Effect of a common UMOD variant on kidney function, blood pressure, cognitive and physical function in a community-based cohort of older adults

Abstract

In genome-wide association studies, genetic variants in the UMOD gene associate with kidney function, blood pressure (BP), and hypertension. Elevated BP is linked to kidney function and impaired cognitive as well as physical performance in later life. We investigated the association between UMOD rs4293393–A > G and kidney function, BP, cognitive and physical function in the Berlin Aging Study II (BASE–II). Data of 1556 older BASE–II participants (mean age 68.2 ± 3.7 years) were analyzed. BP was determined by standardized automated measurements, estimated glomerular filtration rate (eGFR) by CKD Epidemiology Collaboration creatinine equation. Cognitive function was assessed by Mini-Mental State Examination and Digit Symbol Substitution Test, while physical function by Handgrip Strength and Timed Up and Go-Test. Association analyses were performed by covariance and logistic regression models adjusting for sex. G–allele carriers at UMOD rs4293393 exhibited significantly higher eGFR values compared to non–carriers (AA, 76.4 ml/min/1.73 m², CI: 75.7–77.2 vs. AG, 78.4 ml/min/1.73 m², CI: 77.3–79.5 vs. GG, 78.5 ml/min/1.73 m², CI: 75.4–81.7; P = 0.010), and a lower risk of eGFR < 60 mL/min/1.73 m2 (AG, OR: 0.63, CI: 0.41–0.97, P = 0.033). However, UMOD rs4293393 genotypes were not associated with BP, diagnosis of hypertension or cognitive and physical function parameters. Our data corroborate previous findings on the association of UMOD rs4293393-G with better kidney function in older adults. However, no association between UMOD and BP or physical and cognitive parameters in these community-dwelling older adults was detected.

Longitudinal effects of a common UMOD variant on kidney function, blood pressure, cognitive and physical function in older women and men

“…In this cohort study, the association of the minor G-allele of rs4293393 with kidney function-related traits after follow-up was replicated as reported earlier for the baseline cohort [6]. Heterozygous G-allele carriers retained higher levels of eGFR and lower odds of impaired kidney function i.e., eGFR < 60 mL/min/ 1.73 m 2 with men showing significantly lower odds than women.…”

“…Genotype distribution for UMOD rs4293393 at follow-up (N = 1010) was similar to that at baseline (N = 1556) [6] with the genotype AA in 671 (66.4%), AG in 300 (29.7%) and GG in 39 (3.9%) participants which also shows a comparable minor allele frequency (MAF) of 18.7%.…”

“…We have previously reported on the association of rs4293393 in the promotor of the UMOD gene with kidney function-related traits but not with BP-, cognitive-or physical function-related traits in a cohort of community-dwelling older individuals [6]. In this study, we utilize follow-up data from older adults of the BASE-II cohort to evaluate the genetic association of the same UMOD variant with longitudinal changes in the same outcomes after up to 10 years follow-up and whether different effects could be discerned for aging men and women.…”

“…Uromodulin plays an important role in the regulation of renal tubule salt handling presumably through modulation of the apical Na-K-2Cl cotransporter (NKCC2) transporter activity and has been linked to both blood pressure (BP) regulation as well as kidney function. Genetic polymorphisms in the UMOD gene identified by genome-wide association studies [2,3] and animal models [4] have been consistently shown to associate with kidney function [5,6], risk of chronic kidney disease (CKD) [7] but also hypertension [8]. Uromodulin has even been proposed to be a possible target for BP control and a causal relationship between uromodulin and BP was recently suggested by mendelian randomization [9].…”

“…Recently, we reported on a cross-sectional analysis of a UMOD variant, a single nucleotide polymorphism rs4293393-A>G, in the noncoding region of the UMOD gene with BP, kidney function, as well as cognitive and physical function in 1556 participants of a community-based cohort: the Berlin Aging Study II [6]. Our original hypothesis was that UMOD variants associated with lower BP and/ or improved kidney function in midlife could have a positive impact on cognitive and physical abilities in older age.…”