A candidate gene study revealed sex-specific association between the OLR1 gene and carotid plaque.
OBJECTIVE
Sex differences have been recognized in stroke risk; however, the sex-dependent genetic contribution to stroke is unclear. We sought to examine the sex-dependent associations between genes involved in lipid metabolism and carotid atherosclerotic plaque, a subclinical precursor of stroke.


METHODS
For the Genetic Determinant of Subclinical Carotid Disease study, 287 Dominicans ascertained through the Northern Manhattan Study were examined for carotid plaque using high-resolution ultrasound. Sixty-four single nucleotide polymorphisms (SNPs) in 11 lipid-related genes were genotyped. Plaque presence and plaque subphenotypes, including multiple, thick, irregular, and calcified plaque, were analyzed. First, the interaction between each SNP and sex was evaluated for association with each plaque phenotype using multiple logistic regression and controlling for age, smoking, and the main effects of sex and SNP. For SNPs with suggestive evidence for interaction with sex (P<0.1 for the interaction term), stratification analysis by sex was performed to evaluate the sex-specific association between the SNP and plaque phenotypes.


RESULTS
The most compelling finding is with the missense SNP rs11053646 (K167N) in the OLR1 gene, which encodes lectin-like oxidized low-density lipoprotein receptor. Stratification analysis revealed a strong association between rs11053646 and all plaque phenotypes in women (OR, 2.44 to 5.86; P=0.0003 to 0.0081) but not in men (OR, 0.85 to 1.22; P=0.77 to 0.92).


CONCLUSIONS
Genetic variation in genes involved in lipid metabolism may have sex-dependent effects on carotid plaque burden. Our findings provide a plausible biological basis underlying the sex difference in cardiovascular risk.
Dr John T. Macdonald Foundation, Department of Human Genetics, Miller School of Medicine, University of Miami, Clinical Research Building, Suite #CRB-13, 1120 NW 14th Street, Miami, FL 33136, USA.
Liyong
L
Wang
Danielle
D
Yanuck
Ashley
A
Beecham
Hannah
H
Gardener
Susan
S
Slifer
Susan H
SH
Blanton
Ralph L
RL
Sacco
Tatjana
T
Rundek
D000368:Aged; D002340:Carotid Artery Diseases / Q000000981:diagnostic imaging / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D056726:Genetic Association Studies / Q000379:methods; D006801:Humans; D008297:Male; D008875:Middle Aged; D058226:Plaque, Atherosclerotic / Q000000981:diagnostic imaging / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D051127:Scavenger Receptors, Class E / Q000235:genetics*; D012727:Sex Characteristics; D014463:Ultrasonography
C495137:OLR1 protein, human; D051127:Scavenger Receptors, Class E
Stroke. 2008 Jan;39(1):16-23
18032738
Circulation. 2000 May 23;101(20):2393-7
10821816
In Vivo. 2009 Nov-Dec;23(6):969-73
20023241
Stroke. 2002 May;33(5):1420-3
11988625
Neurology. 2008 Apr 1;70(14):1200-7
18354078
Stroke. 2009 Apr;40(4):1032-7
19211484
Stroke. 2001 Aug;32(8):1725-31
11486097
BMC Med Genet. 2008 Apr 02;9:23
18384690
DNA Cell Biol. 2010 Apr;29(4):201-5
20136518
Nat Rev Cardiol. 2009 Aug;6(8):532-42
19564884
Circ Res. 2005 Jul 22;97(2):176-84
15961718
Stroke. 2009 Jul;40(7):2307-12
19498180
Circulation. 1999 Jun 22;99(24):3110-7
10377073
Atherosclerosis. 2009 Feb;202(2):582-8
18492490
J Am Coll Cardiol. 2002 May 1;39(9):1429-35
11985903
Stroke. 2006 Nov;37(11):2696-701
17008627
Brain Res. 2006 Nov 22;1121(1):246-9
17022953
Biochem J. 2008 Jan 15;409(2):349-55
18092947
PLoS One. 2008;3(10):e3615
18974842
J Lipid Res. 2006 May;47(5):990-6
16474174
Stroke. 2000 Mar;31(3):615-21
10700494
Stroke. 2009 Apr;40(4):1082-90
19211488
PLoS One. 2009;4(2):e4648
19247493
Circ Res. 2007 Jun 8;100(11):1634-42
17478727
Stroke. 2004 Feb;35(2):477-81
14739419
Atherosclerosis. 2008 Apr;197(2):814-20
17825306
Stroke. 2009 Jul;40(7):2428-32
19461021
Circulation. 2003 Jul 1;107(25):3146-51
12810610
J Med Genet. 2003 Dec;40(12):933-6
14684693
Eur J Hum Genet. 2006 Jan;14(1):127-30
16251892
Biochem Biophys Res Commun. 2003 Mar 28;303(1):247-50
12646194
Clin Cardiol. 1991 Feb;14(2 Suppl 1):I1-16
2044253