title: Evidence for several independent genetic variants affecting lipoprotein (a) cholesterol levels.
abstract: 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.
authors.affiliation: Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MD 21201, USA, Department of Endocrinology, People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi 530021, China.
authors.forename: Wensheng
authors.initials: W
authors.lastname: Lu
authors.affiliation: Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MD 21201, USA, Veterans Affairs Maryland Health Care System, Baltimore, MD 21201, USA.
authors.forename: Yu-Ching
authors.initials: YC
authors.lastname: Cheng
authors.affiliation: Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Keping
authors.initials: K
authors.lastname: Chen
authors.affiliation: Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.affiliation: Geisinger Obesity Institute, Geisinger Clinic, Danville, PA 17822, USA, Penn State Institute for Personalized Medicine, Penn State College of Medicine, Hershey, PA 17033, USA.
authors.forename: Glenn S
authors.initials: GS
authors.lastname: Gerhard
authors.affiliation: Geisinger Obesity Institute, Geisinger Clinic, Danville, PA 17822, USA.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Still
authors.affiliation: Geisinger Obesity Institute, Geisinger Clinic, Danville, PA 17822, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Chu
authors.affiliation: Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Rongze
authors.initials: R
authors.lastname: Yang
authors.affiliation: Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Ankita
authors.initials: A
authors.lastname: Parihar
authors.affiliation: Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: O'Connell
authors.affiliation: Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Toni I
authors.initials: TI
authors.lastname: Pollin
authors.affiliation: Inserm U1140, Institut National de la Santé et de la Recherche Médicale, Paris, France and Faculty of Pharmaceutical and Biological Sciences, University Paris Descartes, Paris F-75006, France.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Angles-Cano
authors.affiliation: Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Quon
authors.affiliation: Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Braxton D
authors.initials: BD
authors.lastname: Mitchell
authors.affiliation: Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MD 21201, USA, Veterans Affairs Maryland Health Care System, Baltimore, MD 21201, USA.
authors.forename: Alan R
authors.initials: AR
authors.lastname: Shuldiner
authors.affiliation: Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MD 21201, USA, mfu@medicine.umaryland.edu.
authors.forename: Mao
authors.initials: M
authors.lastname: Fu
mesh_terms: D000328:Adult; D000368:Aged; D050197:Atherosclerosis / Q000235:genetics* / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D018082:Kringles; D017270:Lipoprotein(a) / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide
chemical_list: D017270:Lipoprotein(a); D002784:Cholesterol