Abstract | CONTEXT: OBJECTIVE: We aimed to investigate the genetic architecture in the 1p32 region encompassing PCSK9 and its influence on LDL-C in American Indians. DESIGN: The Strong Heart Family Study (SHFS) is a family-based genetic study. PARTICIPANTS: 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.
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Authors | Ching-Wei Tsai, Kari E North, Adrienne Tin, Karin Haack, Nora Franceschini, V Saroja Voruganti, Sandy Laston, Ying Zhang, Lyle G Best, Jean W MacCluer, Terri H Beaty, Ana Navas-Acien, W H Linda Kao, Barbara V Howard |
Journal | The Journal of clinical endocrinology and metabolism
(J Clin Endocrinol Metab)
Vol. 100
Issue 2
Pg. E345-9
(Feb 2015)
ISSN: 1945-7197 [Electronic] United States |
PMID | 25412415
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Chemical References |
- Cholesterol, LDL
- PCSK9 protein, human
- Proprotein Convertase 9
- Proprotein Convertases
- Serine Endopeptidases
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Topics |
- Adult
- Cholesterol, LDL
(blood)
- Female
- Genetic Variation
- Genotype
- Humans
- Indians, North American
(genetics)
- Male
- Middle Aged
- Mutation
- Polymorphism, Single Nucleotide
- Proprotein Convertase 9
- Proprotein Convertases
(genetics)
- Serine Endopeptidases
(genetics)
- Young Adult
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