Genetic Risk Scores and Blood Pressure — The Heart is What Matters

Hypertension affects millions of people around the world and continues to be a leading risk factor for cardiovascular morbidity and mortality. Many studies have shown the direct association of high BP with increased risk of cardiovascular events and progression to ESKD. Although lowering of BP directly lowers cardiovascular events, studies, including a meta-analysis by Xie et al. (¹), have not demonstrated kidney protective effects of general BP lowering. This contrasts with the decreased risk for kidney disease progression with renin-angiotensin-aldosterone system inhibition, as noted by Lewis et al. (²) in 1993 and confirmed by others (³). These divergent results indicate that, although high BP increases risk for kidney disease, BP lowering alone is not sufficient to decrease risk for kidney disease; targeted treatment of hypertension (e.g., renin-angiotensin-aldosterone system inhibition) is necessary to slow progression of kidney disease.

Genome-wide association studies have led to identification of single nucleotide polymorphisms (SNPs) associated with BP and hypertension prevalence. Evangelou et al. (⁴) reported the genetic association of BP traits in >1 million people of European ancestry using 535 BP loci. Studies using genetic data as a proxy for lifetime exposures have become another assessment tool, with studies showing that genetic risk scores (GRSs) associate with disease outcomes. Studies have consistently predicted increased cardiovascular end points in those with elevated genetic risk for high BP. However, the International Consortium for Blood Pressure Genome-Wide Association Studies (⁵), among others, found that GRSs have neither associated with kidney function nor CKD in the general population.

In this issue of Kidney360, Nierenberg and colleagues sought to investigate whether BP GRSs are associated with increased risk for cardiovascular disease (CVD) and CKD progression and kidney failure in patients with kidney disease. They used data from 3074 Chronic Renal Insufficiency Cohort (CRIC) participants with available genotype, covariate, and phenotype data. The authors used 901 BP loci, which account for a portion of BP variability, to construct systolic BP (SBP), diastolic BP (DBP), and pulse pressure (PP) GRSs (884, 885, and 256 SNPs, respectively). Weighted GRSs were calculated using the product of dosage of the risk allele by its effect size, and then summing the products across all SNPs included in the risk score. The primary cardiovascular outcomes were congestive heart failure, myocardial infarction, or stroke, and kidney disease progression was based on incident ESKD or halving of eGFR.

At baseline, GRSs for SBP, DBP, and PP were associated with baseline SBP, DBP, and PP among participants of European ancestry, but not among participants of African ancestry, implying other factors are involved. Among participants of both European and African ancestry, those in the highest GRS quartiles for SBP were on a greater number of antihypertensive medications. BP GRSs were not associated with baseline eGFR or urinary protein-creatinine ratio in either ancestry, nor with change in BP during follow-up.

Increased SBP GRSs in participants of both European and African ancestry were associated with increased risk of CVD events. A similar trend was noted for DBP and PP GRSs in both ancestries, but results were only significant for the PP GRS among participants of African ancestry. This discrepancy (significant findings for SBP GRS but not DBP or PP) may be due to the elderly nature of the population studied, in which elevated SBP is more common and low DBP may reflect vascular stiffness. Increased DBP GRS may be a risk factor for CVD in a younger cohort.

Increased SBP GRSs were found to be associated with a 10% increased risk of CVD events after adjusting for measured BP among participants of European ancestry. After adjusting for measured BP in participants of African ancestry, SBP GRS was only marginally associated with CVD events (P=0.07). These last findings demonstrate the potential for GRSs to provide distinct information for CVD risk from measured BP alone. Finally, Nierenberg et al. found no association between the BP GRSs and kidney disease progression or kidney function decline using eGFR slope or urinary protein-creatinine ratio slope. Hazard ratios for CKD events conferred by SBP GRSs were NS, even after adjusting for measured BP in either ancestry group.

Although clinical trials show BP lowering reduces CVD risk and specific medications lower risk for CKD progression, the data presented by these authors further support two distinct mechanisms underlying hypertension treatment and reduction in CVD and kidney outcomes. The findings of this study are also consistent with other BP GRS studies that do not show a relationship between BP GRSs and kidney disease in the general population. Recently, Yu et al. (⁶) evaluated the effect of genetic markers of BP and kidney function in the CKDGen population, which had a mean age of 50 years and a CKD prevalence of 9%. They found no association between genetic markers of BP and kidney function; however, the genetic markers of kidney function were found to be associated with SBP and DBP. This causal relationship between kidney function and BP presents a challenge and an opportunity to the medical community to control BP by preventing loss of kidney function.

This study reinforces the idea that BP GRS can serve as a proxy for the lifetime burden of high BP. Most CRIC participants were taking antihypertensive medications; treatment effects likely attenuated the associations of BP GRSs and BP levels. Participants of African ancestry were more likely to use antihypertensive medications and were on more medications than their European counterparts. Socioeconomic inequities, differences in therapeutic approaches, and genetic risk may contribute to these differences. The GRS was constructed using loci from a majority European ancestry population, which may also have differentially affected the association between GRSs and BP. The authors discuss the biases in genomics research and the need for more diverse research populations in the future. Nonetheless, Nierenberg et al. have shown us that there is a relationship between BP GRSs and cardiovascular outcomes, but not kidney disease progression, in a CKD cohort. This cohort had a robust number of kidney events and thus was adequately powered to detect GRS associations with kidney outcomes.

The finding that genetic risk for hypertension does not predict kidney progression events and the lack of benefit of lowering BP on kidney function decline challenges us to re-evaluate how we frame our research. What other factors contribute to the burden of kidney disease and what public health measures could be recommended? How do we, as individual physicians, institutions, or—more broadly—on a universal level, use such data effectively to develop guidelines and policies that have an effect on kidney disease? This brings into question what role BP has in the onset and evolution of kidney disease.

These authors challenge some of the concepts around the management of patients with kidney disease. In the age of personalized medicine, how do we use these provoking findings to inform our decision making? A continuous evolution of technology and the developments in molecular diagnostics and genomics increase the possibility of further knowledge and utilization of the human genome, allowing a “personalized” approach to clinical care. Across disciplines, the role of biology, environment, and human behavior will inform how we manage our patients. Current analyses only adjusted for age, sex, CRIC site, and ancestry; the rich CRIC dataset allows for analyses evaluating the association between genetics, socioeconomics, lifestyle factors, and cardiovascular and kidney outcomes.

How will genetics be used to refine patients’ hypertension phenotype and inform their outcome, and how can we positively effect this? The majority of our patients with CKD die of cardiovascular complications long before they progress to ESKD. Should our BP target be informed by other factors, and does their GRS moderate the effect of intensive BP lowering on CVD risk? Further studies are needed to determine whether treatments based on GRSs can more specifically target those at highest risk. For example, it may be appropriate to have a lower threshold for treating patients with higher BP GRSs (e.g., SBP >120 mm Hg or DBP >80 mm Hg). Additionally, patients with higher GRSs may be more likely to benefit from aggressively lowering SBP to <120 mm Hg. Conversely, the benefit of aggressive BP lowering may be less among patients with lower SBP GRSs, in whom a SBP target of <140 mm Hg may be more appropriate. BP GRSs could be shared with patients and may motivate those at high risk to adopt lifestyle modifications that may ameliorate some of their risk for hypertension (⁷). Clearly, more refinement is needed to inform clinical care and public policy so that our approach to hypertension treatment in patients with CKD can be more specifically targeted to decrease the burden of kidney disease and hypertension worldwide.

Disclosures

All authors have nothing to disclose.

Funding

None.