Abstract
Plasma lipoprotein(a) (Lp[a]) level is an independent risk factor of cardiovascular disease that is under strong genetic control. We conducted a genome-wide association study of plasma Lp(a) in 386 members of a founder population that adheres to a communal lifestyle, proscribes cigarette smoking, and prepares and eats meals communally. We identified associations with 77 single nucleotide polymorphisms (SNPs) spanning 12.5 Mb on chromosome 6q26-q27 that met criteria for genome-wide significance (P <or= 1.3 x 10(-7)) and were within or flanking nine genes, including LPA. We show that variation in at least six genes in addition to LPA are significantly associated with Lp(a) levels independent of each other and of the kringle IV repeat polymorphism in the LPA gene. One novel SNP in intron 37 of the LPA gene was also associated with Lp(a) levels and carotid artery disease number in unrelated Caucasians (P = 7.3 x 10(-12) and 0.024, respectively), also independent of kringle IV number. This study suggests a complex genetic architecture of Lp(a) levels that may involve multiple loci on chromosome 6q26-q27.
Highlights
Plasma lipoprotein(a) (Lp[a]) level is an independent risk factor of cardiovascular disease that is under strong genetic control
Among the 290,327 single nucleotide polymorphism (SNP) used in our genome-wide association study, 78 had single-locus association P values #1.3 3 1027, which were genome-wide significant based on permutation-based empirical distributions [28] (Fig. 1)
Because of the large number of associated SNPs on chromosome 6q, we focused our subsequent analyses on this region
Summary
Plasma lipoprotein(a) (Lp[a]) level is an independent risk factor of cardiovascular disease that is under strong genetic control. We show that variation in at least six genes in addition to LPA are significantly associated with Lp(a) levels independent of each other and of the kringle IV repeat polymorphism in the LPA gene. Genome-wide association study of plasma lipoprotein(a) levels identifies multiple genes on chromosome 6q. Polymorphisms in LPA other than the kringle IV repeats have been associated with circulating levels of Lp(a) [16, 17], but the known variants in LPA do not account for the remaining heritability of this trait, indicating that other, as yet unidentified, variation at this locus influences Lp(a) levels and the corresponding risk for cardiovascular disease
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