Telomere length and cardiometabolic disease
Dr Jess Buxton
Centre for Cardiovascular Genetics (CVG)
Prof. Steve Humphries
Overview of research in CVG group
Complex disease/traits
Identifying and characterising common
genetic variants associated with CHD
and related traits (blood lipids,
atherosclerosis, type 2 diabetes)
Monogenic disease
Identifying gene mutations that
cause familial
hypercholesterolaemia (FH)
Genetic
contribution
to heart
disease
Gene ontology
Annotation of proteins and
microRNAs, especially those
involved in CVD pathways
and processes
Cellular mechanisms
Investigating novel
mechanisms underlying CVD
- iron metabolism, micro RNAs
Telomere shortening
Vertebrate telomeres
Armanios and Blackburn, Nature Reviews Genetics 13,
p693-704 (2012)
•
Telomeres protect
linear chromosomes
from degradation and
fusion
•
Consist of 1000’s of
copies of
(TTAGGG)n bound to
shelterin protein
complex
•
Shorten with every cell
division (attenuated by
telomerase enzyme in
germ and stem cells)
•
Cells stop dividing when
telomeres reach
critically short length
•
Mean leukocyte
telomere length (LTL)
can be measured using
qPCR
Telomeres in health and disease
Mean leukocyte telomere length (LTL)
in adults shortens by approx. 20-40bp
per year, due to inherent properties of
linear DNA replication, exacerbated by
oxidative stress + inflammation
Shorter age-adjusted LTL is associated
with increased risk of CHD, type 2
diabetes, insulin resistance, hypertension,
stroke, ….
Pooled relative risk for CHD is 1.54 (95%
confidence intervals 1.30 to 1.83) comparing
people with shortest versus longest third of LTL
Mean LTL declines with age (N=1,632)
R = 0.18, p= 3.4 x 10-13
From Haycock et al, BMJ 349:g4227 (2014).
LTL and cardiometabolic disease risk:
innocent bystander or prime suspect?
Short telomere length (adjusted for age and
gender) is a predictive biomarker for coronary
artery disease and type 2 diabetes
Evidence from genetic studies that telomere length plays a causal role in
the onset of CAD – gene variants associated with longer TL are protective
What are the potential underlying mechanisms?
- Decline in circulating endothelial progenitor cell (EPC) numbers (CAD)?
- Epigenetic changes (DNA methylation of subtelomeric regions)?
- Chromatin conformation changes induced by short telomeres?
Acknowledgements
CVG group
Collaborators
UCL
Aroon Hingorani
Jon White
Livia Carvalho
Chris Power
Marcus Pembrey
Imperial College
London
Dylan Williams
Alex Couto Alves
Marjo-Riitta Jarvelin
Alex Blakemore
University of Oulu
Leena Ala-Mursula
Sylvain Sebert
McGill University,
Canada
Matt Suderman
Jane Pappas
Moshe Szyf