Association of common genetic variation in the insulin/IGF1 signaling pathway with human longevity.
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 > or = 92 years (y), mean +/- standard deviation (SD) = 95.3 +/- 2.2y) and 603 average-lifespan controls (lifespan < or = 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.
Pawlikowska
Ludmila
L
Department of Anesthesia and Perioperative Care, University of California, San Francisco, USA.
Hu
Donglei
D
Huntsman
Scott
S
Sung
Andrew
A
Chu
Catherine
C
Chen
Justin
J
Joyner
Alexander H
AH
Schork
Nicholas J
NJ
Hsueh
Wen-Chi
WC
Reiner
Alexander P
AP
Psaty
Bruce M
BM
Atzmon
Gil
G
Barzilai
Nir
N
Cummings
Steven R
SR
Browner
Warren S
WS
Kwok
Pui-Yan
PY
Ziv
Elad
E
D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D005500:Follow-Up Studies; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics; D015894:Genome, Human; D005838:Genotype; D006801:Humans; D007328:Insulin / Q000235:genetics* / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000235:genetics* / Q000378:metabolism; D008136:Longevity / Q000235:genetics*; D008297:Male; D010024:Osteoporosis / Q000453:epidemiology / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D015398:Signal Transduction
C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D007328:Insulin; D007334:Insulin-Like Growth Factor I; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt