Recessive Genes May Play Role in Coronary Artery Disease, Especially in Inbred Populations Interview with:
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.

MedicalResearch: What should clinicians and patients take away from your report?

Dr. Christofidou: This is the first study that examined whether genome-wide homozygosity levels are a risk factor for Coronary artery disease in outbred populations and whether ROHs might play a role in regulation of gene expression within cells of key importance to atherosclerosis.

Our findings are important because they provide evidence for an excess of ROHs as a potential contributor to Coronary artery disease and therefore support a theory on the role of recessive component in the genetic architecture of CAD that was overseen by previous genome-wide studies.

As the offspring of inbred populations may have lower mean health and fitness because of the homozygous expression of detrimental recessive alleles, similar effects could operate with the more numerous recessive variants influencing complex diseases in outbred populations.

MedicalResearch: What recommendations do you have for future research as a result of this study?

Dr. Christofidou: Additional work is needed to unravel the exact synergistic role of multiple recessive variants, homozygosity levels and their association to coronary artery disease.


Am J Hum Genet. 2015 Jul 7. pii: S0002-9297(15)00237-2. doi: 10.1016/j.ajhg.2015.06.001. [Epub ahead of print]

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

Christofidou P1, Nelson CP2, Nikpay M3, Qu L4, Li M4, Loley C5, Debiec R1, Braund PS1, Denniff M1, Charchar FJ6, Arjo AR7, Trégouët DA7, Goodall AH2, Cambien F7, Ouwehand WH8, Roberts R3, Schunkert H9, Hengstenberg C9, Reilly MP10, Erdmann J11, McPherson R3, König IR5, Thompson JR12, Samani NJ2, Tomaszewski M13.

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Dr. Paraskevi Christofidou (2015). Recessive Genes May Play Role in Coronary Artery Disease, Especially in Inbred Populations 

Last Updated on July 24, 2015 by Marie Benz MD FAAD