Editors' ChoiceGenetics

The Root of All “Bad” Cholesterol

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Science Translational Medicine  10 Aug 2011:
Vol. 3, Issue 95, pp. 95ec126
DOI: 10.1126/scitranslmed.3002998

Low-density lipoprotein (LDL), or “bad,” cholesterol can build up in your arteries and increase your chances of a stroke or heart attack. Discovering the genetic mutations that cause high levels of LDL cholesterol holds promise for developing screening and treatment targets and reducing cardiovascular disease burden. Genome-wide association studies (GWASs) have identified in seven genes single-nucleotide polymorphisms (SNPs) that explain some of the human variability in LDL cholesterol levels. However, those SNPs are unlikely to be responsible for high LDL; they are simply markers for nearby mutations responsible for biological differences. Now that many GWASs have been completed for various diseases and traits, the key question is how to find the truly causal genetic variants that can be used to promote disease prevention and treatment efforts. Sanna et al. present their strategy for identifying protein-altering variants in those seven LDL cholesterol genes (APOE, APOC1, APOC2, SORT1, LDLR, APOB, and PCSK9) and report new variants with stronger effects than those identified by GWASs.

The researchers sequenced all protein-coding regions of the seven LDL genes in 256 individuals with either very low or very high LDL. This effort resulted in the identification of 782 variants and the observation that rare variants (occurring in fewer than 1% of the population) were twice as common in the high LDL group than in the low LDL group. The authors then increased the sample size to over 5000 and genotyped all variants discovered by sequencing as well as variants reported by the 1000 Genomes Project in these genes. Strong associations with LDL were observed for newly identified missense mutations in APOE, LDLR, and PCSK9. Of the 10 variants with the strongest associations, three had frequencies between 0.5 and 4%, but others were more common. The authors conclude that their two-stage study design, variant discovery followed by genotyping, is an efficient and fruitful approach to identifying potentially causal underpinnings of GWAS findings. Because the authors sequenced only coding regions of these genes, future studies that include potential regulatory regions—those that affect the level of production of a gene product rather than the amino acid sequence itself—might contribute additional knowledge of the genetic control of LDL cholesterol and other complex traits.

S. Sanna et al., Fine mapping of five loci associated with low-density lipoprotein cholesterol detects variants that double the explained heritability. PLoS Genet. 7, e1002198 (2011). [Full Text]

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