Clinical Applications
One of the challenges for a successful GWA study in the future will be to apply the findings in a way that accelerates drug and diagnostics development, including better integration of genetic studies into the drug-development process and a focus on the role of genetic variation in maintaining health as a blueprint for designing new drugs and diagnostics. Several studies have looked into the use of risk-SNP markers as a means of directly improving the accuracy of prognosis. Some have found that the accuracy of prognosis improves, while others report only minor benefits from this use. Generally, a problem with this direct approach is the small magnitudes of the effects observed. A small effect ultimately translates into a poor separation of cases and controls and thus only a small improvement of prognosis accuracy. An alternative application is therefore the potential for GWA studies to elucidate pathophysiology.
One such success is related to identifying the genetic variant associated with response to anti-hepatitis C virus treatment. For genotype 1 hepatitis C treated with Pegylated interferon-alpha-2a or Pegylated interferon-alpha-2b combined with ribavirin, a GWA study has shown that SNPs near the human IL28B gene, encoding interferon lambda 3, are associated with significant differences in response to the treatment. A later report demonstrated that the same genetic variants are also associated with the natural clearance of the genotype 1 hepatitis C virus.
The goal of elucidating pathophysiology has also led to increased interest in the association between risk-SNPs and the gene expression of nearby genes, the so-called expression quantitative trait loci (eQTL) studies. The reason is that GWAS studies identify risk-SNPs, but not risk-genes, and specification of genes is one step closer towards actionable drug targets. As a result, major GWA studies of 2011 typically included extensive eQTL analysis. One of the strongest eQTL effects observed for a GWA-identified risk SNP is the SORT1 locus. Functional follow up studies of this locus using small interfering RNA and gene knock-out mice have shed light on the metabolism of low-density lipoproteins, which have important clinical implications for cardiovascular disease.
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