👤 Yonca Bulut

Hypertriglyceridemia is mostly associated with secondary conditions in children but can also result from monogenic disorders. The most prevalent genes identified as the underlying reason for impaired clearance of triglycerides from plasma by genome-wide association studies are the LPL, APOC2, APOA5, LMF1, APOE and GPIHBP1 genes. In this study, 26 pediatric patients with primary hypertriglyceridemia, 12 of whom were severe, were screened for monogenic causes via a next-generation sequencing panel that included 25 genes, namely, ABCA1, ABCG5, ABCG8, ANGPTL3, APOA1, APOA5, APOB, APOC2, APOC3, APOE, CETP, GPD1, GPIHBP1, LCAT, LDLR, LDLRAP1, LIPA, LIPC, LMF1, LPL, MTTP, NPC1L1, OSBPL5, PCSK9 and SAR1B. Additional findings, such as positive family history, hepatomegaly, splenomegaly, history of acute pancreatitis, hepatosteatosis, and atherosclerotic cardiovascular disease, were recorded. Twenty different variants, 16 of which were novel, were detected. Among these, six of the eight clinically significant mutations detected in the LPL, GPD1, GPIHBP1, APOC2, and LIPC genes were novel mutations. At least one variant was identified in 17 of 26 patients (65.4%), whereas no variants were detected in 9 patients (34.6%). Clinically significant variants that could explain the clinical findings were detected in 7 (58.3%) of the 12 patients with severe hypertriglyceridemia. In 4 out of the 6 patients with a familial history of hypertriglyceridemia, we identified pathogenic variants in the GPD1, LIPC, LPL and APOC2 genes, which are associated with hypertriglyceridemia. Targeting gene panels for suspected monogenic hypertriglyceridemia is a promising way to identify the underlying etiology, which enables genetic counseling and family screening to identify new patients and provides a personalized treatment approach. Show less

Experimental and clinical studies link Chlamydia pneumoniae infection to atherogenesis and atherothrombotic events, but the underlying mechanisms are unclear. We tested the hypothesis that C. pneumoniae-induced acceleration of atherosclerosis in apolipoprotein E (ApoE)(-/-) mice is reciprocally modulated by activation of TLR-mediated innate immune and liver X receptor alpha (LXRalpha) signaling pathways. We infected ApoE(-/-) mice and ApoE(-/-) mice that also lacked TLR2, TLR4, MyD88, or LXRalpha intranasally with C. pneumoniae followed by feeding of a high fat diet for 4 mo. Mock-infected littermates served as controls. Atherosclerosis was assessed in aortic sinuses and in en face preparation of whole aorta. The numbers of activated dendritic cells (DCs) within plaques and the serum levels of cholesterol and proinflammatory cytokines were also measured. C. pneumoniae infection markedly accelerated atherosclerosis in ApoE-deficient mice that was associated with increased numbers of activated DCs in aortic sinus plaques and higher circulating levels of MCP-1, IL-12p40, IL-6, and TNF-alpha. In contrast, C. pneumoniae infection had only a minimal effect on atherosclerosis, accumulation of activated DCs in the sinus plaques, or circulating cytokine increases in ApoE(-/-) mice that were also deficient in TLR2, TLR4, or MyD88. However, C. pneumoniae-induced acceleration of atherosclerosis in ApoE(-/-) mice was further enhanced in ApoE(-/-)LXRalpha(-/-) double knockout mice and was accompanied by higher serum levels of IL-6 and TNF-alpha. We conclude that C. pneumoniae infection accelerates atherosclerosis in hypercholesterolemic mice predominantly through a TLR/MyD88-dependent mechanism and that LXRalpha appears to reciprocally modulate and reduce the proatherogenic effects of C. pneumoniae infection. Show less