COMMENTARY

Genetic Basis for End-Stage Renal Disease in Type 2 Diabetes

Lynda Szczech, MD

Disclosures

November 04, 2010

Genetic Variants of the Protein Kinase C-Beta 1 Gene in the Development of End-Stage Renal Disease Patients With Type 2 Diabetes

Ma RC, Tam CH, Wang Y, et al
JAMA. 2010;304:881-889

Study Background

According to observational data, populations of patients of differing races and other demographic parameters vary significantly in their level for risk for kidney disease progression. The predilection for kidney diseases among blacks, for example, may be attributed to the association between the increased risk for focal segmental glomerulosclerosis, HIV-associated nephropathy, and certain MYH9 alleles identified primarily in this racial group.[1,2]

Further, studies in blacks have found that variants of the APOL1 gene are also associated with kidney disease.[3] Of note, the protein coded for by this gene is involved in the body's defense against trypanosome parasites, which cause diseases, such as African sleeping sickness. The higher-risk MYH9 alleles and the variants of the APOL1 gene are found in limited frequency or not found in populations other than blacks, leading investigators to hypothesize that these genetic variants are only part of the mechanism for the higher risk seen in this population.

Study Summary

The study by Ma and colleagues continues the investigation of alleles and their relationship with kidney disease progression. The investigators were motivated by the epidemic of type 2 diabetes mellitus (T2DM) seen among adults in China. They cited a recent study estimating that more than 92 million adults have diabetes in China and another 150 million have prediabetes. Given that Asian patients are at higher risk for end-stage renal disease (ESRD) compared with whites, and that previous studies have suggested a strong genetic component to susceptibility to diabetic kidney disease, they initiated this analysis of 1338 unrelated patients with T2DM from a Hong Kong Diabetes Registry and validated it in an additional cohort of patients with T2DM who were recruited separately. Genotyping on 18 identified single-nucleotide polymorphisms (SNPs) was performed on all study participants with genomic DNA.

The investigators focused on protein kinase C-beta (PKC-beta). This molecule is involved in cell signaling and has been implicated in the vascular complications of diabetes. Randomized controlled trials of PKC-beta inhibitors demonstrate a reduced loss of glomerular filtration rate in patients with diabetes treated with these agents. Additionally, Japanese patients with T2DM who carry a specific SNP in the promoter region of PKC-beta are at an increased risk of declining kidney function.

Of the SNPs, 4 existed in the promoter region; 2 existed in the coding exons; and 6 existed in the noncoding intron region of PRKCB1. More than 1100 patients with T2DM were evaluated. Patients had a mean age of 56 years and a mean duration of diabetes of 8.5 years. During the period of observation, 90 patients progressed to develop ESRD at a mean follow-up of 7.9 years. The frequency of minor T and G alleles was different among patients with and without new ESRD. Adjusting for conventional factors that predicted the development of ESRD (sex, age, duration of diabetes, systolic and diastolic blood pressure, glycated hemoglobin [A1c], total cholesterol, triglycerides, estimated glomerular filtration rate, albumin excretion rate, retinopathy, and use of medications), the T allele at rs3760106 and G allele linked to SNP rs2575390 were both strongly associated with an increased risk for ESRD (hazard ratio [HR], 2.25; 95% confidence interval [CI], 1.31-3.87; P = .003 and HR, 2.26; 95% CI, 1.31-3.88; P = .003, respectively). Additionally observed was the hazard of ESRD associated with an increasing number of risk alleles. The risks for multiple alleles seemed to be independent of each other, not interacting or amplifying each other statistically.

The validation cohort was selected to include patients with early-onset disease (age at onset, < 45 years) who were free of chronic kidney disease (CKD) at baseline. In this cohort of 1049 patients, 14.3% developed CKD during the follow-up period. Note again that the T allele at rs3760106 and the G allele at rs2575390 were found to be statistically associated with the development of the CKD with HRs, respectively, of 1.68 (P = .02) and 1.62 (P = .02).

Viewpoint

As clinicians, our understanding of the usefulness of these genetic markers is important. Whereas autosomal dominant diseases may present the potential for early diagnosis of disease, the utility of genetic markers as identified in the study and those recently published may not carry the same application in the near future. Quite simply, in an autosomal dominant disease, such as polycystic kidney disease, the presence of the abnormal gene is necessary and sufficient to produce disease. However, as identified in this study, the presence of the high-risk alleles is neither necessary nor sufficient but only increases the likelihood of disease. Therefore, it is not likely that genetic screening for these alleles will play a key clinical role in the near future. Rather, the discovery of a gene that plays a role with key alleles can point to a role for that gene in the pathogenesis of diseases, such as diabetic nephropathy. Armed with this analysis, it is reasonable to look to PKC-beta in the pathogenesis of diabetic kidney disease and the potential for an inhibitor of PKC-beta to play a potential therapeutic role.

Abstract

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