Evidence from case-control and longitudinal studies supports associations of genetic variation in APOE, CETP, IL6, and IL6R with human longevity. 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 1,104 oldest-old (ages 95-110) and 1,104 middle-aged Danes. Rs769449 was in modest linkage (R20 0.55) with rs429358 of the APOE-4 haplotype, and adjusting for rs429358 eliminated the effect of rs769449, indicating that the association reflects the well-known effect of rs429358. Family-based analysis confirmed the effects of variation in APOE and CETP and furthermore pointed to IL6 as a longevity gene. In a longitudinal study with 11 years of follow-up on survival in the Danes, only one SNP, rs2069827 (IL6), was significantly associated with survival from age 92 (p=0.064). This advantageous effect of the G allele was supported when investigating a second longitudinal cohort (N=563) of oldest-old (age ≥95 years). Since rs2069827 was located in a putative transcription factor binding site, quantitative RNA studies were conducted. However, no difference in expression was observed between rs2069827 groups. In conclusion, we here support and expand evidence suggesting that genetic variation in CETP, IL6, and possible HSPA14 is associated with human longevity.

Introduction