Role of Y chromosome in inherited coronary artery disease

Published in The Hindu on February 9, 2012

Men develop coronary artery disease (CAD) approximately ten years earlier than women. Does the Y chromosome, which is found only in males, have any role in this?

A study published on today (February 9) in The Lancet journal does show that the Y chromosome plays a role. But not every male shares the same risk of developing coronary artery disease, though. Only those belonging to one of the 13 ancient lineages (haplogroup I) were found to be carriers of coronary artery disease risk.

“Haplogroup I is associated with increased risk of coronary artery disease,” the authors write. Carriers of haplogroup I are at 50 per cent increased risk of CAD compared with men having different variants. The study also revealed that the increased risk is not mediated by traditional cardiovascular risk factors such as high systolic blood pressure and low HDL cholesterol.

No role

Also, the association between haplogroup I and increased risk of CAD was independent of age and other socioeconomic and lifestyle risk factors such as body-mass index, diabetes, smoking, alcohol consumption, and socioeconomic status.

Predictive value

But the authors caution that the haplogroup I on its own is “unlikely to offer sufficiently high positive predictive value of coronary artery disease.” But they also state in the same breath that the “relative estimates of coronary artery disease risk in carriers of haplogroup I are not trivial” from the genetic association analysis point of view.

Most importantly, the study found that men with haplogroup I showed downregulation (where the cells are made less sensitive to a hormone or another agent) of adaptive immunity that provides much more sophisticated immune response. Previous studies have shown that dysfunction of immune response is a “well established contributor to atherosclerosis and coronary artery disease.”

Those with haplogroup I were particularly vulnerable to HIV infection, the authors state. It took longer time to suppress HIV, and these people showed accelerated progression from HIV state to full-blown AIDS. Mortality from AIDS was also significantly higher in those not belonging to haplogroup I.

But it does not stop with downregulation of adaptive immunity. It upregulates inflammatory response pathways in the immune system cells. This heightened inflammatory response affects cardiovascular system.

Carriers of haplogroup I would have probably arrived from the Middle East around 25,000 years ago and spread throughout Europe, the authors postulate. This is based on the absence of this variant in indigenous populations outside Europe.

The study best fits the north-south gradient in west Europe where death from CAD is much higher in the northern populations in Scandinavia, Germany and the Netherlands. The prevalence of haplogroup I in these countries is 15 per cent to 40 per cent.

However, the prevalence of this variant in people from countries like France, Spain and Switzerland in the south of west Europe is lesser.

Data for this study was obtained from two large studies in the UK — the cross-sectional British Heart Foundation Family Heart Study, and the prospective West of Scotland Coronary Prevention Study. Nearly 90 per cent of the more than 3,200 men participating in these two studies belonged either to haplogroup I or another variant.