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

Hye In Kim, Johannes Raffler, Wenyun Lu, Jung Jin Lee, Deepti Abbey, Danish Saleheen, Joshua D. Rabinowitz, Michael J. Bennett, Nicholas J. Hand, Christopher Brown, Daniel J. Rader

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)489-502
Number of pages14
JournalAmerican Journal of Human Genetics
Volume101
Issue number4
DOIs
StatePublished - Oct 5 2017

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Keywords

  • SLC22A1
  • acylcarnitines
  • allelic imbalance
  • fine mapping
  • genomics
  • metabolite GWAS
  • metabolomics

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  • Cite this

    Kim, H. I., Raffler, J., Lu, W., Lee, J. J., Abbey, D., Saleheen, D., Rabinowitz, J. D., Bennett, M. J., Hand, N. J., Brown, C., & Rader, D. J. (2017). Fine Mapping and Functional Analysis Reveal a Role of SLC22A1 in Acylcarnitine Transport. American Journal of Human Genetics, 101(4), 489-502. https://doi.org/10.1016/j.ajhg.2017.08.008