Author Interviews, Genetic Research, Heart Disease / 24.07.2015
Recessive Genes May Play Role in Coronary Artery Disease, Especially in Inbred Populations
MedicalResearch.com Interview with:
Dr. Paraskevi Christofidou
Department of Cardiovascular Sciences, University of Leicester
NIHR Biomedical Research Unit in Cardiovascular Disease, Leicester UK
MedicalResearch: What is the background for this study?
Dr. Christofidou: Homozygosity arises when identical alleles are present on both chromosomes. Runs of homozygosity (ROHs) are very long segments of uninterrupted sequences of homozygous variants across the human genome. Runs of homozygosity represent "re-union" of pieces from DNA from parents in their children. The two DNA copies are identical because have been inherited from a common ancestor somewhere in the distant past.
Runs of homozygosity are recognized signature of recessive inheritance, because they allow unmasking of recessive variants. Recessive variants only show their effect when present on both chromosomes of an individual's genome. Some of these ROHs may potentially harbor variants that exert their pathological effects in the homozygous recessive state. This is important because it helps us better understand the consequences of the recessive model of inheritance in relation to complex diseases.
Coronary artery disease (CAD) is a terminal clinical manifestation of cardiovascular disease and is the leading cause of death worldwide and is the UK's single biggest killer. Nearly one in six men and one in ten women die from CAD. Coronary artery disease is a complex, multifactorial disorder originating from a complicated interplay of multiple genetic and environmental factors.
Contributions of ROHs to the genetic architecture of CAD are not known. The primary goal of this project was a comprehensive analysis of association between genome-wide homozygosity measures and CAD in individuals of white European ancestry. A secondary aim was to explore the association of ROHs and gene expression in human monocytes and macrophages.
MedicalResearch: What are the main findings?
Dr. Christofidou: Our analysis of 24,320 individuals from 11 populations of white European ethnicity revealed statistically significant differences in homozygosity levels between individuals with Coronary artery disease and control subjects.
On average, individuals with CAD had 0.63 ROHs more than control subjects. The average total length of ROHs was approximately 1046.92 kb greater in individuals with CAD than control subjects. We were able to qualify a measure of genome-wide homozygosity levels in relation to CAD - an estimated 13% increase in CAD per 1 standard deviation increase in the proportion of the autosomal genome covered by ROHs.
Individual ROHs showed significant associations with monocyte and macrophage expression of genes located nearby. These associations suggest that many ROHs might be signatures of biologically active recessive variants with a potential to regulate transcription.
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