levels were similar among the genotype groups. In contrast, sitagliptin lowered postprandial glucose to a greater degree in GG as compared with GA/AA individuals (P = 0.035). The relationship between GLP1R rs6923761 genotype and therapies that modulate GLP‐1 signalling merits study in large populations.

Objective To compare the risk of resistant hypertension (RHTN) in patients with systemic lupus erythematosus (SLE) and in controls without SLE, and to define factors associated with RHTN in patients with SLE. Methods We studied 1,044 patients with SLE and 5,241 control subjects using de‐identified electronic health records from a tertiary care center. SLE was defined as ≥4 International Classification of Diseases, Ninth Revision codes for SLE and antinuclear antibody titer ≥1:160. RHTN was defined as uncontrolled blood pressure on 3 antihypertensive medications or requiring 4 or more antihypertensives to attain control. First, we compared the risk of RHTN between groups. Second, we examined the association between RHTN and all‐cause mortality in patients with SLE. Results RHTN was nearly twice as prevalent in patients with SLE compared to control subjects (10.2% and 5.3%, respectively), with an incidence rate of 10.2 versus 6.1 cases per 1,000 person‐years of observation (hazard ratio [HR] 1.72 [95% confidence interval 1.28–2.30]; P < 0.001, adjusted for age, sex, race, baseline end‐stage renal disease [ESRD], creatinine, and calendar year). In patients with SLE, we found associations between RHTN and black race, lower renal function, hypercholesterolemia, and increased inflammatory markers. RHTN was associated with a significantly higher mortality risk (HR 2.91, P = 0.0005) after adjustment for age, sex, race, calendar year, creatinine, baseline ESRD, and number of visits. Conclusion Patients with SLE have a higher risk of RHTN compared to frequency‐matched controls, independent of multiple covariates. RHTN is an important comorbidity for clinicians to recognize in SLE, because it is associated with a higher risk of mortality.