Four novel Loci (19q13, 6q24, 12q24, and 5q14) influence the microcirculation in vivo.
There is increasing evidence that the microcirculation plays an important role in the pathogenesis of cardiovascular diseases. Changes in retinal vascular caliber reflect early microvascular disease and predict incident cardiovascular events. We performed a genome-wide association study to identify genetic variants associated with retinal vascular caliber. We analyzed data from four population-based discovery cohorts with 15,358 unrelated Caucasian individuals, who are members of the Cohort for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and replicated findings in four independent Caucasian cohorts (n  =  6,652). All participants had retinal photography and retinal arteriolar and venular caliber measured from computer software. In the discovery cohorts, 179 single nucleotide polymorphisms (SNP) spread across five loci were significantly associated (p<5.0×10(-8)) with retinal venular caliber, but none showed association with arteriolar caliber. Collectively, these five loci explain 1.0%-3.2% of the variation in retinal venular caliber. Four out of these five loci were confirmed in independent replication samples. In the combined analyses, the top SNPs at each locus were: rs2287921 (19q13; p  =  1.61×10(-25), within the RASIP1 locus), rs225717 (6q24; p = 1.25×10(-16), adjacent to the VTA1 and NMBR loci), rs10774625 (12q24; p  =  2.15×10(-13), in the region of ATXN2,SH2B3 and PTPN11 loci), and rs17421627 (5q14; p = 7.32×10(-16), adjacent to the MEF2C locus). In two independent samples, locus 12q24 was also associated with coronary heart disease and hypertension. Our population-based genome-wide association study demonstrates four novel loci associated with retinal venular caliber, an endophenotype of the microcirculation associated with clinical cardiovascular disease. These data provide further insights into the contribution and biological mechanisms of microcirculatory changes that underlie cardiovascular disease.
Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
M Kamran
MK
Ikram
Xueling
X
Sim
Sim
S
Xueling
Richard A
RA
Jensen
Mary Frances
MF
Cotch
Alex W
AW
Hewitt
M Arfan
MA
Ikram
Jie Jin
JJ
Wang
Ronald
R
Klein
Barbara E K
BE
Klein
Monique M B
MM
Breteler
Ning
N
Cheung
Gerald
G
Liew
Paul
P
Mitchell
Andre G
AG
Uitterlinden
Fernando
F
Rivadeneira
Albert
A
Hofman
Paulus T V M
PT
de Jong
Cornelia M
CM
van Duijn
Linda
L
Kao
Ching-Yu
CY
Cheng
Albert Vernon
AV
Smith
Nicole L
NL
Glazer
Thomas
T
Lumley
Barbara
B
McKnight
Bruce M
BM
Psaty
Fridbert
F
Jonasson
Gudny
G
Eiriksdottir
Thor
T
Aspelund
Tamara B
TB
Harris
Lenore J
LJ
Launer
Kent D
KD
Taylor
Xiaohui
X
Li
Sudha K
SK
Iyengar
Quansheng
Q
Xi
Theru A
TA
Sivakumaran
David A
DA
Mackey
Stuart
S
Macgregor
Nicholas G
NG
Martin
Terri L
TL
Young
Josh C
JC
Bis
Kerri L
KL
Wiggins
Susan R
SR
Heckbert
Christopher J
CJ
Hammond
Toby
T
Andrew
Samantha
S
Fahy
John
J
Attia
Elizabeth G
EG
Holliday
Rodney J
RJ
Scott
F M Amirul
FM
Islam
Jerome I
JI
Rotter
Annie K
AK
McAuley
Eric
E
Boerwinkle
E Shyong
ES
Tai
Vilmundur
V
Gudnason
David S
DS
Siscovick
Johannes R
JR
Vingerling
Tien Y
TY
Wong
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002318:Cardiovascular Diseases / Q000235:genetics / Q000503:physiopathology; D002648:Child; D002675:Child, Preschool; D002881:Chromosomes, Human, Pair 12; D002888:Chromosomes, Human, Pair 19; D002895:Chromosomes, Human, Pair 5; D002896:Chromosomes, Human, Pair 6; D015331:Cohort Studies; D005260:Female; D056426:Genetic Loci / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D008297:Male; D015201:Meta-Analysis as Topic; D008833:Microcirculation; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012171:Retinal Vessels / Q000503:physiopathology; D044465:White People / Q000235:genetics; D055815:Young Adult