STOCKHOLM – Genetic variation in the Y chromosome constitutes a novel, potent, and independent risk factor for coronary artery disease that could help explain the male disadvantage in heart disease.
Among British men, carriage of one of the I-haplogroup variants of the Y chromosome confers a 55% increased risk of coronary heart disease after controlling for the traditional risk factors, including blood pressure, lipids, and smoking, Dr. Nilesh J. Samani reported at the annual congress of the European Society of Cardiology.
That’s a whopping contribution to cardiovascular risk. By comparison, each of the standard risk factors confers a risk more in the 10%-20% range, observed Dr. Samani of the University of Leicester (United Kingdom).
He explained that not all Y chromosomes are the same. Genetic variation evolves far more slowly in the Y chromosome than in other chromosomes because it does not recombine during reproduction. The Y chromosome is passed on from father to son intact.
The I-haplogroup is thought to have been introduced into Europe by the Gravettian culture, which migrated from the Middle East roughly 25,000 years ago. The I-haplogroup is carried by about 15% of British men. However, the prevalence exceeds 60% among men in parts of Scandinavia and Eastern Europe.
To test the hypothesis that genetic variation in the Y chromosome influences cardiovascular risk, Dr. Samani and his coworkers turned first to the British Heart Foundation Family Heart Study. In a cross-sectional sample that comprised 811 men with CAD and 633 controls, the investigators showed that the I-haplogroup was associated with a 67% increased relative risk of CAD, compared with men whose Y chromosome did not contain the I-haplogroup.
For confirmation, the investigators went to the database of the West of Scotland Primary Coronary Prevention Study (WOSCOPS), one of the landmark early randomized trials of statins for primary prevention. Among 1,542 genotyped male participants followed prospectively for 4.9 years, 484 developed CAD. Men who carried the I-haplogroup on their Y chromosome had a 50% increased risk of CAD during the follow-up period.
When the data from the two studies were combined, results yielded a total of 2,986 men, 1,295 of whom developed CAD. Those in the I-haplotype group had a 55% greater risk of CAD, compared with the others after controlling for conventional cardiovascular risk factors.
The specific genes involved in the increased CAD risk associated with the I-haplotype have not yet been identified. Dr. Samani and his coworkers are working on that via ongoing studies of gene expression in cells isolated from men with different Y chromosome haplogroups.
Dr. Samani speculated that the varied prevalence of the I-haplogroup across Europe might help account for the widely variable rates of CAD on the continent. The prevalence of the I-haplogroup is much greater in Northern and Eastern than in Southern and Western Europe – as are CAD rates among men.
“We don’t really have any data to support that now, but we’d like to study it,” Dr. Samani continued.
His Y chromosome study project is funded by the British Heart Foundation. He reported having no financial conflicts.