Abstract
Long-chain acyl-CoA synthetase 1 (ACSL1) converts free fatty acids into acyl-CoAs. Mouse studies have revealed that ACSL1 channels acyl-CoAs to β-oxidation, thereby reducing glucose utilization, and is required for diabetes-accelerated atherosclerosis. The role of ACSL1 in humans is unknown. We therefore examined common variants in the human ACSL1 locus by genetic association studies for fasting glucose, diabetes status, and preclinical atherosclerosis by using the MAGIC and DIAGRAM consortia; followed by analyses in participants from the Multi-Ethnic Study of Atherosclerosis, the Penn-T2D consortium, and a meta-analysis of subclinical atherosclerosis in African Americans; and finally, expression quantitative trait locus analysis and identification of DNase I hypersensitive sites (DHS). The results show that three SNPs in ACSL1 (rs7681334, rs735949, and rs4862423) are associated with fasting glucose or diabetes status in these large (>200,000 subjects) data sets. Furthermore, rs4862423 is associated with subclinical atherosclerosis and coincides with a DHS highly accessible in human heart. SNP rs735949 is in strong linkage disequilibrium with rs745805, significantly associated with ACSL1 levels in skin, suggesting tissue-specific regulatory mechanisms. This study provides evidence in humans of ACSL1 SNPs associated with fasting glucose, diabetes, and subclinical atherosclerosis and suggests links among these traits and acyl-CoA synthesis.
Highlights
Long-chain acyl-CoA synthetase 1 (ACSL1) converts free fatty acids into acyl-CoAs
ACSL1 is expressed in myeloid cells, Abbreviations: ACSL1, acyl-CoA synthetase 1; CAC, coronary artery calcification; CEU, northern Caucasian Europeans; DNase I hypersensitive sites (DHS), DNase I hypersensitive site; DIAGRAM, Diabetes Genetics Replication and Meta-Analysis; eQTL, expression quantitative trait locus; GWAS, genome-wide association study; MAGIC, Meta-Analyses of Glucose and Insulin-Related Traits Consortium; MAF, minor allele frequency; MultiEthnic Study of Atherosclerosis (MESA), Multi-Ethnic Study of Atherosclerosis; MuTHER, Multiple Tissue Human Expression Resource; RREB1, ras responsive element binding protein 1; TLR, Toll-like receptor
Our results demonstrate that three SNPs in the ACSL1 gene are associated with markers of fasting glucose or diabetes status and that one of these SNPs is significantly associated with subclinical atherosclerosis
Summary
Candidate association analyses from large-scale consortia To perform association analysis of common variants within the ACSL1 gene region, we examined published GWAS and customarray results from the MAGIC and DIAGRAM consortia. The SNPs identified through GWAS contributed to the design of the Metabochip, a custom genotyping array used for genetic association analysis of type 2 diabetes in an expanded sample of (primarily European descent) 34,840 cases and 114,981 controls. For each of the three ACSL1 SNPs identified in MAGIC and DIAGRAM associated with fasting glucose and diabetes (Table 1), analyses were focused on replicating and validating association with the corresponding trait analyzed in discovery of each SNP in MESA and the Penn-T2D consortium. GWAS data from both of these consortia contain nonoverlapping participants [29] We used this publicly available data and conducted a fixed-effects meta-analysis yielding a sample size of 37,653 coronary heart disease cases and 80,182 controls. MuTHER was interrogated for changes in probe ILMN_1684585 (ACSL1)
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