A common variant of the p16INK4a genetic region is associated with physical function in older people

Abstract

Abstractp16 INK4a is active in cell senescence, ageing and tumor suppression. Deletion of the small p16 INK4a / ARF / p15 INK4b region occurs in many cancers. We screened 25 common polymorphisms across the region and 3 related genes for associations with physical functioning in older people.In an initial sample of 938 (aged 65 to 80yrs) from the EPIC study (Norfolk, UK) the rs2811712 SNP minor allele (located between the shared p16 INK4a / ARF locus and p15 INK4b ) was associated with reduced physical impairment. This association remained after testing an additional 1319 EPICNorfolk samples (p-value=0.013, total n=2257), and on independent replication in the InCHIANTI Study (n=709, p=0.015), and at one sided significance in Iowa-EPESE (n=419, p=0.079). Overall (n=3372) the prevalence of severely limited physical function was 15.0% in common homozygotes and 7.0% in rare homozygotes (per minor allele Odds Ratio=1.48 95%CI: 1.17−1.88, p =0.001, adjusted for age, sex and study). This estimate was similar excluding screening set 1 (OR=1.45: 95% CI 1.09−1.92, p=0.010, n=2434).These findings require further replication, but provide the first direct evidence that the p16 INK4a / ARF / p15 INK4b genetic region and the senescence machinery are active in physical ageing in heterogeneous human populations. The mechanism involved may be via greater cellular restorative activity and reduced stem cell senescence.

Cell intrinsic and extrinsic mechanisms of stem cell aging depend on telomere status

“…Polymorphisms are associated with aging (Saxena et al, 2007;Scott et al, 2007;Zeggini et al, 2007;Melzer et al, 2007;) P16-deletion: improved regenerative capacity in different stem cell compartments: HSCs, neuronal stem cells, pancreatic islets. (Molofsky et al, 2006;Krishnamurthy et al, 2006;Janzen et al, 2006;Stepanova and Sorrentino, 2005) No improvement in organ maintenance and lifespan in p16Ink4A, P19ARF compound mutant mice (Khoo et al, 2007) (Lynch and Lynch, 2005); Mismatch repair defect Colorectal cancer, extra-CRC cancers.…”

p16INK4a deficiency promotes IL-4–induced polarization and inhibits proinflammatory signaling in macrophages

“…[9][10][11] A genome-wide association study has shown association of the CDKN2A locus with an increased risk of the age-related frailty syndrome. 12 In addition, increased p16 INK4a expression causes the age-dependent decline in proliferation of self-renewing cellular compartments such as HSCs, 13 which give rise to immune cells.…”

“…9-11 A genome-wide association study has shown association of the CDKN2A locus with an increased risk of the age-related frailty syndrome. 12 In addition, increased p16 INK4a expression causes the age-dependent decline in proliferation of self-renewing cellular compartments such as HSCs, 13 which give rise to immune cells.Although the role of p16 INK4a in mature immune cells has not yet been investigated, several studies has shown that the CDKN2A locus is associated with an increased risk for coronary heart disease, 14 atherosclerosis, 15 and type 2 diabetes (T2D). 16 In these pathologies, immune cells, such as macrophages, play a crucial role.…”

Insights Into Stem Cell Aging

“…p16 INK4a and ARF may also be broadly important to diseases of aging beyond their function in stem cells. Specifically, three research consortia that undertook genome-wide association studies across large, carefully annotated patient samples have reported an association between single nucleotide polymorphisms (SNPs) near to INK4a/ARF locus and frailty (Melzer et al, 2007), atherosclerotic heart disease (ASHD) (Helgadottir et al, 2007) (McPherson et al, 2007, and type-2 diabetes (Saxena et al, 2007;Zeggini et al, 2008) in large human cohorts. However, few of the associated SNPs near the locus, and associated with these phenotypes, are not in linkage disequilibrium with each other, which suggests that more than one polymorphism near the locus influences these aging phenotypes.…”