Common variant in umod gene promoter is associated with elevated annualized rate of decline in egfr and rapid deterioration of kidney function in type 2 diabetes

Abstract

Genome-wide association studies have identified three genetic variants associated with both estimated glomerular filtration rate (eGFR) in population based cohorts and diabetic kidney disease- UMOD (rs12917707), PRKAG2 (rs7805747), MYH9 (rs4821480). It is important to understand whether these variants predict decline in eGFR and rapid deterioration of renal function in T2D. We used longitudinal eGFR data from a nationwide clinical diabetes database (SCIDC) for 2985 unrelated people genotyped in the GoDARTs study. The median observation period was 10.6 (IQR) 8.7-12.3) years with a median 3 (IQR 2-4) eGFR readings/year/person. We calculated within-person annualised percent change in eGFR for the whole follow-up period and report its association with the 3 SNPs using a logistic regression model adjusting for age, sex, and body mass index (BMI) and duration of follow-up. To study the association with rapid decline we identified a subgroup of cases (n=257) with a 50% drop in the eGFR, and controls (n=322) with a stable eGFR in the entire follow-up period. Median follow-up was 2.6 (IQR 0.6-3.8) years in cases and 2.6 (IQR 0.8-3.4) Years in controls. For The SNP in the UMOD gene promoter region, rs12917707- the minor allele 'T' (MAF=16%) was associated with a 43% lower annualized percentage loss in eGFR (p= 0.009). In the subset logistic regression model, those with a copy of the 'T' allele were less likely to experience a 50% drop in eGFR compared to those with a 'G' allele (OR= 0.63(0.41, 0.95) P = 0.029) after adjusting for diabetes onset age, sex, BMI, creatinine, systolic blood pressure and diabetes duration. Variants in PRKAG2 and MYH9 did not show these associations. This is the first report of an association of UMOD with annualized percentage change in eGFR and rapid deterioration of kidney function in a T2D population. Understanding the mechanisms relating UMOD and eGFR may lead to better screening and treatment of T2D disease.