Background The genetic determinants of the human innate immune response are poorly understood. Apolipoprotein (Apo) E, a lipid-trafficking protein that affects inflammation, has well-described ...wild-type (ε3) and disease-associated (ε2 and ε4) alleles, but its connection to human innate immunity is undefined. Objective We sought to define the relationship of APOε4 to the human innate immune response. Methods We evaluated APOε4 in several functional models of the human innate immune response, including intravenous LPS challenge in human subjects, and assessed APOε4 association to organ injury in patients with severe sepsis, a disease driven by dysregulated innate immunity. Results Whole blood from healthy APOε3 / APOε4 volunteers induced higher cytokine levels on ex vivo stimulation with Toll-like receptor (TLR) 2, TLR4, or TLR5 ligands than blood from APOε3 / APOε3 patients, whereas TLR7/8 responses were similar. This was associated with increased lipid rafts in APOε3/APOε4 monocytes. By contrast, APOε3 / APOε3 and APOε3 / APOε4 serum neutralized LPS equivalently and supported similar LPS responses in Apoe -deficient macrophages, arguing against a differential role for secretory APOE4 protein. After intravenous LPS, APOε3/APOε4 patients had higher hyperthermia and plasma TNF-α levels and earlier plasma IL-6 than APOε3/APOε3 patients. APOE4-targeted replacement mice displayed enhanced hypothermia, plasma cytokines, and hepatic injury and altered splenic lymphocyte apoptosis after systemic LPS compared with APOE3 counterparts. In a cohort of 828 patients with severe sepsis, APOε4 was associated with increased coagulation system failure among European American patients. Conclusions APOε4 is a determinant of the human innate immune response to multiple TLR ligands and associates with altered patterns of organ injury in human sepsis.
Background Cholesterol exerts complex effects on inflammation. There has been little investigation of whether serum cholesterol is associated with asthma, an inflammatory airways disease with great ...public health impact. Objective To determine relationships between levels of 3 serum cholesterol measures (total cholesterol TC, high-density lipoprotein cholesterol HDL-C, and non–HDL-C) and asthma/wheeze in a sample representative of the US population. Methods Cross-sectional study of 7005 participants age ≥6 years from the 2005 to 2006 National Health and Nutrition Examination Survey. Results Serum TC and non–HDL-C were lower in patients with current asthma than in subjects without current asthma in the overall population (TC, 188.5 vs 192.2 mg/dL; non–HDL-C, 133.9 vs 137.7 mg/dL; P < .05 for both), whereas HDL-C was not different. Adjusted odds ratios (ORs) from multivariate logistic regression per 1-SD increase of TC and non–HDL-C for current asthma were 0.92 (95% CI, 0.86-0.98) and 0.91 (95% CI, 0.85-0.98), respectively. On racial/ethnic stratification, these relationships reflect marked reductions unique to Mexican Americans (MAs; TC, 171.4 vs 189.3 mg/dL; P < .001; OR, 0.62; 95% CI, 0.48-0.80; non–HDL-C, 119.8 vs 137.9 mg/dL; P < .001; OR, 0.62; 95% CI, 0.48-0.79). Among MAs, the adjusted OR for wheeze requiring medical attention was 0.57 (95% CI, 0.43-0.75) for TC and 0.53 (95% CI, 0.33-0.85) for non–HDL-C. Relationships between cholesterol and asthma/wheeze were independent of body mass index and serum C-reactive protein, and similar between atopic and nonatopic participants. Conclusion Serum TC and non–HDL-C are inversely related to asthma in the US population, chiefly reflecting a relationship among MAs.
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