title: HRAS1 and LASS1 with APOE are associated with human longevity and healthy aging.
abstract: The search for longevity-determining genes in human has largely neglected the operation of genetic interactions. We have identified a novel combination of common variants of three genes that has a marked association with human lifespan and healthy aging. Subjects were recruited and stratified according to their genetically inferred ethnic affiliation to account for population structure. Haplotype analysis was performed in three candidate genes, and the haplotype combinations were tested for association with exceptional longevity. An HRAS1 haplotype enhanced the effect of an APOE haplotype on exceptional survival, and a LASS1 haplotype further augmented its magnitude. These results were replicated in a second population. A profile of healthy aging was developed using a deficit accumulation index, which showed that this combination of gene variants is associated with healthy aging. The variation in LASS1 is functional, causing enhanced expression of the gene, and it contributes to healthy aging and greater survival in the tenth decade of life. Thus, rare gene variants need not be invoked to explain complex traits such as aging; instead rare congruence of common gene variants readily fulfills this role. The interaction between the three genes described here suggests new models for cellular and molecular mechanisms underlying exceptional survival and healthy aging that involve lipotoxicity.
authors.affiliation: Department of Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, USA. sjazwins@tulane.edu
authors.forename: S Michal
authors.initials: SM
authors.lastname: Jazwinski
authors.forename: Sangkyu
authors.initials: S
authors.lastname: Kim
authors.forename: Jianliang
authors.initials: J
authors.lastname: Dai
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Xiuhua
authors.initials: X
authors.lastname: Bi
authors.forename: James C
authors.initials: JC
authors.lastname: Jiang
authors.forename: Jonathan
authors.initials: J
authors.lastname: Arnold
authors.forename: Mark A
authors.initials: MA
authors.lastname: Batzer
authors.forename: Jerilyn A
authors.initials: JA
authors.lastname: Walker
authors.forename: David A
authors.initials: DA
authors.lastname: Welsh
authors.forename: Christina M
authors.initials: CM
authors.lastname: Lefante
authors.forename: Julia
authors.initials: J
authors.lastname: Volaufova
authors.forename: Leann
authors.initials: L
authors.lastname: Myers
authors.forename: L Joseph
authors.initials: LJ
authors.lastname: Su
authors.forename: Dorothy B
authors.initials: DB
authors.lastname: Hausman
authors.forename: Michael V
authors.initials: MV
authors.lastname: Miceli
authors.forename: Eric
authors.initials: E
authors.lastname: Ravussin
authors.forename: Leonard W
authors.initials: LW
authors.lastname: Poon
authors.forename: Katie E
authors.initials: KE
authors.lastname: Cherry
authors.forename: Michael A
authors.initials: MA
authors.lastname: Welsch
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics*; D001057:Apolipoproteins E / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D014644:Genetic Variation / Q000235:genetics; D006239:Haplotypes; D006801:Humans; D008136:Longevity / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D051049:Sphingosine N-Acyltransferase
chemical_list: D001057:Apolipoproteins E; D008565:Membrane Proteins; C493790:CERS1 protein, human; D051049:Sphingosine N-Acyltransferase; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)