A common variant of the p16(INK4a) genetic region is associated with physical function in older people.
p16(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 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 p16(INK4a)/ARF locus and p15(INK4b)) 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 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.
Melzer
David
D
Peninsula Medical School, RD&E Wonford Site, Barrack Road, Exeter EX2 5DW, UK. david.melzer@pms.ac.uk
Frayling
Timothy M
TM
Murray
Anna
A
Hurst
Alison J
AJ
Harries
Lorna W
LW
Song
Honglin
H
Khaw
Kaytee
K
Luben
Robert
R
Surtees
Paul G
PG
Bandinelli
Stefania S
SS
Corsi
Anna-Maria
AM
Ferrucci
Luigi
L
Guralnik
Jack M
JM
Wallace
Robert B
RB
Hattersley
Andrew T
AT
Pharoah
Paul D
PD
D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics*; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D009043:Motor Activity / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide
D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16