It’s Complicated! Large Genetic Study Of Coronary Disease Shows How Much We Don’t Know

We still have a very long way to go before we understand the genetic underpinnings of coronary artery disease, according to the largest and most comprehensive study in the field performed to date.

In a series of tweets Sekar Kathiresan, a co-leader of the study, summarized the  meta-analysis of genome-wide association studies, which was published in Nature Genetics:

Our latest analysis of coronary artery disease genetics is out. 58 DNA variants confer risk. Takeaways from latest CAD genetics study:

  • Of 58 variants, <20% relate to known risk factors.
  • Lots of common variants with weak effects, few low-frequency variants of larger effect.
  • Biggest yield = biology @ 80% CAD loci not related to known risk factors– difficult but nothing worth doing is easy.
  • Which risk factors matter most for CAD? Unbiased genetic survey finds only LDL, Lp(a), TG, & SBP.

Responding to email questions, Kathiresan told me that “the holy grail for therapeutics is non-lipid mechanisms. We really need to understand the causal genes and mechanism at the 80% of CAD gene regions that are non-lipid…. Identifying non-lipid causal factors could open the door to a new series of treatments.”

The study therefore lends support to the view that further progress in understanding and treating CAD will depend less on lipid research and more on vessel wall biology. In their paper the researchers write:

A number of preventative strategies target the vessel wall (control of blood pressure and smoking cessation), but the large majority of existing drug treatments for lowering CAD risk operate through manipulation of circulating lipid levels and few directly target vessel wall processes. Detailed investigation of new aspects of vessel wall biology that are implicated by genetic association but have not previously been explored in atherosclerosis may provide new insights into the complex etiology of disease and, hence, identify new targets.






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