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Multicenter Study
. 2011 Jan;42(1):2-9.
doi: 10.1161/STROKEAHA.110.591230. Epub 2010 Dec 2.

Genetic variation in LPAL2, LPA, and PLG predicts plasma lipoprotein(a) level and carotid artery disease risk

James Ronald  1 , Ramakrishnan Rajagopalan, Felecia Cerrato, Alex S Nord, Thomas Hatsukami, Ted Kohler, Santica Marcovina, Patrick Heagerty, Gail P Jarvik
Affiliations
Multicenter Study

Genetic variation in LPAL2, LPA, and PLG predicts plasma lipoprotein(a) level and carotid artery disease risk

James Ronald et al. Stroke. 2011 Jan.

Abstract

Background and purpose: 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.

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Conflict of interest statement

Disclosure: The authors have no conflicts of interest to declare.

Figures

Figure 1
Figure 1. Proportion of variance in Lp(a) level explained by SNPs and KIV2 copy number
Curves show the percent variation in Lp(a) level as SNPs are added sequentially in backward stepwise regression; bold indicates p < 0.05. The upper gray curve and SNPs listed along the top correspond to a model including KIV2 number. The leftmost point on the upper curve corresponds to KIV2 alone.
Figure 2
Figure 2. CAAD association results, gene structure, and LD patterns in the 6q26-27 region
Vertical lines (circles) in the upper panel show −log10 p-values (risk allele odds ratios) for association between tagSNPs and CAAD. Dashed lines indicate p = 0.05 and p = 0.0024 (family wise error rate < 0.05). Solid circles correspond to SNPs with p < 0.05. The lower panel shows HapMap LD, with darker shading indicating larger |r2|.
See this image and copyright information in PMC

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