Authors: Soerensen M; Dato S; Tan Q; Thinggaard M; Kleindorp R; Beekman M; Suchiman HE; Jacobsen R; McGue M; Stevnsner T; Bohr VA; de Craen AJ; Westendorp RG; Schreiber S; Slagboom PE; Nebel A; Vaupel JW; Christensen K; Christiansen L
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-epsilon4 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.
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Journal: Age (Dordrecht, Netherlands) Volume: 35 Issue: 2 Pages: 487-500 Date: Jan. 12, 2012 PMID: 22234866 |
102 SNPs from 16 longevity candidate genes were examined in Danish. 1089 individuals (ages 92.2-93.8, mean age 93.2, 71.3 female) and 736 middle-aged controls (46-55 y, mean age 50.6, 49.6% female) were involved in this case-control study. Then the results were replicated in a German cohort of 1613 individuals (95-110 y, 73.2% female) and 1104 middle-aged controls (mean age 67.2, SD 4.07, 74.3% female). A 11 years study was introduced in Danish cohort to identify the SNPs associated with longevity, then the results were verified in Dutch longitudinal cohort.
The minor allele frequency of rs9923854 in CETP was significantly associated with longevity. Haplotype case–control comparisons identified two haplotypes associated with longevity. Gene-based analysis confirmed the significant association of variations in CETP with longevity. The association of rs9923854 was borderline in the German population.
Soerensen M, Dato S, Tan Q, Thinggaard M, Kleindorp R, Beekman M, Suchiman HE, Jacobsen R, McGue M, Stevnsner T, Bohr VA, de Craen AJ, Westendorp RG, Schreiber S, Slagboom PE, Nebel A, Vaupel JW, Christensen K, Christiansen L (2013) Evidence from case-control and longitudinal studies supports associations of genetic variation in APOE, CETP, and IL6 with human longevity. Age (Dordrecht, Netherlands) 35: 487-500.
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