Lesca M. Holdt1,2,3, Frank Beutner1,2,3, Markus Scholz1,2,3, Stephan Gielen1,2,3, Gábor Gäbel1,2, Hendrik Bergert1,2,3, Gerhard Schüler1,2,3, Joachim Thiery1,2,3, Daniel Teupser1,2,3
1Department of General, Thoracic, and Vascular Surgery (G.G., H.B.), University of Dresden, Dresden, Germany.
2From Institute of Laboratory Medicine, Clinical Chemistry, and Molecular Diagnostics (L.M.H., F.B., J.T., D.T.), University Hospital Leipzig, Leipzig, Germany; Institute of Medical Informatics, Statistics, and Epidemiology (IMISE) (M.S.), University Leipzig, Leipzig, Germany; University Leipzig—Heart Center (S.G., G.S.), Department of Internal Medicine/Cardiology, Leipzig, Germany; Department of General, Thoracic, and Vascular Surgery (G.G., H.B.), University of Dresden, Dresden, Germany.
3Institute of Medical Informatics, Statistics, and Epidemiology (IMISE) (M.S.), University Leipzig, Leipzig, Germany
Tóm tắt
Objective—
We tested the hypothesis that expression of transcripts adjacent to the chromosome 9p21 (Chr9p21) locus of coronary artery disease was affected by the genotype at this locus and associated with atherosclerosis risk.
Methods and Results—
We replicated the locus for coronary artery disease (
P
=0.007; OR=1.28) and other manifestations of atherosclerosis such as carotid plaque (
P
=0.003; OR=1.31) in the Leipzig Heart Study, a cohort of 1134 patients with varying degree of angiographically assessed coronary artery disease. Expression analysis in peripheral blood mononuclear cells (n=1098) revealed that transcripts
EU741058
and
NR_003529
of
antisense noncoding RNA in the INK4 locus
(
ANRIL
) were significantly increased in carriers of the risk haplotype (
P
=2.1×10
−12
and
P
=1.6×10
−5
, respectively). In contrast, transcript
DQ485454
remained unaffected, suggesting differential expression of
ANRIL
transcripts at Chr9p21. Results were replicated in whole blood (n=769) and atherosclerotic plaque tissue (n=41). Moreover, expression of
ANRIL
transcripts was directly correlated with severity of atherosclerosis (
EU741058
and
NR_003529
;
P
=0.02 and
P
=0.001, respectively). No consistent association of Chr9p21 or atherosclerosis was found with expression of other genes such as
CDKN2A
,
CDKN2B
,
C9orf53
, and
MTAP
.
Conclusion—
Our data provide robust evidence for an association of
ANRIL
but not
CDKN2A, CDKN2B, C9orf53
, and
MTAP
, with atherosclerosis and Chr9p21 genotype in a large cohort.
