Gene link to increased risk of coronary heart disease found by scientists

July 13, 2001

Scientists have found that a common gene variant, when carried by cigarette smokers, can significantly increase the risk of coronary heart disease - Britain's single biggest killer.

The new research, funded by the British Heart Foundation (BHF), comes from a collaboration between University College London and the Wolfson Institute at St Bartholemew's Hospital published in THE LANCET today.

While smokers have an increased risk of coronary heart disease (CHD), this new research reveals that some smokers have a significantly higher risk than others. Genetic factors have long been known to be important in determining risk of heart disease, but it is only recently that scientists have been able to identify the particular genes involved. Researchers focused on the Apo-E gene known to be important in controlling the levels of fat in the blood. The gene comes in three common forms - E2,E3 and E4.

The researchers took a group of 3,052 healthy middle aged men (50 to 61 years) drawn from general practices throughout the UK. Participants in the study had their cholesterol and other heart disease risk factors measured as well as completing a smoking questionnaire. Current smokers were defined as 'having smoked at least one cigarette per day for at least one year.' All others were classified as ex or never smokers.

DNA based techniques were used to determine if the men carried one or more copies of the E2 or E4 variant or held the common E3 version. The participants were then monitored annually for an 8 year period. CHD events included all fatal or non-fatal heart attacks plus any coronary artery surgery and silent heart attack - identified by ECG - occurring over the period of the study.

As expected there was a strong association between smoking and risk of coronary heart disease. For every year of the study the CHD events were 5.1 per 1,000 in never smokers and 7.5 per 1,000 in ex-smokers.

Yet the results showed that CHD events in current smokers were a much increased 12.1 per 1,000 - more than double the risk of those who had never taken up the habit.

After taking into account the well known risk factors for CHD, hazard ratios were calculated which compared the risk of the control (never smokers)group with the ex-smokers and current smokers group. The researchers found that, compared to the never-smoker group, ex-smokers had a small and insignificant risk - 1.18 times higher - of CHD, while current smokers had a larger and significant risk - 1.73 times higher.

The researchers then looked at the different versions of Apo-E in these men and found that, in men with the E4 version, the risk of CHD in current smokers was over three times greater than the never-smoked group. The risk was still 2.79 times higher for this group even after taking account all other risk factors. Interestingly, the risk of CHD in E4 ex-smokers was similar to the never smokers, strongly suggesting that the high risk in smokers was reversible by quitting.

Professor Steve Humphries, BHF Professor of Cardiovascular Genetics at UCL, said; ' What is clear from our research is that having the E4 version of the Apo-E gene significantly increases the risk of CHD in current smokers by about three times. However, it should not be forgotten that all current smokers had an increase in risk of CHD whatever version of Apo-E they carried. Our research shows that this risk was larger in the E4 group.'

'The interesting finding in this research is that the effect is independent of cholesterol levels. This means that, regardless of your cholesterol level, if you have the E4 version and smoke, the risk is high. This fact leads us to the view that Apo-E has an important role to play in protecting cholesterol and with it plaque formation.'

Men carrying one or more copies of the E4 variant represent roughly 25% of the population and the research provides further support on the importance of reducing smoking to avoid the risks of coronary heart disease.

Professor George Miller from the Wolfson Institute at St Bartholemew's Hospital and a collaborator in the research said; 'In case anybody views this research as a boon for some smokers, let me say that our findings provide no quick fixes. Each year you continue to smoke you increase your risk of an event. There is no test widely available for this gene and, even if there were, doctors cannot treat you for having a gene. Smoking strongly increases the risk of lung cancer and our research showed that smokers were three times more likely to die from cancer than the non-smoking group. This risk was independent of the version Apo-E carried.'

'The best treatment for reducing all these risk factors is quite simple and we can do it ourselves. We just need to give up smoking.'

Professor Sir Charles George, Medical Director of the British Heart Foundation, said; 'This is an important piece of work in establishing the causes of coronary heart disease. I hope that the information gained from this study will help to motivate the many smokers who want to quit as well as helping us target smoking cessation advice to those most at risk.'

'Smoking is the single most important cause of preventable disease and premature death in the UK. We know that kicking the habit can be hard, but everyone who stops smoking will see the health benefits, whether they have an inherited risk factor or not.'

University College London

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