Analysis of recently identified dyslipidemia alleles reveals two loci that contribute to risk for carotid artery disease.
BACKGROUND
Genome-wide association studies have identified numerous single nucleotide polymorphisms (SNPs) affecting high density lipoprotein (HDL) or low density lipoprotein (LDL) cholesterol levels; these SNPs may contribute to the genetic basis of vascular diseases.


RESULTS
We assessed the impact of 34 SNPs at 23 loci on dyslipidemia, key lipid sub-phenotypes, and severe carotid artery disease (CAAD) in a case-control cohort. The effects of these SNPs on HDL and LDL were consistent with those previously reported, and we provide unbiased estimates of the percent variance in HDL (3.9%) and LDL (3.3%) explained by genetic risk scores. We assessed the effects of these SNPs on HDL subfractions, apolipoprotein A-1, LDL buoyancy, apolipoprotein B, and lipoprotein (a) and found that rs646776 predicts apolipoprotein B level while rs2075650 predicts LDL buoyancy. Finally, we tested the role of these SNPs in conferring risk for ultrasonographically documented CAAD stenosis status. We found that two loci, chromosome 1p13.3 near CELSR2 and PSRC1 which contains rs646776, and 19q13.2 near TOMM40 and APOE which contains rs2075650, harbor risk alleles for CAAD.


CONCLUSIONS
Our analysis of 34 SNPs contributing to dyslipidemia at 23 loci suggests that genetic variation in the 1p13.3 region may increase risk of CAAD by increasing LDL particle number, whereas variation in the 19q13.2 region may increase CAAD risk by promoting formation of smaller, denser LDL particles.
Ronald
James
J
Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, WA, USA. jscr@u.washington.edu
Rajagopalan
Ramakrishnan
R
Ranchalis
Jane E
JE
Marshall
Julieann K
JK
Hatsukami
Thomas S
TS
Heagerty
Patrick J
PJ
Jarvik
Gail P
GP
D000368:Aged; D000483:Alleles; D002340:Carotid Artery Diseases / Q000235:genetics*; D008076:Cholesterol, HDL / Q000235:genetics; D008078:Cholesterol, LDL / Q000235:genetics; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics; D050171:Dyslipidemias / Q000235:genetics*; D056426:Genetic Loci / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors
D008076:Cholesterol, HDL; D008078:Cholesterol, LDL