Two common variants in the lipoprotein(a) gene have been found to correlate with both plasma lipoprotein levels and the risk of coronary disease, according to Dr. Robert Clarke of the University of Oxford (England) and his associates.
The finding supports the hypothesis that lipoprotein plays a causal role in coronary disease.
The investigators examined genetic associations in coronary artery disease using data from the Precocious Coronary Artery Disease (PROCARDIS) Consortium multicenter case-control study. The study cohort included 3,145 patients from the United Kingdom, Italy, Sweden, and Germany who developed coronary artery disease before age 66 years and also had a similarly affected sibling, and 3,352 control subjects.
Genotyping was performed on participants' blood samples using a novel gene chip that was specifically designed to screen more than 48,000 single-nucleotide polymorphisms (SNPs) for 2,100 candidate genes thought to be potentially relevant to heart disease. “With this gene chip, we confirmed the previous identification of three chromosomal regions that were correlated with the risk of coronary disease: 6q26-27, 9p21, and 1p13,” Dr. Clarke and his colleagues noted.
The 6q26-27 region showed the strongest association with coronary disease, and that region is known to include the gene for lipoprotein(a) (LPA).
“We then used comprehensive SNP typing to characterize the spectrum of variation at the LPA locus and showed the independent relevance of several variants … for both the Lp(a) lipoprotein level and the risk of coronary disease,” the investigators wrote (N. Engl. J. Med. 2009;361:2518-28).
Two variants in particular (rs3798220 and rs10455872) together accounted for 36% of the variation in plasma lipoprotein levels among study subjects.
The investigators replicated these findings in separate cohorts from three other clinical trials of coronary disease, which included 4,846 cases and 4,594 control subjects.
“The linear dose-response relationship of the LPA variants with both the Lp(a) lipoprotein level and the risk of coronary disease provided compelling support for a causal role of an elevated plasma level of Lp(a) lipoprotein and the risk of coronary disease,” the researchers said.
“One in six persons carries a variant LPA allele and thus has a risk of coronary disease that is increased by a factor of 1.5,” they added.
Disclosures: This study was supported in part by AstraZeneca. The investigators' financial disclosures are available at NEJM.org