TY - JOUR
T1 - A common variant of the p16INK4a genetic region is associated with physical function in older people
AU - Melzer, David
AU - Frayling, Timothy M.
AU - Murray, Anna
AU - Hurst, Alison J.
AU - Harries, Lorna W.
AU - Song, Honglin
AU - Khaw, KayTee
AU - Luben, Robert
AU - Surtees, Paul G.
AU - Bandinelli, Stefania S.
AU - Corsi, Anna Maria
AU - Ferrucci, Luigi
AU - Guralnik, Jack M.
AU - Wallace, Robert B.
AU - Hattersley, Andrew T.
AU - Pharoah, Paul D.
PY - 2007/5
Y1 - 2007/5
N2 - p16INK4a is active in cell senescence, ageing and tumor suppression. Deletion of the small p16INK4a/ARF/p15INK4b region occurs in many cancers. We screened 25 common polymorphisms across the region and three related genes for associations with physical functioning in older people. In an initial sample of 938 (aged 65-80 years) from the EPIC study (Norfolk, UK), the rs2811712 SNP minor allele (located between the shared p16INK4a/ARF locus and p15INK4b) was associated with reduced physical impairment. This association remained after testing an additional 1319 EPIC-Norfolk 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 p16INK4a/ARF/p15INK4b 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.
AB - p16INK4a is active in cell senescence, ageing and tumor suppression. Deletion of the small p16INK4a/ARF/p15INK4b region occurs in many cancers. We screened 25 common polymorphisms across the region and three related genes for associations with physical functioning in older people. In an initial sample of 938 (aged 65-80 years) from the EPIC study (Norfolk, UK), the rs2811712 SNP minor allele (located between the shared p16INK4a/ARF locus and p15INK4b) was associated with reduced physical impairment. This association remained after testing an additional 1319 EPIC-Norfolk 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 p16INK4a/ARF/p15INK4b 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.
KW - Ageing
KW - Cell senescence
KW - Physical function
KW - Polymorphism
UR - http://www.scopus.com/inward/record.url?scp=34447093842&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=34447093842&partnerID=8YFLogxK
U2 - 10.1016/j.mad.2007.03.005
DO - 10.1016/j.mad.2007.03.005
M3 - Article
C2 - 17459456
AN - SCOPUS:34447093842
SN - 0047-6374
VL - 128
SP - 370
EP - 377
JO - Mechanisms of Ageing and Development
JF - Mechanisms of Ageing and Development
IS - 5-6
ER -