Abstract
Low-frequency coding DNA sequence variants in the proprotein convertase subtilisin/kexin type 9 gene (PCSK9) lower plasma low-density lipoprotein cholesterol (LDL-C), protect against risk of coronary heart disease (CHD), and have prompted the development of a new class of therapeutics. It is uncertain whether the PCSK9 example represents a paradigm or an isolated exception. We used the "Exome Array" to genotype >200,000 low-frequency and rare coding sequence variants across the genome in 56,538 individuals (42,208 European ancestry [EA] and 14,330 African ancestry [AA]) and tested these variants for association with LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglycerides. Although we did not identify new genes associated with LDL-C, we did identify four low-frequency (frequencies between 0.1% and 2%) variants (ANGPTL8 rs145464906 [c.361C>T; p.Gln121*], PAFAH1B2 rs186808413 [c.482C>T; p.Ser161Leu], COL18A1 rs114139997 [c.331G>A; p.Gly111Arg], and PCSK7 rs142953140 [c.1511G>A; p.Arg504His]) with large effects on HDL-C and/or triglycerides. None of these four variants was associated with risk for CHD, suggesting that examples of low-frequency coding variants with robust effects on both lipids and CHD will be limited.
Original language | English |
---|---|
Pages (from-to) | 223-32 |
Number of pages | 10 |
Journal | American Journal of Human Genetics |
Volume | 94 |
Issue number | 2 |
DOIs | |
Publication status | Published - 6 Feb 2014 |
Externally published | Yes |
Keywords
- 1-Alkyl-2-acetylglycerophosphocholine Esterase/genetics
- Adult
- African Continental Ancestry Group/genetics
- Aged
- Alleles
- Animals
- Cholesterol, HDL/blood
- Cholesterol, LDL/blood
- Cohort Studies
- Coronary Disease/blood
- European Continental Ancestry Group/genetics
- Female
- Gene Frequency
- Genetic Association Studies
- Genetic Code
- Genetic Variation
- Humans
- Linear Models
- Male
- Mice
- Mice, Inbred C57BL
- Microtubule-Associated Proteins/genetics
- Middle Aged
- Phenotype
- Sequence Analysis, DNA
- Subtilisins/genetics
- Triglycerides/blood