DENVER—Variants in the genes APOL1 and MYH9 are associated with an increased risk of chronic kidney disease (CKD) progression in African-Americans with hypertensive nephropathy, researchers reported here at the American Society of Nephrology Renal Week 2010 (Abstract SA-FC354), adding to the growing body of evidence on a genetic susceptibility to kidney disease in this racial group.
Previous work has shown that variants in these genes, which are located on chromosome 22, are associated with risk of focal segmental glomerulosclerosis (FSGS) and nondiabetic kidney disease in African-Americans (Nat Genetics 2008;40:1175-1184 and 1185-1192; Science 2010;329:841-845).
“The variants in that MYH9 gene were found first in cross-sectional studies of people with kidney failure and people without kidney failure, and those with kidney disease were more likely to have one of the specific variants in that gene than the others,” said Brad C. Astor, PhD, lead author of the new hypertensive nephropathy study, at a news conference held during Renal Week. Dr. Astor is Associate Professor of Epidemiology and Medicine at Johns Hopkins University.
“More recently, some different study groups found specific variants in the APOL1 gene to be more common in people with kidney disease than without. They hypothesized from the evidence that the variants in the APOL1 gene were actually the ones causing the kidney failure.”
This new study took a different tack.
“The other studies compared people with kidney disease to without,” Dr. Astor said. “In our study, we looked at whether having this gene actually predicted future declines in kidney function and future risk of kidney failure.”
They found that it did.
“It actually is one of the first times any gene has been associated with kidney disease, especially for African-Americans, and I think what we don't want people to focus in on is that now we have some genetic disease that's associated with kidney disease so therefore we don't need to control blood pressure, control diabetes, or lose weight or exercise,” said Bessie A. Young, MD, MPH, of the University of Washington and the VA Puget Sound in Seattle, who moderated the news conference.
“I think the research that needs to be done will be to look at what the contribution is of the gene versus all these other sort of lifestyle issues. If people do actually control all those things, can they keep that predisposition at bay, or does it mean that they actually will develop disease no matter what they do? I think we're still at a point where we need to know more data. We need to see what the research shows.”
AASK Cohort Study
To study the association between these genes and disease progression, Dr. Astor and colleagues used data from the African-American Study of Kidney Disease and Hypertension (AASK).
In the AASK Clinical Trial, 1,094 nondiabetic African-Americans with hypertensive CKD were randomized in a three-by-two factorial design to one of three antihypertensive agents and one of two blood pressure goals (JAMA 2002;288:2421-2431).
For the AASK Cohort Study, trial participants who had not reached end-stage renal disease (ESRD) were enrolled to receive recommended antihypertensive treatment to a blood pressure goal of less than 130/80 mmHg.
Data from the new genotyping study, which were presented by Wen Hong Linda Kao, PhD, MHS, come from this cohort phase. The researchers looked at seven genetic variants in these two genes: four single nucleotide polymorphisms (SNPs) in MYH9, two SNPs in APOL1, and a six-base-pair deletion in APOL1.
Single nucleotide polymorphisms are the most common type of genetic variation in people, with each representing a difference in a single DNA building block, or nucleotide, according to the National Library of Medicine (NLM). A deletion changes the number of DNA bases by removing a piece of DNA, the NLM notes.
Instead of looking at the seven variants individually, the researchers examined them in combination, as haplotypes. People have two haplotypes, one from their mother and one from their father.
This strategy led to the analysis of three different at-risk haplotypes:
* The G1 haplotype, which is found in individuals who have the at-risk variant for the APOL1 SNPs but the low-risk variant for the APOL1 insertion-deletion and either variant for the MYH9 SNPs.
* The G2 haplotype, which is found in individuals who have the at-risk variant for the APOL1 insertion-deletion, the low-risk variant for the APOL1 SNPs, and either variant for the MYH9 SNPs.
* The E1 haplotype, which is found in individuals who have the at-risk variant for the MYH9 SNPs but the low-risk variants for the APOL1 SNPs and for the insertion-deletion.
2.60 Times the Risk
Of the 664 AASK participants included in this analysis, 79 had two copies of the low-risk haplotype, meaning they had low-risk variants at G1, G2, and E1. Of these 79 participants, 21% developed end-stage renal disease.
Among individuals who had one copy of the G1 haplotype, 24% developed ESRD. For those with two copies, 47% developed the condition.
In terms of the G2 haplotype, one copy came with a 23% risk of developing ESRD, and two copies with a 47% risk.
And for the E1 haplotype, 21% of individuals with one copy progressed to ESRD, versus 26% with two copies.
“We found that each of these adds some higher risk,” Dr. Astor said. “It's hard to separate out exactly which one is causing that higher risk because they are sort of linked—they're close on the chromosome—so we can't separate them out completely, but we did find that each of them adds some risk of kidney failure in this population.”
In terms of relative hazard for end-stage renal disease, participants with one copy of any of the at-risk haplotypes were only at a slightly higher risk for ESRD, Dr. Kao said during the presentation. “It's essentially not different from one.”
Individuals with two copies of the G1 haplotype, though, were 2.60 times more likely to develop ESRD, and those with two copies of the G2 haplotype were 2.43 times more likely to progress to the condition.
The relationship between the E1 haplotype and ESRD was not statistically significant, with a 1.41-times increased risk for those with two copies of that haplotype, Dr. Kao said. However, among patients with baseline proteinuria, those with two copies of the E1 haplotype were four times more likely to develop ESRD than those with the protective haplotype.
“These results should be taken with these limitations in mind: First, individuals included in the present study had well-controlled hypertension, so we're unable to assess the impact of adequacy of blood-pressure control on the effect of genetic variants on kidney disease progression,” Dr. Kao said.
“More importantly, despite this being a fairly large study, it still is limited in sample size considering all the haplotypes that we're looking at.”
The data point to areas for further work, she added.
“It remains unknown whether better blood-pressure control can overcome the effect of genetic factors on the risk of ESRD in the population, and that potential interaction between these genetic variants and proteinuria should be explored.”
More research is needed, Dr. Astor agreed.
“First, similar studies need to be done in other populations or even larger populations,” he said. If the results hold up in other populations, the next steps are twofold, he added.
“We need to understand what these gene products do and understand the pathophysiology. We have some idea of the proteins MYH9 and APOL1 produce and how they're involved in the disease and the disease process, but we need to understand more of that.
“Then on the more clinically applied side, if we do find that these genes are associated, the next step is what we can do about it. We can't change the genes, but we can try to intervene on the other risk factors, and again that's going to take a lot of research—whether we can control blood pressure better if that will help, if we can control their diabetes better whether that will help—and at least bring down the baseline risk.
“The other thing is if we can understand the pathway, maybe there are specific interventions that can affect that pathway. That's projecting many years down the road, and that gets into personalized medicine—if you understand the specific pathway you can have a more targeted intervention—but that's beyond the scope of this.”