Thus, we have independently confirmed the association between UMOD rs12917707 and ESRD in a large case-control study. It was of similar direction and magnitude as previously reported , and in a meta-analysis of our results and the cited data convincing statistical significance was reached.
We did not find an association between rs12917707 genotype and etiology of ESRD. This suggests a universal, non-specific effect of the SNP on renal function decline irrespectively of underlying primary disease. A previous study described interaction between UMOD variant rs4293393 (in perfect LD with rs12917707) and age . We, however, did not observe interaction with age or sex in our population.
Importantly, the observed relationship of the UMOD variant with ESRD in native kidneys did not translate into association with renal function loss in the transplanted kidney as we did not find an association between the donor rs12917707 and GF. Although the SNP effect on GF was direction-consistent with the case-control analysis and suggestive of a protective trend, the results were not statistically significant. It might indicate true absence of an association and differential involvement of UMOD in the pathophysiology of native and transplanted kidneys, or point to the fact that our longitudinal study was underpowered to detect the genetic effect due to the moderate sample size.
Remarkably, uromodulin urinary levels in patients after renal transplantation were associated with donor UMOD rs12917707 genotype. The subset of transplant recipients, in which urinary uromodulin was studied, was representative of the whole sample in terms of MAF and genotypes distribution. Uromodulin concentrations were significantly lower in recipient-carriers of the donor rs12917707 minor allele as compared to non-carriers. Thus, the genetic effect on uromodulin urinary level that was previously found in the native kidneys was reproduced in the transplanted kidneys, with similar direction of effect. This implies that it is indeed the UMOD genotype of the kidney that associates with uromodulin production.
Several arguments support the genetic analysis of a kidney transplant cohort. First, a case-control study with kidney donors, instead of the general population, as controls may have augmented statistical power to reveal the subtle genetic effects expected from common variants. Second, a transplant population provides the opportunity to study renal function loss in both native and transplanted kidneys through investigation of ESRD before and GF after transplantation. Finally, uniqueness and elegance of a transplantation setting is that it enables to test effects of both recipient and donor genotype on phenotype and thus discriminate between local (intra-renal) and systemic (extra-renal) processes.
The strengths of our study include the cohort’s size, its wide spectrum of underlying primary kidney disease and the specific design. However, some limitations deserve to be mentioned. Our longitudinal study may have been underpowered to detect significant SNP effect on GF. Power limitations also exist for the analysis of specific ESRD etiologies. Further, the analysis of the risk for ESRD is cross-sectional and needs to be confirmed by longitudinal studies studying incident ESRD. Unfortunately, the design and performance of such studies in CKD patients is challenging, and thus these are only emerging [22–24]. We did not have information on patients ethnicity, however, a reliable estimate for an average patient population in our region is that over 90% of the individuals are of European ancestry. Subsequently, our results are not generalizable to other ethnicities. Urinary uromodulin in renal transplant recipients was measured at different time points ranging from 1 to 9 years after transplantation. For those patients with presence of residual native kidney function, we cannot exclude a possible confounding effect of recipient rs12917707 genotype on urinary uromodulin concentration. However, this would have biased results to a null effect, while we have detected a significant association.
In summary, we have independently confirmed the association between genetic variation at the UMOD locus and ESRD. Also, donor kidney genotype was significantly associated with urinary uromodulin concentration in renal transplant recipients providing evidence that genetic make-up of the kidney determines this intermediate phenotype. Further research, including targeted sequencing of the region, bioinformatic analyses and functional experiments, is required to unravel the mechanisms by which common genetic variation at UMOD cause kidney disease.