Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P < 5 × 10⁻⁸), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes—GALNT2, PPP1R3B and TTC39B—with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.

Mitochondria have emerged as key actors of innate and adaptive immunity. Mitophagy has a pivotal role in cell homeostasis, but its contribution to macrophage functions and host defense remains to be delineated. Here, we showed that lipopolysaccharide (LPS) in combination with IFN-γ inhibited PINK1-dependent mitophagy in macrophages through a STAT1-dependent activation of the inflammatory caspases 1 and 11. In addition, we demonstrated that the inhibition of mitophagy triggered classical macrophage activation in a mitochondrial ROS–dependent manner. In a murine model of polymicrobial infection (cecal ligature and puncture), adoptive transfer of Pink1-deficient bone marrow or pharmacological inhibition of mitophagy promoted macrophage activation, which favored bactericidal clearance and led to a better survival rate. Reciprocally, mitochondrial uncouplers that promote mitophagy reversed LPS/IFN-γ–mediated activation of macrophages and led to immunoparalysis with impaired bacterial clearance and lowered survival. In critically ill patients, we showed that mitophagy was inhibited in blood monocytes of patients with sepsis as compared with nonseptic patients. Overall, this work demonstrates that the inhibition of mitophagy is a physiological mechanism that contributes to the activation of myeloid cells and improves the outcome of sepsis.

Purpose: To validate a triple-echo gradient-echo sequence for measuring the fat content of the liver, by using hydrogen 1 (1H) magnetic resonance (MR) spectroscopy as the reference standard. Materials and Methods: This prospective study was approved by the appropriate ethics committee, and written informed consent was obtained from all patients. In 37 patients with type 2 diabetes (31 men, six women; mean age, 56 years), 3.0-T single-voxel point-resolved 1H MR spectroscopy of the liver (Couinaud segment VII) was performed to calculate the liver fat fraction from the water (4.7 ppm) and methylene (1.3 ppm) peaks, corrected for T1 and T2 decay. Liver fat fraction was also computed from triple-echo (consecutive in-phase, opposed-phase, and in-phase echo times) breath-hold spoiled gradient-echo sequence (flip angle, 20°), by estimating T2* and relative signal intensity loss between in- and opposed-phase values, corrected for T2* decay. Pearson correlation coefficient, Bland-Altman 95% limit of agreement, and ...