title: Evidence from case-control and longitudinal studies supports associations of genetic variation in APOE, CETP, and IL6 with human longevity.
abstract: In this study, we investigated 102 single-nucleotide polymorphisms (SNPs) covering the common genetic variation in 16 genes recurrently regarded as candidates for human longevity: APOE; ACE; CETP; HFE; IL6; IL6R; MTHFR; TGFB1; APOA4; APOC3; SIRTs 1, 3, 6; and HSPAs 1A, 1L, 14. In a case-control study of 1,089 oldest-old (ages 92-93) and 736 middle-aged Danes, the minor allele frequency (MAF) of rs769449 (APOE) was significantly decreased in the oldest-old, while the MAF of rs9923854 (CETP) was significantly enriched. These effects were supported when investigating 1,613 oldest-old (ages 95-110) and 1,104 middle-aged Germans. rs769449 was in modest linkage equilibrium (R (2)=0.55) with rs429358 of the APOE-ε4 haplotype and adjusting for rs429358 eliminated the association of rs769449, indicating that the association likely reflects the well-known effect of rs429358. Gene-based analysis confirmed the effects of variation in APOE and CETP and furthermore pointed to HSPA14 as a longevity gene. In a longitudinal study with 11 years of follow-up on survival in the oldest-old Danes, only one SNP, rs2069827 (IL6), was borderline significantly associated with survival from age 92 (P-corrected=0.064). This advantageous effect of the minor allele was supported when investigating a Dutch longitudinal cohort (N=563) of oldest-old (age 85+). Since rs2069827 was located in a putative transcription factor binding site, quantitative RNA expression studies were conducted. However, no difference in IL6 expression was observed between rs2069827 genotype groups. In conclusion, we here support and expand the evidence suggesting that genetic variation in APOE, CETP, and IL6, and possible HSPA14, is associated with human longevity.
authors.affiliation: The Danish Aging Research Center, Epidemiology, Institute of Public Health, University of Southern Denmark. msoerensen@health.sdu.dk
authors.forename: Mette
authors.initials: M
authors.lastname: Soerensen
authors.forename: Serena
authors.initials: S
authors.lastname: Dato
authors.forename: Qihua
authors.initials: Q
authors.lastname: Tan
authors.forename: Mikael
authors.initials: M
authors.lastname: Thinggaard
authors.forename: Rabea
authors.initials: R
authors.lastname: Kleindorp
authors.forename: Marian
authors.initials: M
authors.lastname: Beekman
authors.forename: H Eka D
authors.initials: HE
authors.lastname: Suchiman
authors.forename: Rune
authors.initials: R
authors.lastname: Jacobsen
authors.forename: Matt
authors.initials: M
authors.lastname: McGue
authors.forename: Tinna
authors.initials: T
authors.lastname: Stevnsner
authors.forename: Vilhelm A
authors.initials: VA
authors.lastname: Bohr
authors.forename: Anton J M
authors.initials: AJ
authors.lastname: de Craen
authors.forename: Rudi G J
authors.initials: RG
authors.lastname: Westendorp
authors.forename: Stefan
authors.initials: S
authors.lastname: Schreiber
authors.forename: P Eline
authors.initials: PE
authors.lastname: Slagboom
authors.forename: Almut
authors.initials: A
authors.lastname: Nebel
authors.forename: James W
authors.initials: JW
authors.lastname: Vaupel
authors.forename: Kaare
authors.initials: K
authors.lastname: Christensen
authors.forename: Lene
authors.initials: L
authors.lastname: Christiansen
mesh_terms: D000369:Aged, 80 and over; D000483:Alleles; D001057:Apolipoproteins E / Q000235:genetics*; D016022:Case-Control Studies; D053480:Cholesterol Ester Transfer Proteins / Q000235:genetics*; D003718:Denmark; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation; D005838:Genotype; D005858:Germany / Q000208:ethnology; D006239:Haplotypes; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics*; D016014:Linear Models; D008136:Longevity / Q000235:genetics*; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009426:Netherlands / Q000208:ethnology; D020641:Polymorphism, Single Nucleotide; D012042:Registries
chemical_list: D001057:Apolipoproteins E; C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins; D015850:Interleukin-6