title: Both rare and common variants in PCSK9 influence plasma low-density lipoprotein cholesterol level in American Indians.
abstract: BACKGROUND
  Elevated LDL cholesterol (LDL-C) is an important risk factor for atherosclerosis and cardiovascular disease. Variants in the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene have been associated not only with plasma LDL-C concentration, but also with ischemic heart disease. Little is known about the genetic architecture of PCSK9 and its influence on LDL-C in American Indians.
  
  
  OBJECTIVE
  We aimed to investigate the genetic architecture in the 1p32 region encompassing PCSK9 and its influence on LDL-C in American Indians.
  
  
  METHODS
  The Strong Heart Family Study (SHFS) is a family-based genetic study.
  
  
  METHODS
  Two thousand four hundred fifty eight American Indians from Arizona, Oklahoma, North Dakota, and South Dakota, who were genotyped by Illumina MetaboChip.
  
  
  RESULTS
  We genotyped 486 SNPs in a 3.9 Mb region at chromosome 1p32 encompassing PCSK9 in 2458 American Indians. We examined the association between these SNPs and LDL-C. For common variants (MAF ≥ 1%), meta-analysis across the three geographic regions showed common variants in PCSK9 were significantly associated with higher LDL-C. The most significant SNP rs12067569 (MAF = 1.7 %, β = 16.9 ± 3.7, P = 5.9 × 10(-6)) was in complete LD (r(2) = 1) with a nearby missense SNP, rs505151 (E670G) (β = 15.0 ± 3.6, P = 3.6 × 10(-5)). For rare variants (MAF < 1%), rs11591147 (R46L, MAF = 0.9%) was associated with lower LDL-C (β = - 31.1 ± 7.1, P = 1.4 × 10(-5)). The mean (SD) of LDL-C was 76.9 (7.8) and 107.4 (1.0) mg/dL for those with and without the R46L mutation, respectively. One person who was homozygous for R46L had LDL-C levels of 11 mg/dL. In one family, 6 out of 8 members carrying the R46L mutation had LDL-C levels below the lower 10% percentile of LDL-C among all study participants.
  
  
  CONCLUSIONS
  Both rare and common variants in PCSK9 influence plasma LDL-C levels in American Indians. Follow-up studies may disclose the influence of these mutations on the risk of CVD and responses to cholesterol-lowering medications.
authors.affiliation: Departments of Epidemiology (C.-W.T., A.T., T.H.B., A.N.-A., W.H.L.K.) and Environmental Health Sciences (A.N.-A.), Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland; Department of Epidemiology (K.E.N., N.F.), University of North Carolina, Chapel Hill, North Carolina; Department of Genetics (K.H., S.L., J.W.M.), Texas Biomedical Research Institute, San Antonio, Texas; Department of Nutrition and University of North Carolina Nutrition Research Institute (V.S.V.), University of North Carolina at Chapel Hill, Kannapolis, North Carolina; Center for American Indian Health Research (Y.Z.), University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; Missouri Breaks Industries Research, Inc. (L.G.B.), Timber Lake, South Dakota; The Welch Center for Prevention (A.N.-A., W.H.L.K.), Epidemiology and Clinical Research, Johns Hopkins Medical Institutions, Baltimore, Maryland; MedStar Health Research Institute (B.V.H.), Hyattsville, Maryland; Georgetown and Howard Universities Center for Clinical and Translational Science (B.V.H.), Washington, D.C.; Kidney Institute and Division of Nephrology, Department of Internal Medicine (C.-W.T.), China Medical University Hospital, Taichung, Taiwan.
authors.forename: Ching-Wei
authors.initials: CW
authors.lastname: Tsai
authors.forename: Kari E
authors.initials: KE
authors.lastname: North
authors.forename: Adrienne
authors.initials: A
authors.lastname: Tin
authors.forename: Karin
authors.initials: K
authors.lastname: Haack
authors.forename: Nora
authors.initials: N
authors.lastname: Franceschini
authors.forename: V
authors.initials: V
authors.lastname: Saroja Voruganti
authors.forename: Sandy
authors.initials: S
authors.lastname: Laston
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Lyle G
authors.initials: LG
authors.lastname: Best
authors.forename: Jean W
authors.initials: JW
authors.lastname: MacCluer
authors.forename: Terri H
authors.initials: TH
authors.lastname: Beaty
authors.forename: Ana
authors.initials: A
authors.lastname: Navas-Acien
authors.forename: W H Linda
authors.initials: WH
authors.lastname: Kao
authors.forename: Barbara V
authors.initials: BV
authors.lastname: Howard
mesh_terms: D000328:Adult; D008078:Cholesterol, LDL / Q000097:blood*; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007198:Indians, North American / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000235:genetics*; D012697:Serine Endopeptidases / Q000235:genetics*; D055815:Young Adult
chemical_list: D008078:Cholesterol, LDL; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases