Citation: Journal of Clinical Endocrinology & Metabolism. 100(2):E345-9, 2015 Feb..Journal: The Journal of clinical endocrinology and metabolism.ISSN: 0021-972X.Full author list: Tsai CW; North KE; Tin A; Haack K; Franceschini N; Saroja Voruganti V; Laston S; Zhang Y; Best LG; MacCluer JW; Beaty TH; Navas-Acien A; Kao WH; Howard BV.UI/PMID: 25412415.Subject(s): Adult | *Cholesterol, LDL/bl [Blood] | Female | *Genetic Variation | Genotype | Humans | *Indians, North American/ge [Genetics] | Male | Middle Aged | Mutation | Polymorphism, Single Nucleotide | *Proprotein Convertases/ge [Genetics] | *Serine Endopeptidases/ge [Genetics] | Young AdultInstitution(s): MedStar Health Research InstituteActivity type: Journal Article.Medline article type(s): Journal Article | Research Support, N.I.H., ExtramuralOnline resources: Click here to access onlineDigital Object Identifier: http://dx.doi.org/10.1210/jc.2014-3340 (Click here)Abbreviated citation: J Clin Endocrinol Metab. 100(2):E345-9, 2015 Feb.Local Holdings: Available online through MWHC library: 1999- June 2013, Available in print through MWHC library: 1999 - 2006.Abstract: CONTEXT: 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.Abstract: OBJECTIVE: We aimed to investigate the genetic architecture in the 1p32 region encompassing PCSK9 and its influence on LDL-C in American Indians.Abstract: DESIGN: The Strong Heart Family Study (SHFS) is a family-based genetic study.Abstract: PARTICIPANTS: Two thousand four hundred fifty eight American Indians from Arizona, Oklahoma, North Dakota, and South Dakota, who were genotyped by Illumina MetaboChip.Abstract: 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 %, beta = 16.9 +/- 3.7, P = 5.9 x 10(-6)) was in complete LD (r(2) = 1) with a nearby missense SNP, rs505151 (E670G) (beta = 15.0 +/- 3.6, P = 3.6 x 10(-5)). For rare variants (MAF < 1%), rs11591147 (R46L, MAF = 0.9%) was associated with lower LDL-C (beta = - 31.1 +/- 7.1, P = 1.4 x 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.Abstract: 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.