Genetics of Atherosclerosis

Our research team in the Atherosclerosis and Lipid Genomics Laboratory has used a wide range of tools to understand the genetic basis of atherosclerotic vascular disease, including family history, linkage studies, candidate gene-association studies, genome-wide association studies and genome sequencing.

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Study 1: Family history

Patients participating in our lab's Vascular Diseases Biorepository were asked to complete a questionnaire related to family history of various atherosclerotic vascular diseases. This questionnaire allowed us to assess association of family history of atherosclerotic cardiovascular disease to prevalent peripheral artery disease, carotid artery stenosis and abdominal aortic aneurysm.

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Study 2: Linkage studies

Linkage studies, performed by using polymorphic DNA markers, have the potential to identify new candidate genes that previously would have remained unsuspected on the basis of a priori knowledge of disease mechanisms. The limitations associated with linkage studies of complex diseases include low statistical power and the inability to specify precise limits on the location of the causal gene or mutation.

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Study 3: Candidate gene-association studies

These studies assess whether variants in genes that may be biologically relevant for a trait or disease are associated with that trait or disease.

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Study 4: Genome-wide association studies

Association studies compare allele frequencies in cases and controls to assess the contribution of genetic variants to phenotypes of interest. In contrast to linkage studies, association studies of complex diseases localize disease-related genomic regions more precisely and have greater statistical power for detecting small gene effects.

Our lab has performed genome-wide association studies (GWAS) of several cardiovascular traits, including red blood cell indices, and traits related to atherosclerotic vascular disease.

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Study 5: Genome sequencing in clinical practice

The Atherosclerosis and Lipid Genomics Lab used whole-exome sequencing to identify the mutation underlying a syndrome affecting two siblings with aortic hypoplasia, calcific atherosclerosis, systolic hypertension and premature cataract.

The two siblings were homozygous for a rare novel missense mutation (Ser818Cys) in INO80D, a component of the human INO80 chromatin remodeling complex. INO80D encodes a key component of the human IN080 complex, a multiprotein complex involved in DNA binding, chromatin modification, organization of chromosome structure, and ATP-dependent nucleosome sliding.

Our lab's findings suggested a link between INO80D, a component of the human INO80 chromatin remodeling complex, and accelerated arterial aging.

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Study 6: Gene expression profiling

Patterns of gene expression in tissues can be used to predict a disease state or potential susceptibility. Such an approach may help prioritize genes and SNPs for large-scale analyses of gene variants.

A recent strategy — genomic convergence — combines QTL mapping and gene expression analysis of disease-relevant tissues. Genes identified by both approaches can be considered high-priority candidate genes in human genetic association studies.

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