Fine Mapping and Functional Analysis Reveal a Role of SLC22A1 in Acylcarnitine Transport

Genome-wide association studies have identified a signal at the SLC22A1 locus for serum acylcarnitines, intermediate metabolites of mitochondrial oxidation whose plasma levels associate with metabolic diseases. Here, we refined the association signal, performed conditional analyses, and examined the...

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Vydané v:	American journal of human genetics Ročník 101; číslo 4; s. 489
Hlavní autori:	Kim, Hye In, Raffler, Johannes, Lu, Wenyun, Lee, Jung-Jin, Abbey, Deepti, Saleheen, Danish, Rabinowitz, Joshua D, Bennett, Michael J, Hand, Nicholas J, Brown, Christopher, Rader, Daniel J
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	United States 05.10.2017
Predmet:	Alleles Alternative Splicing Animals Biological Transport Carnitine - analogs & derivatives Carnitine - blood Carnitine - pharmacokinetics Cells, Cultured Cohort Studies CRISPR-Cas Systems Female Gene Expression Regulation Genome-Wide Association Study High-Throughput Nucleotide Sequencing Humans Liver - metabolism Male Metabolic Diseases - blood Metabolic Diseases - genetics Metabolic Diseases - metabolism Metabolomics Mice Mice, Inbred BALB C Mice, Inbred C57BL Mice, Knockout Organic Cation Transporter 1 - antagonists & inhibitors Organic Cation Transporter 1 - genetics Organic Cation Transporter 1 - metabolism Polymorphism, Single Nucleotide Tissue Distribution metabolomics SLC22A1 metabolite GWAS genomics acylcarnitines fine mapping allelic imbalance
ISSN:	1537-6605, 1537-6605
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Shrnutí:	Genome-wide association studies have identified a signal at the SLC22A1 locus for serum acylcarnitines, intermediate metabolites of mitochondrial oxidation whose plasma levels associate with metabolic diseases. Here, we refined the association signal, performed conditional analyses, and examined the linkage structure to find coding variants of SLC22A1 that mediate independent association signals at the locus. We also employed allele-specific expression analysis to find potential regulatory variants of SLC22A1 and demonstrated the effect of one variant on the splicing of SLC22A1. SLC22A1 encodes a hepatic plasma membrane transporter whose role in acylcarnitine physiology has not been described. By targeted metabolomics and isotope tracing experiments in loss- and gain-of-function cell and mouse models of Slc22a1, we uncovered a role of SLC22A1 in the efflux of acylcarnitines from the liver to the circulation. We further validated the impacts of human variants on SLC22A1-mediated acylcarnitine efflux in vitro, explaining their association with serum acylcarnitine levels. Our findings provide the detailed molecular mechanisms of the GWAS association for serum acylcarnitines at the SLC22A1 locus by functionally validating the impact of SLC22A1 and its variants on acylcarnitine transport.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1537-6605 1537-6605
DOI:	10.1016/j.ajhg.2017.08.008