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Runs of Homozygosity: Association with Coronary Artery Disease and Gene Expression in Monocytes and Macrophages.

ABSTRACT: Runs of homozygosity (ROHs) are recognized signature of recessive inheritance. Contributions of ROHs to the genetic architecture of coronary artery disease and regulation of gene expression in cells relevant to atherosclerosis are not known. Our combined analysis of 24,320 individuals from 11 populations of white European ethnicity showed an association between coronary artery disease and both the count and the size of ROHs. Individuals with coronary artery disease had approximately 0.63 (95% CI: 0.4-0.8) excess of ROHs when compared to coronary-artery-disease-free control subjects (p = 1.49 × 10(-9)). The average total length of ROHs was approximately 1,046.92 (95% CI: 634.4-1,459.5) kb greater in individuals with coronary artery disease than control subjects (p = 6.61 × 10(-7)). None of the identified individual ROHs was associated with coronary artery disease after correction for multiple testing. However, in aggregate burden analysis, ROHs favoring increased risk of coronary artery disease were much more common than those showing the opposite direction of association with coronary artery disease (p = 2.69 × 10(-33)). Individual ROHs showed significant associations with monocyte and macrophage expression of genes in their close proximity-subjects with several individual ROHs showed significant differences in the expression of 44 mRNAs in monocytes and 17 mRNAs in macrophages when compared to subjects without those ROHs. This study provides evidence for an excess of homozygosity in coronary artery disease in outbred populations and suggest the potential biological relevance of ROHs in cells of importance to the pathogenesis of atherosclerosis.

SUBMITTER: Christofidou P

PROVIDER: S-EPMC4573243 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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Runs of Homozygosity: Association with Coronary Artery Disease and Gene Expression in Monocytes and Macrophages.

Christofidou Paraskevi P Nelson Christopher P CP Nikpay Majid M Qu Liming L Li Mingyao M Loley Christina C Debiec Radoslaw R Braund Peter S PS Denniff Matthew M Charchar Fadi J FJ Arjo Ares Rocanin AR Trégouët David-Alexandre DA Goodall Alison H AH Cambien Francois F Ouwehand Willem H WH Roberts Robert R Schunkert Heribert H Hengstenberg Christian C Reilly Muredach P MP Erdmann Jeanette J McPherson Ruth R König Inke R IR Thompson John R JR Samani Nilesh J NJ Tomaszewski Maciej M

American journal of human genetics 20150709 2

Runs of homozygosity (ROHs) are recognized signature of recessive inheritance. Contributions of ROHs to the genetic architecture of coronary artery disease and regulation of gene expression in cells relevant to atherosclerosis are not known. Our combined analysis of 24,320 individuals from 11 populations of white European ethnicity showed an association between coronary artery disease and both the count and the size of ROHs. Individuals with coronary artery disease had approximately 0.63 (95% CI ...[more]

PMID: 26166477

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Project description:ImportanceMutations in known causal Alzheimer disease (AD) genes account for only 1% to 3% of patients and almost all are dominantly inherited. Recessive inheritance of complex phenotypes can be linked to long (>1-megabase [Mb]) runs of homozygosity (ROHs) detectable by single-nucleotide polymorphism (SNP) arrays.ObjectiveTo evaluate the association between ROHs and AD in an African American population known to have a risk for AD up to 3 times higher than white individuals.Design, setting, and participantsCase-control study of a large African American data set previously genotyped on different genome-wide SNP arrays conducted from December 2013 to January 2015. Global and locus-based ROH measurements were analyzed using raw or imputed genotype data. We studied the raw genotypes from 2 case-control subsets grouped based on SNP array: Alzheimer's Disease Genetics Consortium data set (871 cases and 1620 control individuals) and Chicago Health and Aging Project-Indianapolis Ibadan Dementia Study data set (279 cases and 1367 control individuals). We then examined the entire data set using imputed genotypes from 1917 cases and 3858 control individuals.Main outcomes and measuresThe ROHs larger than 1 Mb, 2 Mb, or 3 Mb were investigated separately for global burden evaluation, consensus regions, and gene-based analyses.ResultsThe African American cohort had a low degree of inbreeding (F ~ 0.006). In the Alzheimer's Disease Genetics Consortium data set, we detected a significantly higher proportion of cases with ROHs greater than 2 Mb (P = .004) or greater than 3 Mb (P = .02), as well as a significant 114-kilobase consensus region on chr4q31.3 (empirical P value 2 = .04; ROHs >2 Mb). In the Chicago Health and Aging Project-Indianapolis Ibadan Dementia Study data set, we identified a significant 202-kilobase consensus region on Chr15q24.1 (empirical P value 2 = .02; ROHs >1 Mb) and a cluster of 13 significant genes on Chr3p21.31 (empirical P value 2 = .03; ROHs >3 Mb). A total of 43 of 49 nominally significant genes common for both data sets also mapped to Chr3p21.31. Analyses of imputed SNP data from the entire data set confirmed the association of AD with global ROH measurements (12.38 ROHs >1 Mb in cases vs 12.11 in controls; 2.986 Mb average size of ROHs >2 Mb in cases vs 2.889 Mb in controls; and 22% of cases with ROHs >3 Mb vs 19% of controls) and a gene-cluster on Chr3p21.31 (empirical P value 2 = .006-.04; ROHs >3 Mb). Also, we detected a significant association between AD and CLDN17 (empirical P value 2 = .01; ROHs >1 Mb), encoding a protein from the Claudin family, members of which were previously suggested as AD biomarkers.Conclusions and relevanceTo our knowledge, we discovered the first evidence of increased burden of ROHs among patients with AD from an outbred African American population, which could reflect either the cumulative effect of multiple ROHs to AD or the contribution of specific loci harboring recessive mutations and risk haplotypes in a subset of patients. Sequencing is required to uncover AD variants in these individuals.

Project description:ObjectivesTo analyze the gene expression profile of peripheral blood monocytes in different stages of coronary artery disease (CAD) by transcriptome sequencing, and to explore potential genes and pathway involved in CAD pathogenesis.MethodsAccording to the screening of coronary angiography and quality control of blood samples, eight intermediate coronary lesion patients were selected, then eight patients with acute myocardial infarction, and eight patients with normal coronary angiography were matched by age and gender. Transcriptomics sequencing was conducted for the peripheral blood monocytes of these 24 samples by using the Illumina HiSeq high-throughput platform. Then, differentially expressed genes (DEGs) were analyzed. Gene Ontology (GO) functional annotation, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway annotation, and protein-protein interaction (PPI) network were applied to annotate the potential functions of DEGs.ResultsCompared with the normal coronary angiography group, we identified a total of 169 DEGs in the intermediate coronary lesion group, which were significantly enriched in 59 GO terms and 17 KEGG pathways. Compared with the normal coronary angiography group, we found a total of 2,028 DEGs, which were significantly enriched in 311 GO terms and 20 KEGG pathways in the acute myocardial infarction group. The cross-comparison between normal versus intermediate coronary lesion group, and normal versus acute myocardial infarction group included 98 differential genes with 65 up regulated and 33 down regulated genes, which were significantly enriched in 46 GO terms and 10 KEGG pathways. During the progression of CAD, there was a significant up-regulated expression of CSF3, IL-1A, CCR7, and IL-18, and down-regulated expression of MAPK14. Besides GO items such as inflammatory response was significantly enriched, KEGG analysis showed the most remarkable enrichments in IL-17 signaling pathway and cytokine-cytokine receptor interactions.ConclusionsTranscriptomics profiles vary in patients with different severity of CAD. CSF3, IL-1A, CCR7, IL-18, and MAPK14, as well as IL-17 signaling pathway and cytokine and cytokine receptor interaction signaling pathway related with inflammatory response might be the potential biomarker and targets for the treatment of coronary artery disease.

Dataset Information

Runs of Homozygosity: Association with Coronary Artery Disease and Gene Expression in Monocytes and Macrophages.

Publications

Runs of Homozygosity: Association with Coronary Artery Disease and Gene Expression in Monocytes and Macrophages.

Similar Datasets

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