Association of common genetic variation in the insulin/IGF1 signaling pathway with human longevity - PubMed (original) (raw)

doi: 10.1111/j.1474-9726.2009.00493.x. Epub 2009 May 31.

Donglei Hu, Scott Huntsman, Andrew Sung, Catherine Chu, Justin Chen, Alexander H Joyner, Nicholas J Schork, Wen-Chi Hsueh, Alexander P Reiner, Bruce M Psaty, Gil Atzmon, Nir Barzilai, Steven R Cummings, Warren S Browner, Pui-Yan Kwok, Elad Ziv; Study of Osteoporotic Fractures

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Association of common genetic variation in the insulin/IGF1 signaling pathway with human longevity

Ludmila Pawlikowska et al. Aging Cell. 2009 Aug.

Abstract

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.

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Figures

Figure 1

Figure 1. Graphic of insulin/IGF1 signaling pathway showing proteins encoded by scanned genes

Figure 2

Figure 2. Genomic context and linkage disequilibrium for (A) AKT1 and (B, C) FOXO3A

UCSC genome browser tracks show mRNA isoforms for both genes, CpG islands, ESPERR regulatory potential and conservation across 28 mammalian species (indicator line at 70%). Linkage disequilibrium plots below show r2 in HapMap Caucasians. All HapMap variants are tagged at r2>0.8. SNPs genotyped in SOF are marked by black triangles. Longevity-associated SNPs are marked by white triangles and red lines and other SNPs in LD with them are boxed.

Figure 2

Figure 2. Genomic context and linkage disequilibrium for (A) AKT1 and (B, C) FOXO3A

UCSC genome browser tracks show mRNA isoforms for both genes, CpG islands, ESPERR regulatory potential and conservation across 28 mammalian species (indicator line at 70%). Linkage disequilibrium plots below show r2 in HapMap Caucasians. All HapMap variants are tagged at r2>0.8. SNPs genotyped in SOF are marked by black triangles. Longevity-associated SNPs are marked by white triangles and red lines and other SNPs in LD with them are boxed.

Figure 2

Figure 2. Genomic context and linkage disequilibrium for (A) AKT1 and (B, C) FOXO3A

UCSC genome browser tracks show mRNA isoforms for both genes, CpG islands, ESPERR regulatory potential and conservation across 28 mammalian species (indicator line at 70%). Linkage disequilibrium plots below show r2 in HapMap Caucasians. All HapMap variants are tagged at r2>0.8. SNPs genotyped in SOF are marked by black triangles. Longevity-associated SNPs are marked by white triangles and red lines and other SNPs in LD with them are boxed.

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