Evidence for several independent genetic variants affecting lipoprotein (a) cholesterol levels

• Published in: Human molecular genetics 2015-04, Vol.24 (8), p.2390-2400
• Main Authors: Lu, Wensheng, Cheng, Yu-Ching, Chen, Keping, Wang, Hong, Gerhard, Glenn S, Still, Christopher D, Chu, Xin, Yang, Rongze, Parihar, Ankita, O'Connell, Jeffrey R, Pollin, Toni I, Angles-Cano, Eduardo, Quon, Michael J, Mitchell, Braxton D, Shuldiner, Alan R, Fu, Mao
• Format: Article
• Language: English
• Subjects: Adult; Aged; Association Studies; Atherosclerosis - genetics; Atherosclerosis - metabolism; Cholesterol - metabolism; Chromosomes, Human, Pair 6 - genetics; Female; Genetic Predisposition to Disease; Genome-Wide Association Study; Genotype; Humans; Kringles; Lipoprotein(a) - chemistry; Lipoprotein(a) - genetics; Lipoprotein(a) - metabolism; Male; Middle Aged; Polymorphism, Single Nucleotide
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddu731

Lipoprotein (a) [Lp(a)] is an independent risk factor for atherosclerosis-related events that is under strong genetic control (heritability = 0.68-0.98). However, causal mutations and functional validation of biological pathways modulating Lp(a) metabolism are lacking. We performed a genome-wide association scan to identify genetic variants associated with Lp(a)-cholesterol levels in the Old Order Amish. We confirmed a previously known locus on chromosome 6q25-26 and found Lp(a) levels also to be significantly associated with a SNP near the APOA5-APOA4-APOC3-APOA1 gene cluster on chromosome 11q23 linked in the Amish to the APOC3 R19X null mutation. On 6q locus, we detected associations of Lp(a)-cholesterol with 118 common variants (P = 5 × 10(-8) to 3.91 × 10(-19)) spanning a ∼5.3 Mb region that included the LPA gene. To further elucidate variation within LPA, we sequenced LPA and identified two variants most strongly associated with Lp(a)-cholesterol, rs3798220 (P = 1.07 × 10(-14)) and rs10455872 (P = 1.85 × 10(-12)). We also measured copy numbers of kringle IV-2 (KIV-2) in LPA using qPCR. KIV-2 numbers were significantly associated with Lp(a)-cholesterol (P = 2.28 × 10(-9)). Conditional analyses revealed that rs3798220 and rs10455872 were associated with Lp(a)-cholesterol levels independent of each other and KIV-2 copy number. Furthermore, we determined for the first time that levels of LPA mRNA were higher in the carriers than non-carriers of rs10455872 (P = 0.0001) and were not different between carriers and non-carriers of rs3798220. Protein levels of apo(a) were higher in the carriers than non-carriers of both rs10455872 and rs3798220. In summary, we identified multiple independent genetic determinants for Lp(a)-cholesterol. These findings provide new insights into Lp(a) regulation.