Association of genetic variants in uromodulin with blood pressure responses to dietary salt and potassium intake / 西安交通大学学报(医学版)

【Objective】 Based on our previously established salt-sensitive hypertension cohort, we aimed to examine the association of genetic variants in uromodulin with blood pressure(BP) responses to dietary interventions of sodium and potassium intake. 【Methods】 In 2004, 514 subjects from 124 families in Mei County, Shaanxi Province, were recruited to establish the salt-sensitive hypertension study cohort. Among them, 333 non-parent subjects were selected and sequentially maintained on a normal-diet for 3 days, low-salt diet for 7 days, then a high-salt diet for 7 days and a high-salt diet with potassium supplementation for another 7 days. Thirteen single nucleotide polymorphisms(SNPs) in the uromodulin gene were genotyped on the MassARRAY platform. 【Results】 BP levels decreased from the baseline to low-salt diet, increased from low-salt to high-salt diet, and decreased again from the high-salt diet to the high-salt plus potassium supplementation intervention. SNPs rs77875418 and rs4997081 of the uromodulin gene were significantly associated with diastolic BP(DBP) and mean arterial pressure(MAP) responses to high-salt diet. In addition, SNPs rs77875418, rs79245268, rs4293393, rs6497476, rs4997081, rs13333226, and rs12917707 were significantly associated with systolic BP(SBP), DBP, and MAP responses to high-salt diet with potassium supplementation. 【Conclusion】 Genetic variants in uromodulin gene are significantly associated with BP responses to sodium and potassium supplementation, suggesting that uromodulin may be mechanistically involved in BP sodium-sensitivity and potassium-sensitivity.

Uromodulin- Glycated Hemoglobin Ratio Plays The Trump In Diabetic Nephropathy Detection- A Case Control Study

Background:To investigate urine uromodulin as a marker for Diabetic nephropathy (DN) and its relation with glycaemic control.Material &Methods:a cross-sectional comparative study on 180 healthy controls (Group I), 205 patients of Diabetes Mellitus were classified as Group II without microalbuminuria and those with microalbuminuria as Group III.Urineuromodulin, albumin and creatinine was estimated along with routine biochemistry.Results:The FBS, PPBS, HbA1c and serum creatinine were lowest in Group I as compared to groups II and III (p < 0.01, <0.01, <0.01, 0.008 respectively). There was no difference in urine uromodulin levels among the three groups (p= 0.609) but the Uromodulin HbA1cRatio (UHR) showed a significant difference (p <0.01). UHR showed a statistically significant negative correlation with FBS, PPBS, HbA1c and urine (p= <0.01, <0.01, <0.01 and 0.004 respectively). The Odds of having DN with UHR > 8.6 was 0.49 (95% CI is 0.308-0.78).Conclusion:The non-occurrence of a diabetic complication that is nephropathy in our studygroup is favourable to those diabetic patients with a higher UHR (>8.6). Estimation of urine uromodulin will be beneficial along with albuminuria in detecting DN.

Clinical and Biochemical Association between Single-Nucleotide Polymorphism of the Uromodulin Gene and Albuminuria in Patients with Type-2 Diabetes Mellitus

Objective: This study aimed to investigate the association of single nucleotide polymorphism (SNP) of UMOD gene (three SNP at promoter region; rs13333226, rs12917707, and rs4293393) with albuminuria and other renal function biomarkers in patients with type-2 diabetes mellitus. Methods: A case-control study design was employed to enroll 120 subjects, where 30 healthy subjects (as control group), 30 diabetic patients with normo-albuminuria (as first case group), 30 diabetic patients with microalbuminuria (as second case group) and 30 diabetic patients with macroalbuminuria (as third case group) were involved. Blood and urine samples were collected from the patients during their visits to diabetic clinics. Age, gender and BMI were taken for each participant. Fasting serum glucose (FSG), serum creatinine and blood urea were measured by a spectrophotometer, serum cystatin-c by ELISA technique, HbA1c was measured by the CLOVER A1c system, urinary albumin was measured by turbidimetric end-point method, (UACR) urinary albumin creatinine ratio were estimated, eGFR was also calculated. A whole blood sample was used for DNA extraction, finally, real time PCR technique was used for the determination of SNP genotype. Results: The results showed that the G minor allele of rs13333226 has a protective factor in patients with albuminuria. Also, the common variant AA of rs13333226 genotype was associated with a reduction in GFR. For the rs12917707 the common variant GG was associated with the development of albuminuria in diabetic patients and with the reduction in GFR. Finally, the frequency of (rs4293393) CC genotype was common and associated with the development of albuminuria in diabetic patients when compared with healthy controls. Conclusions: SNP in the regulatory region of the UMOD gene has a role in the protection from albuminuria in diabetes mellitus patients.

Identification of a novel UMOD mutation (c. 163G>A) in a Brazilian family with autosomal dominant tubulointerstitial kidney disease

Autosomal dominant tubulointerstitial kidney disease (ADTKD) is characterized by autosomal dominant inheritance, progressive chronic kidney disease, and a bland urinary sediment. ADTKD is most commonly caused by mutations in the UMOD gene encoding uromodulin (ADTKD-UMOD). We herein report the first confirmed case of a multi-generational Brazilian family with ADTKD-UMOD, caused by a novel heterozygous mutation (c.163G>A, GGC→AGC, p.Gly55Ser) in the UMOD gene. Of 41 family members, 22 underwent genetic analysis, with 11 individuals found to have this mutation. Three affected individuals underwent hemodialysis, one peritoneal dialysis, and one patient received a kidney transplant from a family member later found to be genetically affected. Several younger individuals affected with the mutation were also identified. Clinical characteristics included a bland urinary sediment in all tested individuals and a kidney biopsy in one individual showing tubulointerstitial fibrosis. Unlike most other reported families with ADTKD-UMOD, neither gout nor hyperuricemia was found in affected individuals. In summary, we report a novel UMOD mutation in a Brazilian family with 11 affected members, and we discuss the importance of performing genetic testing in families with inherited kidney disease of unknown cause.

Association of uromodulin gene polymorphism with diabetic kidney disease in Han population in Tianjin of China / 中华肾脏病杂志

Objective To investigate the association of single nucleotide polymorphism (SNP) rs13333226 in uromodulin (UMOD) gene with diabetic kidney diseases (DKD) in Han population in Tianjin,China.Methods A total of 210 type 2 diabetes (T2DM),90 normal controls (NC) and 280 DKD patients were recruited.According to the level of estimated glomerular filtration rate (eGFR),the DKD subjects were further subdivided into three groups:GFR≥90 ml/min group (n=105),60 ml/mim≤GFR ＜ 90 ml/min group (n=84) and GFR ＜ 60 ml/min group (n=91).Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used for UMOD rs13333226C genotyping.Results The frequencies of AA,GA,GG genotype were 27.8％,58.9％,13.3％ in NC group and 41.0％,48.6％,10.5％ in T2DM group and 54.3％,36.1％,9.6％ in DKD group.The frequency of G allele was 42.8％ in NC group,34.8％ in T2DM group and 27.7％ in DKD group.The genotype distribution of UMOD was statistically significant between NC group and DKD group,and between T2DM group and DKD group (P ＜ 0.05).G allele of UMOD was an independent protective gene polymorphism of DKD in Logistic regression (B=-0.248,Wald=8.012,P=0.021,OR=0.780,95％ CI 0.612-0.968).Conclusion The G allele of UMOD gene may be an independent protective factor of DKD in Han population in Tianjin,China.

Familial Juvenile Hyperuricemic Nephropathy and Uromodulin Gene Mutation

Familial Juvenile hyperuricemic nephropathy (FJHN) is a rare autosomal dominant disorder, characterized by early onset of hyperuricemia, gout and progressive kidney disease. Hyperuricemia prior to renal impairment and decreased fractional excretion of uric acid are hallmarks of FJHN. Renal dysfunction gradually appears early in life and results in end-stage renal disease usually between the ages of 20 and 70 years. FJHN is mostly caused by mutations in the uromodulin gene located at 16p12. The course of FJHN is highly variable. Treatment includes management for hyperuricemia, gout and progressive kidney disease. Individuals with gout have been usually treated with allopurinol. But controversy exists as to whether uric acid lowering therapy prevents the progression of chronic kidney disease.

A Novel UMOD Mutation (c.187T>C) in a Korean Family with Juvenile Hyperuricemic Nephropathy

Familial juvenile hyperuricemic nephropathy (FJHN; OMIM 162000) is an autosomal dominant disorder characterized by hyperuricemia and gouty arthritis due to reduced kidney excretion of uric acid and progressive renal failure. Gradual progressive interstitial renal disease, with basement membrane thickening and glomerulosclerosis resulting from fibrosis, starts in early life. In most cases of FJHN, uromodulin gene (UMOD) is responsible for the disease; however, there has been only one report of a genetically confirmed FJHN family in Korea. Here we report another Korean family with FJHN, in which three male members. a father and 2 sons.developed gout and progressive renal insufficiency. The clinical, laboratory, and radiological findings were consistent with FJHN, and renal biopsy showed chronic parenchymal damage, which can be found in FJHN but is not specific to this disease. In order to confirm the diagnosis, sequence analysis of the UMOD was performed, and a novel heterozygous missense variant (c.187T>C; p.Cys63Arg) in exon 3 was identified. We assume that this variant is likely to be the causative mutation in this family, as the variant segregated with the disease. In addition, approximately two-thirds of the known mutations lead to a cysteine amino acid change in uromodulin, and all such variants have been shown to cause UMOD-associated kidney disease. In summary, we report a Korean FJHN family with three affected members by genetic analysis of the UMOD, and provide the first report of a novel heterozygous missense mutation.