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- Kathiresan, Sekar, et al.
(författare)
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Common variants at 30 loci contribute to polygenic dyslipidemia
- 2009
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 41:1, s. 56-65
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Tidskriftsartikel (refereegranskat)abstract
- Blood low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglyceride levels are risk factors for cardiovascular disease. To dissect the polygenic basis of these traits, we conducted genome-wide association screens in 19,840 individuals and replication in up to 20,623 individuals. We identified 30 distinct loci associated with lipoprotein concentrations (each with P < 5 x 10(-8)), including 11 loci that reached genome-wide significance for the first time. The 11 newly defined loci include common variants associated with LDL cholesterol near ABCG8, MAFB, HNF1A and TIMD4; with HDL cholesterol near ANGPTL4, FADS1-FADS2-FADS3, HNF4A, LCAT, PLTP and TTC39B; and with triglycerides near AMAC1L2, FADS1-FADS2-FADS3 and PLTP. The proportion of individuals exceeding clinical cut points for high LDL cholesterol, low HDL cholesterol and high triglycerides varied according to an allelic dosage score (P < 10(-15) for each trend). These results suggest that the cumulative effect of multiple common variants contributes to polygenic dyslipidemia.
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| 2. |
- Kathiresan, Sekar, et al.
(författare)
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Defining the spectrum of alleles that contribute to blood lipid concentrations in humans
- 2008
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Ingår i: Current Opinion in Lipidology. - 1473-6535. ; 19:2, s. 122-127
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Forskningsöversikt (refereegranskat)abstract
- Purpose of review Recently, genome-wide genetic screening of common DNA sequence variants has proven a successful approach to identify novel genetic contributors to complex traits. This review summarizes recent genome-wide association studies for lipid phenotypes, and evaluates the next steps needed to obtain a full picture of genotype-phenotype correlation and apply these findings to inform clinical practice. Recent findings So far, genome-wide association studies have defined at least 19 genomic regions that contain common DNA single nucleotide polymorphisms associated with LDL cholesterol, HDL cholesterol and/or triglycerides. Of these, eight represent novel loci in humans, whereas 11 genes have been previously implicated in lipoprotein metabolism. Many of the same loci with common variants have already been shown to lead to monogenic lipid disorders in humans and/or mice, suggesting that a spectrum of common and rare alleles at each validated locus contributes to blood lipid concentrations. Summary At least 19 loci harbor common variations that contribute to blood lipid concentrations in humans. Larger scale genome-wide association studies should identify additional loci, and sequencing of these loci should pinpoint all relevant alleles. With a full catalog of DNA polymorphisms in hand, a panel of lipid-related variants can be studied to provide clinical risk stratification and targeting of therapeutic interventions.
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| 3. |
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| 4. |
- Musunuru, Kiran, et al.
(författare)
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Ion Mobility Analysis of Lipoprotein Subfractions Identifies Three Independent Axes of Cardiovascular Risk.
- 2009
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Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - 1524-4636. ; 29, s. 628-1975
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Whereas epidemiological studies show that levels of low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) predict incident cardiovascular disease (CVD), there is limited evidence relating lipoprotein subfractions and composite measures of subfractions to risk for CVD in prospective cohort studies. METHODS AND RESULTS: We tested whether combinations of lipoprotein subfractions independently predict CVD in a prospective cohort of 4594 initially healthy men and women (the Malmö Diet and Cancer Study, mean follow-up 12.2 years, 377 incident cardiovascular events). Plasma lipoproteins and lipoprotein subfractions were measured at baseline with a novel high-resolution ion mobility technique. Principal component analysis (PCA) of subfraction concentrations identified 3 major independent (ie, zero correlation) components of CVD risk, one representing LDL-associated risk, a second representing HDL-associated protection, and the third representing a pattern of decreased large HDL, increased small/medium LDL, and increased triglycerides. The last corresponds to the previously described "atherogenic lipoprotein phenotype." Several genes that may underlie this phenotype-CETP, LIPC, GALNT2, MLXIPL, APOA1/A5, LPL-are suggested by SNPs associated with the combination of small/medium LDL and large HDL. CONCLUSIONS: PCA on lipoprotein subfractions yielded three independent components of CVD risk. Genetic analyses suggest these components represent independent mechanistic pathways for development of CVD.
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