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Functional genetic screen of human diversity reveals that a methionine salvage enzyme regulates inflammatory cell death.

Publication ,  Journal Article
Ko, DC; Gamazon, ER; Shukla, KP; Pfuetzner, RA; Whittington, D; Holden, TD; Brittnacher, MJ; Fong, C; Radey, M; Ogohara, C; Stark, AL ...
Published in: Proc Natl Acad Sci U S A
August 28, 2012

Genome-wide association studies can identify common differences that contribute to human phenotypic diversity and disease. When genome-wide association studies are combined with approaches that test how variants alter physiology, biological insights can emerge. Here, we used such an approach to reveal regulation of cell death by the methionine salvage pathway. A common SNP associated with reduced expression of a putative methionine salvage pathway dehydratase, apoptotic protease activating factor 1 (APAF1)-interacting protein (APIP), was associated with increased caspase-1-mediated cell death in response to Salmonella. The role of APIP in methionine salvage was confirmed by growth assays with methionine-deficient media and quantitation of the methionine salvage substrate, 5'-methylthioadenosine. Reducing expression of APIP or exogenous addition of 5'-methylthioadenosine increased Salmonellae-induced cell death. Consistent with APIP originally being identified as an inhibitor of caspase-9-dependent apoptosis, the same allele was also associated with increased sensitivity to the chemotherapeutic agent carboplatin. Our results show that common human variation affecting expression of a single gene can alter susceptibility to two distinct cell death programs. Furthermore, the same allele that promotes cell death is associated with improved survival of individuals with systemic inflammatory response syndrome, suggesting a possible evolutionary pressure that may explain the geographic pattern observed for the frequency of this SNP. Our study shows that in vitro association screens of disease-related traits can not only reveal human genetic differences that contribute to disease but also provide unexpected insights into cell biology.

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Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

August 28, 2012

Volume

109

Issue

35

Start / End Page

E2343 / E2352

Location

United States

Related Subject Headings

  • Young Adult
  • Thionucleosides
  • Salmonella typhimurium
  • Salmonella Infections
  • Quantitative Trait Loci
  • Polymorphism, Single Nucleotide
  • Middle Aged
  • Mice, Inbred C57BL
  • Mice
  • Methionine
 

Citation

APA
Chicago
ICMJE
MLA
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Ko, D. C., Gamazon, E. R., Shukla, K. P., Pfuetzner, R. A., Whittington, D., Holden, T. D., … Miller, S. I. (2012). Functional genetic screen of human diversity reveals that a methionine salvage enzyme regulates inflammatory cell death. Proc Natl Acad Sci U S A, 109(35), E2343–E2352. https://doi.org/10.1073/pnas.1206701109
Ko, Dennis C., Eric R. Gamazon, Kajal P. Shukla, Richard A. Pfuetzner, Dale Whittington, Tarah D. Holden, Mitchell J. Brittnacher, et al. “Functional genetic screen of human diversity reveals that a methionine salvage enzyme regulates inflammatory cell death.Proc Natl Acad Sci U S A 109, no. 35 (August 28, 2012): E2343–52. https://doi.org/10.1073/pnas.1206701109.
Ko DC, Gamazon ER, Shukla KP, Pfuetzner RA, Whittington D, Holden TD, et al. Functional genetic screen of human diversity reveals that a methionine salvage enzyme regulates inflammatory cell death. Proc Natl Acad Sci U S A. 2012 Aug 28;109(35):E2343–52.
Ko, Dennis C., et al. “Functional genetic screen of human diversity reveals that a methionine salvage enzyme regulates inflammatory cell death.Proc Natl Acad Sci U S A, vol. 109, no. 35, Aug. 2012, pp. E2343–52. Pubmed, doi:10.1073/pnas.1206701109.
Ko DC, Gamazon ER, Shukla KP, Pfuetzner RA, Whittington D, Holden TD, Brittnacher MJ, Fong C, Radey M, Ogohara C, Stark AL, Akey JM, Dolan ME, Wurfel MM, Miller SI. Functional genetic screen of human diversity reveals that a methionine salvage enzyme regulates inflammatory cell death. Proc Natl Acad Sci U S A. 2012 Aug 28;109(35):E2343–E2352.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

August 28, 2012

Volume

109

Issue

35

Start / End Page

E2343 / E2352

Location

United States

Related Subject Headings

  • Young Adult
  • Thionucleosides
  • Salmonella typhimurium
  • Salmonella Infections
  • Quantitative Trait Loci
  • Polymorphism, Single Nucleotide
  • Middle Aged
  • Mice, Inbred C57BL
  • Mice
  • Methionine