14 research outputs found
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Biological, clinical and population relevance of 95 loci for blood lipids.
Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P < 5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD
Endothelial Bmx tyrosine kinase activity is essential for myocardial hypertrophy and remodeling
Candidate driver genes in microsatellite-unstable colorectal cancer
Defects in the mismatch repair system lead to microsatellite instability (MSI), a feature observed in similar to 15% of all colorectal cancers (CRCs). Microsatellite mutations that drive tumourigenesis, typically inactivation of tumour suppressors, are selected for and are frequently detected in MSI cancers. Here, we evaluated somatic mutations in microsatellite repeats of 790 genes chosen based on reduced expression in MSI CRC and existence of a coding mononucleotide repeat of 6 similar to 10 bp in length. All the repeats were initially sequenced in 30 primary MSI CRC samples and whenever frameshift mutations were identified in >20%, additional 70 samples were sequenced. To distinguish driver mutations from passengers, we similarly analyzed the occurrence of frameshift mutations in 121 intronic control repeats and utilized a statistical regression model to determine cut-off mutation frequencies for repeats of all types (A/T and C/G, 610 bp). Along with several know target genes, including TGFBR2, ACVR2, and MSH3, six novel candidate driver genes emerged that harbored significantly more mutations than identical control repeats. The mutation frequencies in 100 MSI CRC samples were 51% in G8 of GLYR1, 47% in T9 of ABCC5, 43% in G8 of WDTC1, 33% in A8 of ROCK1, 30% in T8 of OR51E2, and 28% in A8 of TCEB3. Immunohistochemical staining of GLYR1 revealed defective protein expression in tumors carrying biallelic mutations, supporting a loss of function hypothesis. This is a large scale, unbiased effort to identify genes that when mutated are likely to contribute to MSI CRC development.</p
Transcript profiles of dendritic cells of PLOSL patients link demyelinating CNS disorders with abnormalities in pathways of actin bundling and immune response
Rare monogenic dementias have repeatedly exposed novel pathways guiding to details of the molecular pathogenesis behind this complex clinical phenotype. In this paper, we have studied polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL), an early onset dementia with bone fractures caused by mutations in TYROBP (DAP12) and TREM2 genes, which encode important signaling molecules in human dendritic cells (DCs). To identify the pathways and biological processes associated with DAP12/TREM2-mediated signaling, we performed genome wide transcript analysis of in vitro differentiated DCs of PLOSL patients representing functional knockouts of either DAP12 or TREM2. Both DAP12- and TREM2-deficient cells differentiated into DCs and responded to pathogenic stimuli. However, the DCs showed morphological differences compared to control cells due to defects in the actin filaments. Not unexpectedly, transcript profiles of the patient DCs showed differential expression of genes involved in immune response. Importantly, significantly diverging transcript levels were also evident for genes earlier associated with other disorders of the central nervous system (CNS) and genes involved in the remodeling of bone, linking these two immunological genes with critical tissue phenotypes of patients. The data underline the functional diversity of the molecules of the innate immune system and implies their significant contribution also in demyelinating CNS disorders, including those resulting in dementia
The genome-wide patterns of variation expose significant substructure in a founder population
Although high-density SNP genotyping platforms generate a momentum for detailed genome-wide association (GWA) studies, an offshoot is a new insight into population genetics. Here, we present an example in one of the best-known founder populations by scrutinizing ten distinct Finnish early- and late-settlement subpopulations. By determining genetic distances, homozygosity, and patterns of linkage disequilibrium, we demonstrate that population substructure, and even individual ancestry, is detectable at a very high resolution and supports the concept of multiple historical bottlenecks resulting from consecutive founder effects. Given that genetic studies are currently aiming at identifying smaller and smaller genetic effects, recognizing and controlling for population substructure even at this fine level becomes imperative to avoid confounding and spurious associations. This study provides an example of the power of GWA data sets to demonstrate stratification caused by population history even within a seemingly homogeneous population, like the Finns. Further, the results provide interesting lessons concerning the impact of population history on the genome landscape of humans, as well as approaches to identify rare variants enriched in these subpopulation
Transcript profiles of dendritic cells of PLOSL patients link demyelinating CNS disorders with abnormalities in pathways of actin bundling and immune response
Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts
Recent genome-wide association (GWA) studies of lipids have been conducted in samples ascertained for other phenotypes, particularly diabetes. Here we report the first GWA analysis of loci affecting total cholesterol (TC), low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglycerides sampled randomly from 16 population-based cohorts and genotyped using mainly the Illumina HumanHap300-Duo platform. Our study included a total of 17,797–22,562 persons, aged 18–104 years and from geographic regions spanning from the Nordic countries to Southern Europe. We established 22 loci associated with serum lipid levels at a genome-wide significance level (P < 5 10-8), including 16 loci that were identified by previous GWA studies. The six newly identified loci in our cohort samples are ABCG5 (TC, P = 1.5 10-11; LDL, P = 2.6 10-10), TMEM57 (TC, P = 5.4 10-10), CTCF-PRMT8 region (HDL, P = 8.3 10-16), DNAH11 (LDL, P = 6.1 10-9), FADS3-FADS2 (TC, P = 1.5 10-10; LDL, P = 4.4 10-13) and MADD-FOLH1 region (HDL, P = 6 10-11). For three loci, effect sizes differed significantly by sex. Genetic risk scores based on lipid loci explain up to 4.8% of variation in lipids and were also associated with increased intima media thickness (P = 0.001) and coronary heart disease incidence (P = 0.04). The genetic risk score improves the screening of high-risk groups of dyslipidemia over classical risk factors