title: Functional genetic screen of human diversity reveals that a methionine salvage enzyme regulates inflammatory cell death.
abstract: 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.
authors: Department of Microbiology, University of Washington, Seattle, WA 98195, USA.
authors: Dennis C
authors: DC
authors: Ko
authors: Eric R
authors: ER
authors: Gamazon
authors: Kajal P
authors: KP
authors: Shukla
authors: Richard A
authors: RA
authors: Pfuetzner
authors: Dale
authors: D
authors: Whittington
authors: Tarah D
authors: TD
authors: Holden
authors: Mitchell J
authors: MJ
authors: Brittnacher
authors: Christine
authors: C
authors: Fong
authors: Matthew
authors: M
authors: Radey
authors: Cassandra
authors: C
authors: Ogohara
authors: Amy L
authors: AL
authors: Stark
authors: Joshua M
authors: JM
authors: Akey
authors: M Eileen
authors: ME
authors: Dolan
authors: Mark M
authors: MM
authors: Wurfel
authors: Samuel I
authors: SI
authors: Miller
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology; D020170:Caspase 1 / Q000235:genetics* / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D003839:Deoxyadenosines / Q000378:metabolism; D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation; D057809:HEK293 Cells; D060148:HapMap Project; D006801:Humans; D008715:Methionine / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D040641:Quantitative Trait Loci; D012480:Salmonella Infections / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D012486:Salmonella typhimurium / Q000276:immunology*; D013872:Thionucleosides / Q000378:metabolism; D055815:Young Adult
chemical_list: C573917:APIP protein, human; D051017:Apoptosis Regulatory Proteins; D003839:Deoxyadenosines; D013872:Thionucleosides; C008500:5'-methylthioadenosine; D008715:Methionine; C506433:CASP9 protein, human; D053453:Caspase 9; D020170:Caspase 1