Open AccessAssociation of common genetic variation in the insulin/IGF1 signaling pathway with human longevity
Author(s) -
Pawlikowska Ludmila,
Hu Donglei,
Huntsman Scott,
Sung Andrew,
Chu Catherine,
Chen Justin,
Joyner Alexander H.,
Schork Nicholas J.,
Hsueh WenChi,
Reiner Alexander P.,
Psaty Bruce M.,
Atzmon Gil,
Barzilai Nir,
Cummings Steven R.,
Browner Warren S.,
Kwok PuiYan,
Ziv Elad
Publication year - 2009
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/j.1474-9726.2009.00493.x
Subject(s) - biology , single nucleotide polymorphism , longevity , genetics , genotyping , haplotype , cohort , genetic variation , genome wide association study , gene , insulin receptor , genetic association , genotype , insulin , medicine , insulin resistance , endocrinology
Summary The insulin/IGF1 signaling pathways affect lifespan in several model organisms, including worms, flies and mice. To investigate whether common genetic variation in this pathway influences lifespan in humans, we genotyped 291 common variants in 30 genes encoding proteins in the insulin/IGF1 signaling pathway in a cohort of elderly Caucasian women selected from the Study of Osteoporotic Fractures (SOF). The cohort included 293 long‐lived cases (lifespan ≥ 92 years (y), mean ± standard deviation (SD) = 95.3 ± 2.2y) and 603 average‐lifespan controls (lifespan ≤ 79y, mean = 75.7 ± 2.6y). Variants were selected for genotyping using a haplotype‐tagging approach. We found a modest excess of variants nominally associated with longevity. Nominally significant variants were then replicated in two additional Caucasian cohorts including both males and females: the Cardiovascular Health Study and Ashkenazi Jewish Centenarians. An intronic single nucleotide polymorphism in AKT1 , rs3803304, was significantly associated with lifespan in a meta‐analysis across the three cohorts (OR = 0.78 95%CI = 0.68–0.89, adjusted P = 0.043); two intronic single nucleotide polymorphisms in FOXO3A demonstrated a significant lifespan association among women only (rs1935949, OR = 1.35, 95%CI = 1.15–1.57, adjusted P = 0.0093). These results demonstrate that common variants in several genes in the insulin/IGF1 pathway are associated with human lifespan.