Epistatic Role of the MYH9/APOL1 Region on Familial Hematuria Genes

Abstract

Familial hematuria (FH) is explained by at least four different genes (see below). About 50% of patients develop late proteinuria and chronic kidney disease (CKD). We hypothesized that MYH9/APOL1, two closely linked genes associated with CKD, may be associated with adverse progression in FH. Our study included 102 thin basement membrane nephropathy (TBMN) patients with three known COL4A3/COL4A4 mutations (cohort A), 83 CFHR5/C3 glomerulopathy patients (cohort B) with a single CFHR5 mutation and 15 Alport syndrome patients (cohort C) with two known COL4A5 mild mutations, who were categorized as “Mild” (controls) or “Severe” (cases), based on renal manifestations. E1 and S1 MYH9 haplotypes and variant rs11089788 were analyzed for association with disease phenotype. Evidence for association with “Severe” progression in CFHR5 nephropathy was found with MYH9 variant rs11089788 and was confirmed in an independent FH cohort, D (cumulative p value = 0.001, odds ratio = 3.06, recessive model). No association was found with APOL1 gene. Quantitative Real time PCR did not reveal any functional significance for the rs11089788 risk allele. Our results derive additional evidence supporting previous reports according to which MYH9 is an important gene per se, predisposing to CKD, suggesting its usefulness as a prognostic marker for young hematuric patients.

Digenic inheritance and genetic modifiers

“…Previous genome-wide association studies have identified variants in the MYH9 and its closely linked APOL1 gene to confer major susceptibility towards ESRD in various types of renal diseases. 20 In the same Cypriot CFHR5 nephropathy cohort, we presented evidence for yet another putative modifier. 21 Specifically, a variant in the target site of miR-1207-5p in the 3 0 UTR of HBEGF was associated with severity of disease.…”

“…Exploiting several cohorts of patients with familial hematuria as a common finding, we showed association of “Severe” disease in CFHR5 nephropathy (a form of C3 glomerulopathy) with MYH9 variant rs11089788 that we confirmed in an independent cohort. Previous genome‐wide association studies have identified variants in the MYH9 and its closely linked APOL1 gene to confer major susceptibility towards ESRD in various types of renal diseases …”

COL4A5 and LAMA5 variants co-inherited in familial hematuria: digenic inheritance or genetic modifier effect?

“…To date, these results have been verified by multiple groups [ 13 – 17 ]. The exact mechanisms for this adverse outcome remain unknown but the role of genetic modifiers has been implicated [ 18 – 22 ]. A significant feature of heterozygous COL4A mutations is the broad phenotypic heterogeneity, while the clinical outcome is at times better described as later-onset Alport-related nephropathy (LOAN) [ 23 ].…”

Effect of donor non-muscle myosin heavy chain (MYH9) gene polymorphisms on clinically relevant kidney allograft dysfunction

“…In previous studies, MYH9 variants have been shown to be predictive for kidney function in the general adult population [ 10 – 12 ] as well as in progression of primary [ 20 , 21 ] or secondary nephropathies [ 22 – 24 ]. Freedman et al were the first to denote potential MYH9 genotype impact on post-transplant FSGS relapse [ 25 ] while this study of ours investigates an association of MYH9 variants with eGFR and proteinuria in a setting of kidney transplantation.…”