Person:

Aragam, Krishna

Less than 3% of protein-coding genetic variants are predicted to result in loss of protein function through the introduction of a stop codon, frameshift, or the disruption of an essential splice site; however, such predicted loss-of-function (pLOF) variants provide insight into effector transcript and direction of biological effect. In >400,000 UK Biobank participants, we conduct association analyses of 3759 pLOF variants with six metabolic traits, six cardiometabolic diseases, and twelve additional diseases. We identified 18 new low-frequency or rare (allele frequency < 5%) pLOF variant-phenotype associations. pLOF variants in the gene GPR151 protect against obesity and type 2 diabetes, in the gene IL33 against asthma and allergic disease, and in the gene IFIH1 against hypothyroidism. In the gene PDE3B, pLOF variants associate with elevated height, improved body fat distribution and protection from coronary artery disease. Our findings prioritize genes for which pharmacologic mimics of pLOF variants may lower risk for disease.

Objective: The impact of the severity of secondary mitral regurgitation (MR) on the risk of death and heart failure (HF) hospitalisations in patients with reduced left ventricular (LV) systolic function is poorly defined. The study sought to identify the incremental risk of secondary MR in patients with reduced LV systolic function. Methods: We studied 615 consecutive patients with LV ejection fraction ≤35% by transthoracic echocardiography at a single medical centre. Patients were divided into three groups of no MR, mild, or moderate to severe MR. The median follow-up was 2.9 years. The primary endpoint was a composite of death or HF hospitalisations. Results: Compared with patients with no MR, the risk of death or HF hospitalisations was higher for mild MR (HR 1.7, P=0.003) and moderate to severe MR (HR 2.7, P<0.001). The risk was also higher for the component endpoints of HF hospitalisations (mild MR: HR 2.3, P=0.001; moderate to severe MR: HR 3.5, P<0.001) and death (mild MR: HR 1.6, P=0.033; moderate to severe MR: HR 2.6, P<0.001). After adjustment for other covariates, MR was no longer significantly associated with death or HF hospitalisations, or death alone, but remained significantly associated with HF hospitalisations (mild MR: HR 1.7, P=0.028; moderate to severe MR: HR 2.2, P=0.002). Conclusions: In patients with reduced LV systolic function, secondary MR is associated with an increased risk of HF hospitalisations but not death.