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Y chromosome linked to increased risk for CAD

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Among men of European ancestry, a variant on the Y chromosome is associated with a 50% higher risk for coronary artery disease, likely caused by interactions of immunity and inflammation, according to recent study data.

The researchers genotyped 11 male-specific markers of the Y chromosome in 3,233 biologically unrelated men from three cohorts: BHF-FHS, WOSCOPS and Cardiogenics study. By examining this information, they traced each Y chromosome back to one of 13 ancient lineages, defined as haplogroups. Of nine haplogroups identified, researchers found two — R1b1b2 and I — that accounted for approximately 90% of Y chromosome variants among British men.

Men with haplogroups I, approximately 15% to 20% of British men, had about a 50% higher age-adjusted risk for CAD vs. men with other Y chromosome lineages in BHF-FHS (OR=1.75; 95% CI, 1.2-2.54), WOSCOPS (OR=1.45; 95% CI, 1.08-1.95) and a joint analysis of both populations (OR=1.56-; 95% CI, 1.24-1.97), according to study results. Researchers found men with CAD in the BHF-FHS cohort were more likely to have haplogroup I (20%) vs. controls without CAD (13%; P=.0001). Similarly, haplogroup I was more common in men who developed CAD during 4.9 years (18%) vs. controls (13%; P=.014) in the WOSCOPS cohort. Adjustment for socioeconomic and traditional CV variables did not weaken the association of haplogroup I with CAD (OR=1.60; 95% CI, 1.16-2.19). Study results showed that haplogroup I was the most significant prediction of CAD after HDL and lipid-lowering treatment.

In a functional analysis of macrophage transcriptome in the Cardiogenics study, researchers found that 19 molecular pathways showing strong differential expression between men with haplogroup I and other lineages of the Y chromosome were interconnected by common genes related to inflammation and immunity, suggesting that some of these pathways may affect the development of atherosclerosis.

In an accompanying editorial, Virginia Miller, PhD, of the department of surgery and physiology at the Mayo Clinic, wrote: “These findings are exciting because they identify a genetic haplotype linking response to infection — adaptive immunity — rather than innate immunity with perhaps an exaggerated inflammatory response and CVD in men.”

According to Miller, when it comes to inheritance of CAD, both sex and family matter. She said future research should include interconnections of pathways relating immunity to other forms of CVD and whether comparable genes in the X chromosome are susceptible to autoimmune disorders.

For more information:

• Charchar FJ. Lancet. 2012;doi:10.1016/S0140-6736(11)61453-0.
• Miller V. Lancet. 2012;doi:10.1016/S0140-6736(12)60200-1.

Disclosure: The researchers report no relevant financial disclosures. Dr. Miller reports no relevant financial disclosures.

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