Intersecting Genetics of Frailty and Cardiovascular Disease.

OBJECTIVES: To determine the genetic correlates of physical frailty and sarcopenia, focusing on single nucleotide polymorphisms (SNPs) in genome-wide association studies (GWAS), and to explore the genetic overlap of frailty with cardiovascular disease (CVD) and its risk factors. METHODS: PubMed was systematically searched for GWAS studies investigating the association between SNPs and objective measures of physical frailty or sarcopenia. SNPs were retained if they were associated with one of the phenotypes of interest by a p-value of 5.0x10-8 or less. RESULTS: Ten studies were included, with a total of 237 SNPs in 181 genes being associated with physical frailty or sarcopenia; as measured by handgrip strength or lean (muscle) mass. These genes were cross-referenced in the GWAS Catalog, and many of them were found to be associated with CVD or metabolic syndrome. CONCLUSIONS: Evidence from GWAS has shown that frailty is associated with common genetic polymorphisms. Many of these polymorphisms have been implicated in CVD, supporting the hypothesis of a shared pathophysiology between these entities. Future studies are eagerly anticipated to map out the mechanistic links and discover therapeutic targets and novel biomarkers for frailty.

Omega-3 fatty acids and the genetic risk of early onset acute coronary syndrome.

BACKGROUND AND AIMS: Recent gene-environment interaction studies suggest that diet may influence an individual's genetic predisposition to cardiovascular risk. We evaluated whether omega-3 fatty acid intake may influence the risk for acute coronary syndrome (ACS) conferred by genetic polymorphisms among patients with early onset ACS. METHODS AND RESULTS: Our population consisted of 705 patients of white European descent enrolled in GENESIS-PRAXY, a multicenter cohort study of patients aged 18-55 years and hospitalized with ACS. We used a case-only design to investigate interactions between the omega-3 index (a validated biomarker of omega-3 fatty acid intake) and 30 single nucleotide polymorphisms (SNPs) robustly associated with ACS. We used logistic regression to assess the interaction between each SNP and the omega-3 index. Interaction was also assessed between the omega-3 index and a genetic risk score generated from the 30 SNPs. All models were adjusted for age and sex. An interaction for increased ACS risk was found between carriers of the chromosome 9p21 variant rs4977574 and low omega-3 index (OR 1.57, 95% CI 1.07-2.32, p = 0.02), but this was not significant after correction for multiple testing. Similar results were obtained in the adjusted model (OR 1.55, 95% CI 1.05-2.29, p = 0.03). We did not observe any interaction between the genetic risk score or any of the other SNPs and the omega-3 index. CONCLUSION: Our results suggest that omega-3 fatty acid intake may modify the genetic risk conferred by chromosome 9p21 variation in the development of early onset ACS and requires independent replication.

Enhanced susceptibility to pulmonary infection with Burkholderia cepacia in Cftr(-/-) mice.

Progressive pulmonary infection is the dominant clinical feature of cystic fibrosis (CF), but the molecular basis for this susceptibility remains incompletely understood. To study this problem, we developed a model of chronic pneumonia by repeated instillation of a clinical isolate of Burkholderia cepacia (genomovar III, ET12 strain), an opportunistic gram-negative bacterium, from a case of CF into the lungs of Cftr (m1unc-/-) (Cftr(-/-)) and congenic Cftr(+/+) controls. Nine days after the last instillation, the CF transmembrane regulator knockout mice showed persistence of viable bacteria with chronic severe bronchopneumonia while wild-type mice remained healthy. The histopathological changes in the lungs of the susceptible Cftr(-/-) mice were characterized by infiltration of a mixed inflammatory-cell population into the peribronchiolar and perivascular spaces, Clara cell hyperplasia, mucus hypersecretion in airways, and exudation into alveolar airspaces by a mixed population of macrophages and neutrophils. An increased proportion of neutrophils was observed in bronchoalveolar lavage fluid from the Cftr(-/-) mice, which, despite an increased bacterial load, demonstrated minimal evidence of activation. Alveolar macrophages from Cftr(-/-) mice also demonstrated suboptimal activation. These observations suggest that the pulmonary host defenses are compromised in lungs from animals with CF, as manifested by increased susceptibility to bacterial infection and lung injury. This murine model of chronic pneumonia thus reflects, in part, the situation in human patients and may help elucidate the mechanisms leading to defective host defense in CF.