Genome-wide association study of plasma lipoprotein(a) levels identifies multiple genes on chromosome 6q

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 # 1.3 3 10 27 ) 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 5 7.3 3 10 212 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. Lipoprotein (a) [Lp(a)] is recognized as an independent risk factor for atherosclerotic cardiovascular disease (1, 2). The mechanisms underlying this pathogenesis are poorly understood, although proatherogenic, prothrombotic, and inflammatory pathways contribute. Moreover, plasma Lp(a) levels are not responsive to statins and other cholesterol-lowering drugs, except for niacin, for which the long-term efficacy and safety is not yet established (3). Lp(a) is produced in the liver (4) and circulates in the plasma as an LDL particle having as a protein moiety apolipoprotein(a) [apo(a)], encoded by the LPA gene, linked by a disulfide bond to an apolipoprotein B-100 particle, on a 1:1 molecular basis (5). While apolipoprotein B-100 remains relatively constant in size, apo(a) varies in size due to polymorphism in the number of tandemly repeated kringle IV type 2 domains encoded by sequences in exons 1 and 2 of the LPA gene (6).The human LPA gene arose as a duplication of the PLG gene in the primate lineage and retains 80% sequence identity to PLG (7), which has only a single kringle IV structure. The number of kringle IV repeats in Lp(a) is under genetic control and inversely correlates with plasma levels of Lp(a), likely as result of the lower secretion rate in hepatocytes of apo(a) isoforms with larger numbers of kringle IV repeats (8, 9). The LPA locus accounts for 70-90% of the variability in Lp(a) levels in worldwide Abbreviations: apo(a), apolipoprotein(a); BMI, body mass index; LD, linkage disequilibrium; Lp(a), lipoprotein (a); SNP, single nucleotide polymorphism; RSS, residual sum of squares.

Association between ESR1 and ESR2 gene polymorphisms and hyperlipidemia in Chinese Han postmenopausal women

“…7 Recently, a genome-wide association study of plasma lipoprotein(a) suggested a complex genetic architecture of plasma lipoprotein(a) levels that might involve multiple loci on chromosome 6q26Àq27, in which the ESR1 gene is located. 8 In our study, we found a positive association between polymorphisms of ESR1 and hyperlipidemia in Chinese Han postmenopausal Association between ESR1, ESR2 and hyperlipidemia T Zhao et al women. Women who carried the PvuII T allele of ESR1 had an increased risk of hyperlipidemia.…”

“…7 Recently, a genome-wide association study of plasma lipoprotein(a) suggested a complex genetic architecture of plasma lipoprotein(a) levels that might involve multiple loci on chromosome 6q26-q27 in which the ESR1 gene is located. 8 A number of independent studies that investigated the effects of single-nucleotide polymorphisms (SNPs) of ESR1 and ESR2 genes on estrogen-related characteristics had shown some interesting SNPs, such as PvuII (rs2234693) and XbaI (rs9340799) of ESR1 and 1082A4G (rs1256049) and 1730A4G (rs4986938) of ESR2 and so on. The PvuII (rs2234693) polymorphism may affect the binding of the transcription factor, resulting in the alteration of protein expression.…”

Lipoprotein (a) as a cause of cardiovascular disease: insights from epidemiology, genetics, and biology

“…They found that the rs10455872 and rs3798220 SNPs in the LPA gene explained 25% and 8% of the variation in plasma Lp(a) concentrations, and each was associated with high risk of coronary heart disease. Importantly, in numerous other studies, including genome-wide linkage and association studies, multiple genetic variants in or around LPA on chromosome 6q27 were also found to be major determinants of plasma Lp(a) concentrations (39, [89][90][91][92][93]. For Mendelian residence time, e.g., enhanced binding of Lp(a) selectively to the matrix in the intima.…”

Lipoprotein (a) and Cardiovascular Risk

“…Apo(a) gen (6q2.6-q2.7) (39,40) have different kringle domains that show a high degree of homology to the kringle domains IV and V of plasminogen (41).…”