Like Father, Like Son: Y-Chromosome Variant May Explain CAD

February 10, 2012

February 8, 2012 (Ballarat, Australia)A novel method of genetic analysis has established that a common variant on the male Y chromosome is associated with a significant 50% increased risk of coronary artery disease (CAD) [1]. The new findings may partly explain why some men develop CAD 10 years earlier than women, say Dr Fadi J Charchar (University of Ballarat, Australia) and colleagues in their paper published online February 8, 2012 in the Lancet.

And importantly, this association was independent of traditional cardiovascular and socioeconomic risk factors. Rather, it appears to be somehow mediated through the immune system, second author Lisa DS Bloomer (University of Leicester, UK) told heartwire .

"The most important findings are that this is the reason for the sexual dimorphism in coronary artery disease and that the Y chromosome has important roles outside of sex differentiation; it has a role in disease and different pathology, and finding that out means we can open up different avenues of treatment," she notes. She adds that previous associations have been identified between certain variants on the Y chromosome and other conditions, such as HIV progression and autism.

The findings require confirmation before being considered bona fide; this is a very interesting result, but it probably needs a bit more work to be convincing.

In an accompanying comment [2], Dr Virginia M Miller (Mayo Clinic Rochester, MN) says the new research "provides insight into genetic variants and potential new approaches to the understanding of inheritable coronary artery disease in men."

Meanwhile, genetics expert Dr Sekar Kathiresan (Massachusetts General Hospital, Boston)--who was not involved with this work--told heartwire that the study addresses a question not previously evaluated in large-scale genomewide association studies (GWAS) for CAD and generates "an intriguing hypothesis." But the findings "require confirmation before being considered bona fide; this is a very interesting result, but it probably needs a bit more work to be convincing."

Research Required International Collaboration

The researchers explain that there are not many genes on the Y sex chromosome--which is transmitted from father to son--and that the chromosome's "fundamental role" is to impart male characteristics. However, some polymorphisms have been previously linked to blood pressure and cholesterol levels.

Because of the nature of the main part of the Y chromosome--the male-specific region--the usual methods of analysis, such as GWAS, cannot be employed to investigate variations, Bloomer explained. In fact, Y chromosomes are excluded from GWAS, she adds.

Instead, the team used haplogroup analysis, which "requires specialist knowledge and is not as well understood or as well established [as other genetic research], and there are fewer people who can do it," she observes; hence the need for international collaboration.

The team used material from more than 3000, primarily white British men participating in two large UK trials: the cross-sectional British Heart Foundation (BHF) Family Heart Study and the prospective West of Scotland Coronary Prevention Study (WOSCOPS). Of nine haplogroups (groups of haplotypes, which are combinations of alleles at adjacent loci), they identified two that accounted for 90% of the variation on the Y chromosome in British men.

Carriers of one of these, haplogroup I, had about a 50% higher age-adjusted risk of CAD than did men with other Y chromosome lineages. Specifically, in the BHF study, the odds ratio was 1.75 (p=0.004); in WOSCOPS it was 1.45 (p=0.012); and in a joint analysis of both populations it was 1.56 (p=0.0002).

While the association was independent of traditional risk factors, men with haplogroup I had deregulation of the immune system, "affecting autoimmunity and inflammation almost equally," compared with carriers of other Y-chromosome types, Bloomer explained.

"These data show that predisposition to CAD in men might, at least in part, be determined by the paternal lineage of their Y chromosome and that this effect on risk of CAD is most likely mediated through the immune response," the authors observe.

"Future resequencing efforts and functional experiments will be needed to identify the causative variants underlying the increased susceptibility to CAD in carriers of haplogroup I and to decipher the complex interplay between the human Y chromosome, immunity, and cardiovascular disease,” they conclude.

Miller agrees: "Results from this study raise several questions and opportunities for future research."

Authors and editorialists report no conflicts of interest.

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