👤 Mathew A Cherny

The association between rheumatoid arthritis (RA) and blood lipid levels has often been described as paradoxical, despite the strong association between RA and cardiovascular disease (CVD) risk. We aimed to clarify the genetic architecture that would explain the relationship between RA and blood-lipid levels, while considering inflammation as measured by C-reactive protein (CRP). Genome-wide association study (GWAS) summary statistics were collected from the CHARGE Consortium and Global Lipids Genetics Consortium. Blood-lipid levels includes HDL-C, LDL-C, triglycerides (TG), and total cholesterol (TC). Causality was examined by assessing Mendelian Randomization (MR) analysis. Pleiotropy, the identification of shared causal variants between traits, was assessed by conducting colocalization analyses. Using the MR Egger method, RA did not appear to causally predict alterations in lipid factors, rather the MR Egger intercept revealed that the genetic relationship between RA and HDL-C, LDL-C and TC may be explained by horizontal pleiotropy (p=0.003, 0.006, and 0.018, respectively). MR was suggestive of a horizontally pleiotropic relationship between CRP and lipid factors, while a causal relationship could not be ruled out. Recurring genes arising from shared causal genetic variants between RA and varying lipid factors included NAT2/PSD3, FADS2/FADS1, SH2B3, and YDJC. Horizontal pleiotropy appears to explain the genetic relationship between RA and blood-lipid levels. In addition, blood-lipid levels appear to suggest a horizontally pleiotropic relationship to CRP, if not mediated through RA as well. Consideration of the pleiotropic genes between RA and blood lipid levels may aid in enhancing diagnostic means to predict CVD. Show less

Fibroblast growth factor 21 (FGF21) is increasingly recognized as an important metabolic regulator of glucose homeostasis. Here, we conducted an exome-chip association analysis by genotyping 5,169 Chinese individuals from a community-based cohort and two clinic-based cohorts. A custom Asian exome-chip was used to detect genetic determinants influencing circulating FGF21 levels. Single-variant association analysis interrogating 70,444 single nucleotide polymorphisms identified a novel locus, Show less

Hepatocyte nuclear factor-4alpha (HNF-4alpha) regulates transcription of several genes involved in lipid metabolism, including that of apolipoprotein (apo) A-IV, which is tightly regulated by lipid absorption and enhances enterocyte chylomicron secretion. Studies were performed to define the role of HNF-4alpha in the regulation of apo A-IV gene transcription by dietary fatty acid in neonatal swine small intestine. HNF-4alpha mRNA was expressed in liver > intestine > kidney in suckling, weanling, and weaned pigs. Jejunal HNF-4alpha mRNA and protein and apo A-IV and swine microsomal triglyceride transfer protein (MTP) large subunit mRNA expression were induced in parallel in 2-day-old swine by a 24-h high-fat intraduodenal infusion. In IPEC-1 cells, incubation with oleic acid (OA) resulted in coordinate induction of both HNF-4alpha, apo A-IV, and MTP mRNA, similar to that observed in vivo. When HNF-4alpha expression was driven by doxycycline by using the TET-On system in the absence of OA to observe the effect of HNF-4alpha directly on apo A-IV and MTP mRNA levels in the absence of other factors that might be concomitantly induced by fatty acid absorption, apo A-IV and MTP expression were increased. In luciferase reporter gene assays in IPEC-1 cells using apo A-IV/C-III intergenic region constructs, TET-On-regulated HNF-4alpha expression without OA increased luciferase activity, and incubation with OA did not further increase activity. These data suggest that acute induction of the apo A-IV and MTP genes by dietary lipid in newborn intestine occurs, at least in part, via ligand-independent transactivation by HNF-4alpha that is itself induced by a lipid-mediated mechanism. Show less