Genetic variation in LPAL2, LPA, and PLG predicts plasma lipoprotein(a) level and carotid artery disease risk.
OBJECTIVE
lipoprotein(a) [Lp(a)] level is an established risk factor for coronary artery disease and has been implicated in carotid artery disease (CAAD). The relationship between genetic variation in the LPA gene region and CAAD risk remains unknown.


METHODS
we genotyped single nucleotide polymorphisms (SNPs) in the LPAL2, LPA, and PLG regions in 530 individuals with severe CAAD and 770 controls and kringle IV type 2 (KIV2) repeat length in a subset of 90 individuals.


RESULTS
nine SNPs collectively accounted for 30% of the variance in Lp(a) level. Six SNPs were associated with Lp(a) level after accounting for KIV2 copy number, and the dominant KIV2 allele combined with these markers explained 60% of the variance in Lp(a) level. Five SNPs, including rs10455872, which had an odds ratio of 2.1 per minor allele and haplotypes formed by rs10455872, rs6919346, and rs3123629, were significant predictors of CAAD. After accounting for Lp(a) level, all evidence of CAAD-genotype association in the LPA region was eliminated.


CONCLUSIONS
LPA region SNPs capture some but not all of the effect of KIV2 repeat length on Lp(a) level. There are associations between LPA region SNPs and CAAD that appear to be attributable to effects on Lp(a) level.
Department of Medicine, Division of Medical Genetics, University of Washington Medical Center Box 357720, Seattle, WA 98195-7720, USA.
James
J
Ronald
Ramakrishnan
R
Rajagopalan
Felecia
F
Cerrato
Alex S
AS
Nord
Thomas
T
Hatsukami
Ted
T
Kohler
Santica
S
Marcovina
Patrick
P
Heagerty
Gail P
GP
Jarvik
D000368:Aged; D000483:Alleles; D016633:Apolipoprotein A-II / Q000097:blood / Q000235:genetics; D002340:Carotid Artery Diseases / Q000097:blood / Q000235:genetics; D005260:Female; D005799:Genes, Dominant; D020022:Genetic Predisposition to Disease; D006801:Humans; D017270:Lipoprotein(a) / Q000097:blood / Q000235:genetics; D008297:Male; D020641:Polymorphism, Single Nucleotide; D017434:Protein Structure, Tertiary; D020449:Repetitive Sequences, Amino Acid
C115794:APOA2 protein, human; D016633:Apolipoprotein A-II; D017270:Lipoprotein(a)