Sirtuin/uncoupling protein gene variants and carotid plaque area and morphology.
BACKGROUND
Sirtuins and uncoupling proteins have been implicated in cardiovascular diseases by controlling oxidative stress.


OBJECTIVE
We sought to investigate the association of sirtuins and uncoupling proteins single nucleotide polymorphisms with total carotid plaque area and morphology measured by ultrasonographic gray scale median.


METHODS
We analyzed 1356 stroke-free subjects (60% women, mean age = 68 ± 9 years) from the Northern Manhattan Study. Multiple linear regression models were used to evaluate the association of 85 single nucleotide polymorphisms in 11 sirtuins/uncoupling protein genes with total plaque area and gray scale median after controlling for demographics, vascular risk factors (RFs), and population stratification. We investigated effect modifications of these relationship by gender and RFs and performed stratified analysis if the interaction effect had P < 0·005.


RESULTS
Among individuals with present plaque (55%), the mean total plaque area was 20·3 ± 20·8 mm(2) and gray scale median 90 ± 29. After adjustment, SIRT6 rs107251 was significantly associated with total plaque area (β = 0·30 per copy of T allele increase, Bonferroni-corrected P = 0·005). T allele carriers of rs1430583 in UCP1 showed a decreased gray scale median in women but not in men. The minor allele carriers of rs4980329 and rs12363280 in SIRT3 had higher gray scale median in men but not in women. Variants in UCP3 gene were significantly associated with higher mean gray scale median in individuals with dyslipidemia.


CONCLUSIONS
Our findings suggest that polymorphisms in SIRT6/UCP1 genes may be important for increased carotid plaque burden and echodensity, but translation of these findings to an individual risk of cerebrovascular events needs further investigation. Significant associations of rs1430583 in women, rs12363280 in men, and rs1685354 in those with dyslipidemia also deserve further investigations.
Department of Neurology, Miller School of Medicine, University of Miami, Miami, FL, USA.
Chuanhui
C
Dong
Department of Neurology, Miller School of Medicine, University of Miami, Miami, FL, USA.|Department of Systems Medicine, School of Medicine, University of Rome Tor Vergata, Rome, Italy.|IRCCS San Raffaele Pisana, Rome, Italy.
David
D
Della-Morte
Department of Neurology, Miller School of Medicine, University of Miami, Miami, FL, USA.
Digna
D
Cabral
John T. McDonald Department of Human Genetics, John P Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL, USA.
Liyong
L
Wang
John T. McDonald Department of Human Genetics, John P Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL, USA.
Susan H
SH
Blanton
Department of Neurology, Miller School of Medicine, University of Miami, Miami, FL, USA.
Chaturvedi
C
Seemant
Department of Neurology, Miller School of Medicine, University of Miami, Miami, FL, USA.|John T. McDonald Department of Human Genetics, John P Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL, USA.|Department of Epidemiology, Miller School of Medicine, University of Miami, Miami, FL, USA.
Ralph L
RL
Sacco
Department of Neurology, Miller School of Medicine, University of Miami, Miami, FL, USA.|Department of Epidemiology, Miller School of Medicine, University of Miami, Miami, FL, USA.
Tatjana
T
Rundek
D000368:Aged; D002339:Carotid Arteries / Q000000981:diagnostic imaging; D002340:Carotid Artery Diseases / Q000000981:diagnostic imaging* / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D060005:Genotyping Techniques; D006801:Humans; D007473:Ion Channels / Q000235:genetics; D016014:Linear Models; D008297:Male; D024101:Mitochondrial Proteins / Q000235:genetics; D009519:New York City; D058226:Plaque, Atherosclerotic / Q000000981:diagnostic imaging* / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D056566:Sirtuin 3 / Q000235:genetics; D037761:Sirtuins / Q000235:genetics; D014463:Ultrasonography; D000071256:Uncoupling Protein 1; D000071247:Uncoupling Protein 3
D007473:Ion Channels; D024101:Mitochondrial Proteins; C000604371:UCP1 protein, human; C000604392:UCP3 protein, human; D000071256:Uncoupling Protein 1; D000071247:Uncoupling Protein 3; C466093:SIRT3 protein, human; C516592:SIRT6 protein, human; D056566:Sirtuin 3; D037761:Sirtuins
atherosclerosis; carotid total plaque area; genetics; gray scale median; mitochondrial uncoupling proteins; sirtuins