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Gene linked to heart disease in women

Researchers have identified a gene which is linked to an increased risk of heart disease in women, according to a study published recently in Circulation: Cardiovascular Genetics.1

The researchers from University College London (UCL) studied a group of genes that have previously been linked to an increased risk of disease in the arteries. They studied data from nearly 4,000 men and women from across Europe, comparing their genes, their artery thickness and their artery health.

The scientists, led by British Heart Foundation (BHF) Professor Steve Humphries, believe they have pinpointed the gene in the group that is associated with an increased risk of a heart attack or stroke in women, but not in men. Called BCAR1, the gene is involved in many processes in the body that are affected by oestrogen.

The researchers believe that a high risk version of the BCAR1 gene – the GG version – when combined with a woman’s naturally occurring high oestrogen levels, could lead to the increased risk of cardiovascular disease compared with the low risk version – the AA version. Men with the GG version of the BCAR1 gene do not seem to be affected.

Over the five year study, women with the high risk BCAR1 gene – around a third of those studied – had an increased risk (6.1%) of having a myocardial infarction, stroke or diseased blood vessels compared with those with the low risk version of the gene (2.5%).

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Freya Boardman-Pretty (University College London)

Freya Boardman-Pretty, a PhD student at UCL who carried out the research, said: “We’ve known for a long time that risk factors for heart disease are different for men and women. This gene effect, seen only in women, could be contributing to this difference, although we expect there are a lot of other factors at play…If we can confirm that this gene is involved, and work out exactly how it leads to an increased risk of heart disease in women, it could become a new target for drugs in the future.”

Dr Shannon Amoils, Senior Research Adviser at the British Heart Foundation, which funded the study, said: “Heart disease is often seen as a disease which predominantly affects men, but this is simply not the case. We know that women have a lower overall risk of coronary heart disease compared with men but as this study shows, women do get coronary heart disease, and it is important to find out more about the factors that increase their risk. We will only be able to do this through further research.”

“It’s imperative that heart disease is seen as a disease which can affect anyone regardless of their gender and that everyone takes steps to help prevent it. Women can reduce their risk by not smoking, getting regular physical exercise and eating healthily,” Dr Amolis added.

Speaking to BJC Arrhythmia Watch, Ms Boardman-Pretty gave us a summary of the study’s key messages:

Carotid intima-media thickness is an established marker of subclinical atherosclerosis and a precursor to coronary heart disease. We examined a locus that had previously been found to be associated with carotid intima-media thickness, looking for the gene involved and the mechanism of the potential functional variant.

Using molecular techniques, we identified the SNP rs4888378 as affecting transcription factor binding and reporter gene activity. This matches with analysis of in vivo expression data from aortic artery and tibial artery tissue, which showed the protective A allele of the SNP to be associated with lower expression of BCAR1.

rs4888378 is therefore likely to affect regulation of BCAR1 (Breast Cancer Anti-Estrogen Resistance 1), which plays a role in cell adhesion and proliferation in vascular smooth muscle cells, and therefore may be important in atherosclerosis and artery wall remodelling. We hypothesise that the G allele of the SNP increases expression of BCAR1, stimulating vascular smooth muscle cell migration and increasing formation of neointima in the vessel wall, resulting in larger plaques and greater carotid intima-media thickness.

Performing a meta-analysis and stratifying the data by sex showed the interaction between the variant and carotid intima media thickness and vascular events (heart attacks, stroke or peripheral artery disease) to be seen only in women. The rate of events in women during the IMPROVE 5-year study was 55% higher for each G allele of the SNP (although the incidence over the study was average 4.2%, so absolute risk increase is from 2.5% for low-risk AA genotype  to 6.1% high-risk GG).

This raises questions about how physiological differences between the sexes may affect cardiovascular disease. BCAR1 is involved in many processes in the body affected by oestrogen, having a potential effect on endothelial cell function, for example. We hypothesise that there is an interaction between the effect of oestrogen and the effect of the variant on endothelial cells during plaque formation.

The BCAR1 protein is already known to have connections with oestrogen: it was characterised under the name breast cancer antiestrogen resistance 1 when overexpression was found to confer antiestrogen resistance in breast cancer cells.

We do not expect individual testing for the SNP to be a priority, as stronger genetic factors that are already known are likely to provide more relevance in terms of individual risk testing. Instead, confirmation of the role of BCAR1 in atherosclerotic risk may help identify novel pathways for disease, particularly sex-specific pathways, enabling the development of novel therapeutics to target this pathway.

References

1. Boardman-Pretty F, Smith AJP, Cooper J, et al. Functional analysis of a carotid intima-media thickness locus implicates BCAR1 and suggests a causal variant. Circ Cardiovasc Genet 2015;8:696–706. http://dx.doi.org/10.1161/CIRCGENETICS.115.001062

Published on: October 30, 2015

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