Common and rare genetic markers of lipid variation in subjects with type 2 diabetes from the ACCORD clinical trial

Background Individuals with type 2 diabetes are at an increased risk of cardiovascular disease. Alterations in circulating lipid levels, total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides (TG) are heritable risk factors for cardiovascular disease. Here we conduct a genome-wide association study (GWAS) of common and rare variants to investigate associations with baseline lipid levels in 7,844 individuals with type 2 diabetes from the ACCORD clinical trial. Methods DNA extracted from stored blood samples from ACCORD participants were genotyped using the Affymetrix Axiom Biobank 1 Genotyping Array. After quality control and genotype imputation, association of common genetic variants (CV), defined as minor allele frequency (MAF) ≥ 3%, with baseline levels of TC, LDL, HDL, and TG was tested using a linear model. Rare variant (RV) associations (MAF < 3%) were conducted using a suite of methods that collapse multiple RV within individual genes. Results Many statistically significant CV ( p  < 1 × 10 −8 ) replicate findings in large meta-analyses in non-diabetic subjects. RV analyses also confirmed findings in other studies, whereas significant RV associations with CNOT2 , HPN-AS1 , and SIRPD appear to be novel ( q  < 0.1). Discussion Here we present findings for the largest GWAS of lipid levels in people with type 2 diabetes to date. We identified 17 statistically significant ( p  < 1 × 10 −8 ) associations of CV with lipid levels in 11 genes or chromosomal regions, all of which were previously identified in meta-analyses of mostly non-diabetic cohorts. We also identified 13 associations in 11 genes based on RV, several of which represent novel findings

Genetic Variants in HSD17B3, SMAD3, and IPO11 Impact Circulating Lipids in Response to Fenofibrate in Individuals With Type 2 Diabetes

Individuals with type 2 diabetes (T2D) and dyslipidemia are at an increased risk of cardiovascular disease. Fibrates are a class of drugs prescribed to treat dyslipidemia, but variation in response has been observed. To evaluate common and rare genetic variants that impact lipid responses to fenofibrate in statin-treated patients with T2D, we examined lipid changes in response to fenofibrate therapy using a genomewide association study (GWAS). Associations were followed-up using gene expression studies in mice. Common variants in SMAD3 and IPO11 were marginally associated with lipid changes in black subjects (P < 5 × 10 -6 ). Rare variant and gene expression changes were assessed using a false discovery rate approach. AKR7A3 and HSD17B13 were associated with lipid changes in white subjects (q < 0.2). Mice fed fenofibrate displayed reductions in Hsd17b13 gene expression (q < 0.1). Associations of variants in SMAD3, IPO11, and HSD17B13, with gene expression changes in mice indicate that transforming growth factor-beta (TGF-β) and NRF2 signaling pathways may influence fenofibrate effects on dyslipidemia in patients with T2D

Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management

Even at low-density lipoprotein cholesterol (LDL-C) goal, patients with cardiometabolic abnormalities remain at high risk of cardiovascular events. This paper aims (i) to critically appraise evidence for elevated levels of triglyceride-rich lipoproteins (TRLs) and low levels of high-density lipoprotein cholesterol (HDL-C) as cardiovascular risk factors, and (ii) to advise on therapeutic strategies for management. Current evidence supports a causal association between elevated TRL and their remnants, low HDL-C, and cardiovascular risk. This interpretation is based on mechanistic and genetic studies for TRL and remnants, together with the epidemiological data suggestive of the association for circulating triglycerides and cardiovascular disease. For HDL, epidemiological, mechanistic, and clinical intervention data are consistent with the view that low HDL-C contributes to elevated cardiovascular risk; genetic evidence is unclear however, potentially reflecting the complexity of HDL metabolism. The Panel believes that therapeutic targeting of elevated triglycerides (≥1.7 mmol/L or 150 mg/dL), a marker of TRL and their remnants, and/or low HDL-C (<1.0 mmol/L or 40 mg/dL) may provide further benefit. The first step should be lifestyle interventions together with consideration of compliance with pharmacotherapy and secondary causes of dyslipidaemia. If inadequately corrected, adding niacin or a fibrate, or intensifying LDL-C lowering therapy may be considered. Treatment decisions regarding statin combination therapy should take into account relevant safety concerns, i.e. the risk of elevation of blood glucose, uric acid or liver enzymes with niacin, and myopathy, increased serum creatinine and cholelithiasis with fibrates. These recommendations will facilitate reduction in the substantial cardiovascular risk that persists in patients with cardiometabolic abnormalities at LDL-C goal