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Keywords:

  • genetics;
  • human;
  • longevity;
  • longevity gene

Summary

A mutation in the LMNA gene is responsible for the most dramatic form of premature aging, Hutchinson–Gilford progeria syndrome (HGPS). Several recent studies have suggested that protein products of this gene might have a role in normal physiological cellular senescence. To explore further LMNA’s possible role in normal aging, we genotyped 16 SNPs over a span of 75.4 kb of the LMNA gene on a sample of long-lived individuals (LLI) (US Caucasians with age ≥ 95 years, = 873) and genetically matched younger controls (= 443). We tested all common nonredundant haplotypes (frequency ≥ 0.05) based on subgroups of these 16 SNPs for association with longevity. The most significant haplotype, based on four SNPs, remained significant after adjustment for multiple testing (OR = 1.56, = 2.5 × 10−5, multiple-testing-adjusted = 0.0045). To attempt to replicate these results, we genotyped 3619 subjects from four independent samples of LLI and control subjects from (i) the New England Centenarian Study (NECS) (= 738), (ii) the Southern Italian Centenarian Study (SICS) (= 905), (iii) France (= 1103), and (iv) the Einstein Ashkenazi Longevity Study (= 702). We replicated the association with the most significant haplotype from our initial analysis in the NECS sample (OR = 1.60, = 0.0023), but not in the other three samples (> 0.15). In a meta-analysis combining all five samples, the best haplotype remained significantly associated with longevity after adjustment for multiple testing in the initial and follow-up samples (OR = 1.18, = 7.5 × 10−4, multiple-testing-adjusted = 0.037). These results suggest that LMNA variants may play a role in human lifespan.