February 09, 2012

Y-chromosomes and coronary artery disease in Britain

I first reported about this research in 2010. Now, a paper on the topic has appeared in The Lancet. Apart from the potential health implications, it serves to remind us that at least some of the dramatic shifts in Y-haplogroup frequencies between modern and ancient populations may have been driven -at least in part- by natural selection.

The Lancet, Early Online Publication, 9 February 2012 doi:10.1016/S0140-6736(11)61453-0

Inheritance of coronary artery disease in men: an analysis of the role of the Y chromosome

Fadi J Charchar PhD et al.


Background A sexual dimorphism exists in the incidence and prevalence of coronary artery disease—men are more commonly affected than are age-matched women. We explored the role of the Y chromosome in coronary artery disease in the context of this sexual inequity.

Methods We genotyped 11 markers of the male-specific region of the Y chromosome in 3233 biologically unrelated British men from three cohorts: the British Heart Foundation Family Heart Study (BHF-FHS), West of Scotland Coronary Prevention Study (WOSCOPS), and Cardiogenics Study. On the basis of this information, each Y chromosome was tracked back into one of 13 ancient lineages defined as haplogroups. We then examined associations between common Y chromosome haplogroups and the risk of coronary artery disease in cross-sectional BHF-FHS and prospective WOSCOPS. Finally, we undertook functional analysis of Y chromosome effects on monocyte and macrophage transcriptome in British men from the Cardiogenics Study.

Findings Of nine haplogroups identified, two (R1b1b2 and I) accounted for roughly 90% of the Y chromosome variants among British men. Carriers of haplogroup I had about a 50% higher age-adjusted risk of coronary artery disease than did men with other Y chromosome lineages in BHF-FHS (odds ratio 1·75, 95% CI 1·20—2·54, p=0·004), WOSCOPS (1·45, 1·08—1·95, p=0·012), and joint analysis of both populations (1·56, 1·24—1·97, p=0·0002). The association between haplogroup I and increased risk of coronary artery disease was independent of traditional cardiovascular and socioeconomic risk factors. Analysis of macrophage transcriptome in the Cardiogenics Study revealed 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, and that some of them have a strong relevance to atherosclerosis. 

Interpretation The human Y chromosome is associated with risk of coronary artery disease in men of European ancestry, possibly through interactions of immunity and inflammation.



Andrew Oh-Willeke said...

The differential expression piece does support non-neutral NRY-DNA but, in general, it is appropriate to clearly rule out the possibility that social class/cultural practices that happen track to ancestry informative genetic information.

As an intentionally unrealistic and exaggerated example to illustrate the idea, if eating Haggus is an immense risk factor for heart disease and Scots are disproportionately Y-DNA I due to their demographic history as a people, then it could look like Y-DNA was causing effects that were really due to diet.

On the other hand, there is no reason that Y-DNA shouldn't have selective effects, and indeed, since it is the only uniparental marker in the ordinary genome (as opposed to the mitchondrial genome) and is the place where adapations that are selectively fitness enhancing in men but reduce selective fitness in women are most favored, one would expect there to be selectively non-neutral alleles in Y-DNA (although I'm inclined to think that the individual level selection effects on Y-DNA have probably swamped by the group selection effects on Y-DNA since the Neolithic - coronary artery disease, for example, had very little impact on selective fitness until the germ theory of disease and accompanying hygene measures, vaccines, antibiotics, and improved diet quality and consistency dramatically reduced the importance of other selective factors that swamped the relevance of coronary artery disease (which typically strikes only once one has had children who are at least adolescents, if not adults by the time it strikes and which is typically not a visible factor in choice of mate or in pre-death economic success).

A plausible heuristic and hypothesis to explain the difference would be that Y-DNA I may reflect pre-Neolithic hunting and gathering lifestyles when the wild meats they ate were leaner and there were more low cholesterol nuts as protein sources in their diets, while R1b1b2 may have adaptations that thrived in the Neolithic or later that involved higher fat diets associated with eating livestock.

Average Joe said...

This might help to explain why R1b is so common in western Europe while being apparently very young. If R1b had a genetic advantage over Haplogroup I then natural selection would have favored the R1b carriers.