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I read with great interest the article by Morris et al entitled,
"Marginal role for 53 common genetic variants in cardiovascular disease
prediction" (1). The article analyzed a large sample of 11, 851
individuals from 7 prospective studies aimed at primary prevention of
fatal or non-fatal coronary heart disease (CHD) or stroke.
The study incorporated susceptibility variants for CHD and str...
The study incorporated susceptibility variants for CHD and stroke
into a genetic risk score (GRS), to match the two conditions predicted by
a conventional risk score QRISK-2. Results for population-wide utility of
the GRS, and estimates from a sequential screening strategy proposed for
individuals at intermediate risk, were provided. The study extrapolated
that 462 intermediate-risk individuals would need to be screened in order
to prevent one coronary heart disease or stroke event in 10 years.
Based on these results, a GRS could become a novel method for
determining which intermediate-risk individuals should be managed
aggressively, if reclassified to high-risk. However, before these results
are adopted in clinical practice, the following should be considered.
First, the extrapolated estimates should be confirmed prospectively.
Second, the 53 variants include 46 for CHD and 7 for stroke. The CHD
variants are not necessarily found to associate with stroke, and vice
versa. This may limit predictions for each disorder. Third, 46 CHD
variants account for 10% of heritability, and do not capture the entire
contribution of genetics estimated at 40-60% (3). Fourth, the GRS included
29 variants unique for CHD, as well as 17 additional variants that also
associate with CHD risk factors, such as cholesterol, blood pressure, and
diabetes (3); these risk factors are already accounted for in QRISK2 and
are not providing independent information. Fifth, the GRS did not
incorporate 10 additional variants recently discovered (4).
Reclassification and discrimination analyses should be redone with only 29
variants (then adding in the 10 new variants) in population-wide analysis
and for intermediate-risk individuals. Finally, a weak effect on mortality
was reported. This is likely due to the GRS being developed using case-
control prevalence and not incidence.
Overall, there is still work to be done before these excellent
results can be implemented.
1. Morris RW, Cooper JA, Shah T, Wong A, Drenos F, Engmann J, et al.
Marginal role for 53 common genetic variants in cardiovascular disease
prediction. Heart. 2016 Jun 30. 2. Kullo IJ, Jouni H, Austin EE, Brown SA,
Kruisselbrink TM, Isseh IN, et al. Incorporating a Genetic Risk Score Into
Coronary Heart Disease Risk Estimates: Effect on Low-Density Lipoprotein
Cholesterol Levels (the MI- GENES Clinical Trial). Circulation. 2016
Mar;133(12):1181-8. 3. Deloukas P, Kanoni S, Willenborg C, Farrall M,
Assimes TL, Thompson JR, et al. Large-scale association analysis
identifies new risk loci for coronary artery disease. Nat Genet. 2013
Jan;45(1):25-33. 4. Nikpay M, Goel A, Won HH, Hall LM, Willenborg C,
Kanoni S, et al. A comprehensive 1,000 Genomes-based genome-wide
association meta-analysis of coronary artery disease. Nat Genet. 2015