Using genetic studies to assess the impact of hyperuricemia in cardiometabolic and chronic kidney disease
Observational and epidemiologic studies have linked cardiovascular diseases, metabolic diseases, and chronic kidney disease (CKD) with hyperuricemia. The cause of this association is uncertain, but may be due to the following:
- shared pathophysiologic mechanisms between these diseases;
- medications commonly used to treat gout, such as NSAIDs; and
- causal association of these diseases, which are common within the general population of developed countries.
The impact of hyperuricemia treatment on associated comorbid diseases
It is unclear whether treatment of hyperuricemia provides any additional health benefits, such as reduction of cardiovascular risk, other than the clinical benefits observed in patients with gout. If there are any additional benefits, these may be related to better treatment of associated comorbid conditions in patients with gout compared with those without. Even if a causal association were to be demonstrated, robust intervention trials would be required to show that treatment of hyperuricemia reduces the risk for undesirable renal or cardiovascular outcomes, in order to justify prescription of urate-lowering therapies. Genetic studies may also play a role in explaining the relationship between treatment of hyperuricemia and risk for associated comorbid diseases.
Mendelian randomization studies investigating the association of serum urate levels with risk for comorbid diseases
Mendelian randomization (MR) studies are based on the fact that genetic alleles are randomly assorted during meiosis. Alleles for genetic variants that are associated with a biomarker are used to study the causal inference for a disorder. These studies have confirmed association of coronary heart disease with low-density lipoprotein and not high-density lipoprotein levels, which is contrary to observational studies. To date, MR studies have shown only causal inference of serum urate (sUr) levels with gout and nephrolithiasis.
Researchers have recently published an MR study showing no causal effect of sUr levels on the risk for CKD. Their analysis of four population-based cohorts with aggregated genome-wide association data showed an association between increasing sUr levels and both reduced estimated glomerular filtration rate (eGFR) and increased risk for clinically significant chronic CKD. However, the authors were unable to show any causal effect either on risk for CKD, or on eGFR levels.
A previous MR study also showed no causal role of sUr in the risk for cardiometabolic disorders including type 2 diabetes, ischemic stroke, coronary heart disease, and heart failure.
Recall-by-genotype (RbG) is a different approach that includes detailed phenotyping and genotypic strata assignment to evaluate polygenic contributions more efficiently than in conventional MR studies. This design is therefore not subject to reverse causality or confounding factors with respect to the phenotype as they are randomly distributed, allowing the study of the inference of modifiable factors.
To the author´s knowledge, there are no ongoing studies investigating hyperuricemia or gout using this type of approach. Were studies like this available that showed plausible causality, this could provide the opportunity for treating hyperuricemia in the absence of gout, or in early gout, in order to reduce the risk for cardiovascular events or the development and progression of CKD.
In summary, despite epidemiologic and observational studies linking hyperuricemia with cardiovascular and metabolic disorders, robust evidence showing the benefit of intervention on these disorders is scarce. MR studies to date have also failed to show any causal association, preventing any treatment recommendations of asymptomatic hyperuricemia in clinical practice. The initiation of large, adequately designed and powered, placebo-controlled randomized clinical trials is needed in order to confirm if such a causal association exists.