Review and meta-analysis of genetic polymorphisms associated with exceptional human longevity

Mary Revelas; Anbupalam Thalamuthu; Christopher Oldmeadow; Tiffany-Jane Evans; Nicola J Armstrong; John B Kwok; Henry Brodaty; Peter R Schofield; Rodney J Scott; Perminder S Sachdev; John R Attia; Karen A Mather

doi:10.1016/j.mad.2018.06.002

Review and meta-analysis of genetic polymorphisms associated with exceptional human longevity

Mech Ageing Dev. 2018 Oct:175:24-34. doi: 10.1016/j.mad.2018.06.002. Epub 2018 Jun 8.

Affiliations

¹ Centre for Healthy Brain Ageing, School of Psychiatry, UNSW Medicine, University of New South Wales, Sydney, Australia.
² Hunter Medical Research Institute, Newcastle, Australia.
³ Centre for Healthy Brain Ageing, School of Psychiatry, UNSW Medicine, University of New South Wales, Sydney, Australia; Mathematics and Statistics, Murdoch University, Perth, Australia.
⁴ Neuroscience Research Australia, Randwick, Australia; School of Medical Sciences, University of New South Wales, Sydney, Australia.
⁵ Centre for Healthy Brain Ageing, School of Psychiatry, UNSW Medicine, University of New South Wales, Sydney, Australia; Dementia Centre for Research Collaboration, University of New South Wales, Sydney, Australia.
⁶ Faculty of Health, University of Newcastle, Newcastle NSW, Australia; Hunter Area Pathology Service, John Hunter Hospital, Newcastle, New South Wales, Australia.
⁷ Centre for Healthy Brain Ageing, School of Psychiatry, UNSW Medicine, University of New South Wales, Sydney, Australia; Neuropsychiatric Institute, Prince of Wales Hospital, Barker Street, Randwick, NSW, Australia.
⁸ Hunter Medical Research Institute, Newcastle, Australia; Hunter Area Pathology Service, John Hunter Hospital, Newcastle, New South Wales, Australia.
⁹ Centre for Healthy Brain Ageing, School of Psychiatry, UNSW Medicine, University of New South Wales, Sydney, Australia. Electronic address: Karen.mather@unsw.edu.au.

PMID: 29890178
DOI: 10.1016/j.mad.2018.06.002

Abstract

Background: Many factors contribute to exceptional longevity, with genetics playing a significant role. However, to date, genetic studies examining exceptional longevity have been inconclusive. This comprehensive review seeks to determine the genetic variants associated with exceptional longevity by undertaking meta-analyses.

Methods: Meta-analyses of genetic polymorphisms previously associated with exceptional longevity (85+) were undertaken. For each variant, meta-analyses were performed if there were data from at least three independent studies available, including two unpublished additional cohorts.

Results: Five polymorphisms, ACE rs4340, APOE ε2/3/4, FOXO3A rs2802292, KLOTHO KL-VS and IL6 rs1800795 were significantly associated with exceptional longevity, with the pooled effect sizes (odds ratios) ranging from 0.42 (APOE ε4) to 1.45 (FOXO3A males).

Conclusion: In general, the observed modest effect sizes of the significant variants suggest many genes of small influence play a role in exceptional longevity, which is consistent with results for other polygenic traits. Our results also suggest that genes related to cardiovascular health may be implicated in exceptional longevity. Future studies should examine the roles of gender and ethnicity and carefully consider study design, including the selection of appropriate controls.

Keywords: ACE; APOE; Centenarians; FOXO3A; Longevity; Meta-analysis.

Publication types

Meta-Analysis
Research Support, Non-U.S. Gov't
Review

MeSH terms

Age Factors
Aged, 80 and over
Female
Genotype
Healthy Aging / genetics*
Heredity
Humans
Longevity / genetics*
Male
Pedigree
Phenotype
Polymorphism, Genetic*