title: Human longevity and common variations in the LMNA gene: a meta-analysis.
abstract: 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, N=873) and genetically matched younger controls (N=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, P=2.5 × 10(-5) , multiple-testing-adjusted P=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) (N=738), (ii) the Southern Italian Centenarian Study (SICS) (N=905), (iii) France (N=1103), and (iv) the Einstein Ashkenazi Longevity Study (N= 702). We replicated the association with the most significant haplotype from our initial analysis in the NECS sample (OR=1.60, P=0.0023), but not in the other three samples (P > 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, P=7.5 × 10(-4) , multiple-testing-adjusted P=0.037). These results suggest that LMNA variants may play a role in human lifespan.
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA. kconnee@emory.edu
authors.forename: Karen N
authors.initials: KN
authors.lastname: Conneely
authors.forename: Brian C
authors.initials: BC
authors.lastname: Capell
authors.forename: Michael R
authors.initials: MR
authors.lastname: Erdos
authors.forename: Paola
authors.initials: P
authors.lastname: Sebastiani
authors.forename: Nadia
authors.initials: N
authors.lastname: Solovieff
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Swift
authors.forename: Clinton T
authors.initials: CT
authors.lastname: Baldwin
authors.forename: Temuri
authors.initials: T
authors.lastname: Budagov
authors.forename: Nir
authors.initials: N
authors.lastname: Barzilai
authors.forename: Gil
authors.initials: G
authors.lastname: Atzmon
authors.forename: Annibale A
authors.initials: AA
authors.lastname: Puca
authors.forename: Thomas T
authors.initials: TT
authors.lastname: Perls
authors.forename: Bard J
authors.initials: BJ
authors.lastname: Geesaman
authors.forename: Michael
authors.initials: M
authors.lastname: Boehnke
authors.forename: Francis S
authors.initials: FS
authors.lastname: Collins
mesh_terms: D000367:Age Factors; D000369:Aged, 80 and over; D016022:Case-Control Studies; D005260:Female; D006239:Haplotypes; D006801:Humans; D034904:Lamin Type A / Q000235:genetics*; D015810:Linkage Disequilibrium; D008136:Longevity / Q000235:genetics*; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011371:Progeria / Q000235:genetics*
chemical_list: C494847:LMNA protein, human; D034904:Lamin Type A