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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Bibliographic Details
Published in:American journal of human genetics Vol. 101; no. 4; p. 489
Main Authors: 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
Format: Journal Article
Language:English
Published: United States 05.10.2017
Subjects:
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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Summary: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.
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ISSN:1537-6605
1537-6605
DOI:10.1016/j.ajhg.2017.08.008