Association of single nucleotide polymorphism (rs741301) of the ELMO1 gene with diabetic kidney disease in Polish patients with type 2 diabetes: a pilot study

Introduction: Multifactorial pathogenesis of diabetic kidney disease (DKD) consists of a combination of metabolic, environmental, and genetic factors. A genome-wide association study has shown that ELMO1 is a candidate gene for DKD occurrence and progression. The aim of this study was to assess the association of a single nucleotide polymorphism (rs741301) of the ELMO1 gene with DKD in Polish patients with type 2 diabetes (T2DM). Material and methods: This was a case/control study of 272 T2DM patients with or without DKD. Patients were divided into groups depending on DKD definition according to the American Diabetes Association (ADA) and the National Kidney Foundation (NKF). The association of the rs741301 polymorphism with DKD was assessed in the whole study group as well as in the subgroups stratified according to the presence of DKD. Results: There was no association between rs741301 polymorphisms and the presence of DKD in relation to the ADA definition (p = 0.6) or the NKF definition (p = 0.5) of DKD and with estimated glomelural filtration rate (eGFR) value reflecting the stage of the chronic kidney disease (p = 0.8). Conclusions: Even though the results of this study are negative, there is still a great need for larger studies assessing the genetic susceptibility to DKD to identify patients who are particularly prone to this complication

Brak związku między polimorfi zmami pojedynczego nukleotydu genów CPA4, LEP oraz AKR1B1 zlokalizowanych na długim ramieniu chromosomu 7 (7q31-q35) a występowaniem i progresją przewlekłej choroby nerek

BACKGROUND The aim of the study was to investigate the infl uence of single nucleotide polymorphisms (SNPs) of carboxypeptidase A4, CPA4, leptin, LEP and aldo-keto reductase family 1, AKR1B1 genes located at the long arm of chromosome 7 (7q31-q35) on development and progression of chronic kidney disease (CKD). MATERIAL AND METHODS There was an association study by PCR-RFLP method of following SNPs in parent-off spring trios performed: G934T of CPA4 gene, A19G of LEP gene and C-106T of AKR1B gene. 471 subjects, 157 patients with CKD and 314 their biological parents were examined. The patients were divided into 3 groups: diabetic nephropathy due to type 1 diabetes (n = 34), chronic primary glomerulonephritis (n = 70) and chronic inter- stitial nephritis (n = 53). The mode of alleles transmission was determined using the transmission disequilibrium test (TDT). RESULTS There was no association of studied SNPs and CKD occurrence or pro- gression rate of renal function loss. Transmission of alleles of investigated SNPs did not diff er signifi cantly: G934T of CPA4 gene: P = 0.61 in whole group of CKD patients, p = 0.66 in GN group, p = 0.70 – IN group and p = 0.61 in DN one; A19G of LEP gene: p = 0.58, 0.71, 0.78 and 0.49, respectively; C-106T of ALDR1 gene: p = 0.31, 0.47, 0.12 and 0.38, respectively. No impact of examined polymorphisms on the rate of progression of renal function loss was observed. CONCLUSIONS The results, obtained in the study, suggest that the investigated SNPs: G934T of CPA4 gene, A19G of LEP gene and C-106T of AKR1B gene may not play a major role in the development and progression of chronic nephropathies.WSTĘP Celem badań było zbadanie wpływu polimorfi zmów pojedynczego nukleotydu (SNPs) genów karboksypepsydazy A4, CPA4, leptyny, LEP i reduktazy aldozy, AKR1B1, znajdujących się na długim ramieniu chromosomu 7 (7q31-q35) na rozwój i progresję przewlekłej choroby nerek (PChN). MATERIAŁ I METODY Wykorzystując metodę PCR-RFLP przebadano następujące polimorfizmy: G934T CPA4 genu, A19G LEP i C-106T genu AKR1B. Badaniami objęto 471 osoby: 157 z PChN i 314 ich biologicznych rodziców. Pacjentów podzielono na 3 grupy: z nefropatią cukrzycową w przebiegu cukrzycy typu 1 (DN, n = 34), z przewlekłym pierwotnym kłębuszkowym zapaleniem nerek (GN, n = 70) oraz z przewlekłym śródmiąższowym zapaleniem nerek (IN, n = 53). Tryb przekazywania alleli został oceniony testem nierównowagi przekazywania (Transmission-Disequilibrium Test, TDT). WYNIKI Częstość przekazywania alleli analizowanych SNPs nie odbiegała znacząco od oczekiwanej: G934T CPA4: p = 0,61 w całej grupie badanej, p = 0,66 w grupie GN, p = 0,70 – w grupie IN oraz p = 0,61 w grupie DN; A19G LEP: p = 0,58; 0,71; 0,78 i 0,49, odpowiednio; C-106T genu ALDR1: p = 0,31; 0,47; 0,12 i 0,38, odpowiednio. Nie zaobserwowano żadnego wpływu badanych polimorfi zmów na szybkość utraty funkcji nerek. WNIOSKI Uzyskane w badaniu wyniki wskazują, że badane SNPs: G934T genu CPA4, A19G LEP i C-106T genu AKR1B nie odgrywają istotnej roli w rozwoju i progresji przewlekłych nefropatii

Wpływ polimorfizmu rs 1617640 promotora genu erytropoetyny na występowanie i progresję przewlekłej choroby nerek; badania rodzinne

INTRODUCTION The aetiology of chronic kidney disease (CKD) and its progression are multifactorial in nature. A number of reports have demonstrated the nonhaematological local protective properties of erythropoietin in diff erent tissues, including those in the kidneys. The primary goal of the reported, family-based study was to assess the influence of rs 1617640 erythropoietin gene promoter polymorphism on the incidence and progression of CKD. MATERIAL AND METHODS For that purpose, 109 patients with CKD (72.5% with chronic interstitial nephritis and 27.5% with chronic glomerulonephritis) and their parents were examined. At the time of the study, the mean glomerular filtration rate was 28.2 ml/min and 53.2% patients were maintained on renal replacement therapy. Fluorescence labelled probes of the TaqMan Pre-designed SNP Genotyping Assay (Applied Biosystems Company) were used for rs1617640 polymorphism investigation. RESULTS The genome distribution of rs 1617640 polymorphism of the erythropoietin gene promoter was: 48.6% AC, 25.7% AA and 25.7% CC patients. Based on Transmission Disequilibrium Test results, the bordeline statistical significance of preferential C allele transfer from parents to their affected children with glomerulonephritis was observed. CONCLUSIONS No influence of rs 1617640 promoter polymorphism of the erythropoietin gene on the incidence of CKD in the course of chronic interstitial nephritis was observed. The bordeline signifi cance of preferential C allele transfer in patients with glomerulonephritis suggests association between rs1617640 and CKD of this aethiology.WSTĘP Etiologia przewlekłego uszkodzenia nerek oraz jego progresji jest wieloczynnikowa. Prace ostatnich lat dowodzą znaczenia pozaszpikowego miejscowego działania ochronnego erytropoetyny w wielu tkankach, w tym także w nerkach. Celem pracy była ocena w modelu rodzinnym wpływu polimorfizmu rs1617640 promotora genu dla erytropoetyny na rozwój i progresję przewlekłej choroby nerek. MATERIAŁ I METODY Badania przeprowadzono w grupie 109 chorych na przewlekłą chorobę nerek w przebiegu przewlekłego śródmiąższowego zapalenia nerek (72,5%) i przewlekłego kłębuszkowego zapalenia nerek (27,5%) oraz u 218 ich biologicznych rodziców. W momencie prowadzenia badania średnia filtracja kłębuszkowa (GFR) wynosiła 28,2 ml/min, a 53,2% chorych było leczonych nerkozastępczo. Genotypowanie polimorfizmu rs1617640 w promotorze genu erytropoetyny wykonano, wykorzystując znakowane fluorescencyjnie sondy z zestawu TaqMan Pre-designed SNP Genotyping Assay firmy Applied Biosystems. WYNIKI Analizując rozkład genotypów badanego polimorfizmu, stwierdzono: u 48,6% chorych genotyp AC, a u pozostałych chorych w równym procencie (po 25,7%) genotyp AA i CC. W teście TDT (Transmission Disequilibrium Test) wykazano na granicy istotności statystycznej przekazywanie preferencyjne allelu C w grupie chorych z przewlekłym kłębuszkowym zapaleniem nerek. WNIOSKI Nie obserwowano wpływu polimorfizmu rs1617640 genu promotora dla erytropoetyny na występowanie przewlekłego uszkodzenia nerek w przebiegu przewlekłego środmiąższowego zapalenia nerek. Stwierdzone na granicy istotności statystycznej, preferencyjne przekazywanie allelu C w grupie chorych na przewlekłe kłębuszkowe zapalenie nerek, sugeruje związek rs1617640 z przewlekłą chorobą nerek o tej etiologii

Związek polimorfizmu rs 3807337 genu CALD1 z nefropatią cukrzycową w przebiegu cukrzycy typu 1 — wstępne wyniki badania rodzin

  Introduction: The worldwide growing burden of diabetes and end-stage renal disease due to diabetic nephropathy has become the reason for research looking for a single marker of chronic kidney disease development and progression that can be found in the early stages of the disease, when preventive action delaying the destructive process could be performed. The aim of the study was to investigate the influence of rs3807337 polymorphism of the caldesmon 1 (CALD1) gene located on the long arm of chromosome 7 encoding for protein that is connected with physiological kidney function on development of diabetic nephropathy. Material and methods: There was an association study of rs3807337 polymorphism of the CALD1 gene in parent-offspring trios by PCRRFLP method. Ninety-nine subjects: 33 patients with diabetic nephropathy due to type 1 diabetes and 66 of their biological parents, were examined. The mode of alleles transmission from heterozygous parents to affected offspring was determined using the transmission disequilibrium test. Results: The allele G of rs3807337 polymorphism of the CALD1 gene was transmitted to affected offspring significantly more often than expected for no association. Conclusions: The obtained results suggest that the genetic variability of the CALD1 gene may influence the development of diabetic nephropathy in type 1 diabetes, but further studies involving larger studied groups of patients are needed. (Endokrynol Pol 2017; 68 (1): 13–17)    Wstęp: Znaczne rozpowszechnienie występowania cukrzycy i schyłkowej niewydolności nerek na tle cukrzycy na całym świecie sprawia, że poszukuje się obecnie pojedynczego markera rozwoju i progresji przewlekłej choroby nerek, który mógłby być wykrywany na wczesnych etapach choroby, gdy możliwe byłoby jeszcze podjęcie działań prewencyjnych w celu opóźnienia destrukcyjnego procesu chorobowego. Celem badania było sprawdzenie czy istnieje związek polimorfizmu rs3807337 genu kaldesmonu 1 (CALD1) zlokalizowanego na ramieniu długim chromosomu 7, który koduje białko związane fizjologicznie z funkcją nerek, z rozwojem nefropatii cukrzycowej. Materiał i metody: Przeprowadzono badanie związku polimorfizmu rs3807337 genu CALD1 w układzie rodzice–dziecko przy użyciu metody PCR-RFLP. Przebadano 99 osób w tym 33 pacjentów chorujących na nefropatie cukrzycową w przebiegu cukrzycy typu 1 i 66 ich biologicznych rodziców. W celu oceny sposobu przekazywania alleli od heterozygotycznego rodzica do dotkniętego chorobą dziecka wykorzystano test nierównowagi transmisji (TDT, transmission disequilibrium test). Wyniki: Allel G polimorfizmu rs3807337 genu CALD1 był przekazywany chorym dzieciom istotnie częściej niż w przypadku braku związku. Wnioski: Uzyskane wyniki sugerują, że zmienność genetyczna genu CALD1 może wywierać wpływ na rozwój nefropatii cukrzycowej w przebiegu cukrzycy typu 1, ale niezbędne są dalsze badania na większej populacji osób. (Endokrynol Pol 2017; 68 (1): 13–17)

Genotypes of renin-angiotensin system and plasma adiponectin concentration in kidney transplant patients

Background: Low plasma adiponectin concentration was recently recognized as a novel risk factor for new-onset diabetes after transplantation. Pharmacological modulation of the renin-angiotensin system activity and genetic predisposition were shown to have an influence on plasma adiponectin level. Therefore the aim of this study is to analyze the association between angiotensin-converting enzyme (ACE) I/D, angiotensin II type 1 receptor (AT 1 R) A1166C and angiotensinogen (AGT) M235T genotypes and plasma adiponectin concentration as well as insulin resistance in a cohort of kidney transplant patients. Material/Methods: AGT M235T, ACE I/D and AT 1 R A1166C genotyping and plasma adiponectin and insulin concentrations assessment were performed in 372 patients with functioning kidney allograft (eGFR >20 ml/min/1.73 m(2)) from 2 transplant centres. Results: Females with II ACE I/D genotype had a significantly higher plasma adiponectin concentration than the ID+DD subgroup, which could partially be explained by a lower BMI in the II subgroup. Males with TT genotype of the AGT M235T gene polymorphism (and higher BMI) had higher plasma concentration of insulin and HOMA-IR values than those in the MT+MM subgroup. A multiple regression analysis revealed that only female sex (beta=0.239), BMI (beta=-0.208) and ACE II genotype (beta=0.129) were significantly associated with plasma adiponectin concentration variability. A similar analysis for HOMA-IR showed that its variability was associated with BMI (beta=0.333), eGFR (beta=-0.115) and plasma adiponectin concentration (beta=-0.064) irrespective of any of the analyzed genotypes. Conclusions: Plasma adiponectin concentration, but not insulin resistance, seems to be modulated only by ACE I/D polymorphism in kidney transplant patients. Polymorphisms of the other renin-angiotensin system components do not influence plasma adiponectin concentration or insulin resistance in these patients

Association of CX3CR1 Gene Polymorphisms with Fractalkine, Fractalkine Receptor, and C-Reactive Protein Levels in Patients with Kidney Failure

Fractalkine (CX3CL1) is a chemokine that plays a significant role in inflammation, one of the pathophysiological processes underlying end-stage renal disease (ESRD). Genetic factors are significantly involved in cytokine expression and have been studied as potential risk factors for chronic kidney disease (CKD). Objectives: We aimed to elucidate the association of CX3CR1 gene polymorphisms rs3732378 and rs3732379 with the levels of CX3CL1, CX3CL1 receptor (CX3CR1), as well as C-reactive protein (CRP). Patients and methods: We enrolled 198 participants, including 106 patients with ESRD and 92 controls. Peripheral blood samples were collected from each patient for genetic (rs3732378 and rs3732379 polymorphisms) and immunoenzymatic (fractalkine, CX3CR1, CRP) tests. Results: CX3CR1 and CRP levels were higher in patients with ESRD than in controls (p < 0.05). Fractalkine levels were significantly higher in ESRD patients who were homozygous for the G allele of the rs3732378 polymorphism and for the C allele of the rs3732379 polymorphism than in homozygous controls. Moreover, carriers of these alleles among patients with ESRD had significantly higher CX3CR1 levels than controls. Conclusions: The G allele of the rs3732378 polymorphism and the C allele of the rs3732379 polymorphism of the CX3CR1 gene are associated with higher CX3CL1 and CX3CR1 levels. Our study suggests that CX3CR1 gene polymorphisms could be potentially involved in the pathogenesis of ESRD, but the study needs to be replicated in a larger population with a longitudinal follow-up study. Identification of genetic factors associated with inflammation in ESRD may contribute to the development of targeted gene therapies in the future

Association of chemotactic cytokine receptor 5 (CCR5) gene polymorphism (59029 A/G, rs1799987) with diabetic kidney disease in patients with type 2 diabetes from Poland

Introduction: Diabetic kidney disease (DKD) pathogenesis is multifactorial and is a combination of metabolic, genetic, and environmental factors. Due to a long period of asymptomatic course, it is often diagnosed late when advanced stages of the disease are present. Among patients with diabetes, the presence of chemotactic cytokine receptor 5 (CCR5) gene polymorphism is suspected to be associated with the risk of DKD occurrence; however, the results of the research conducted so far are inconclusive. The aim of this study was to evaluate the CCR5 gene polymorphism (rs1799987, 59029 A/G) association with DKD among patients with type 2 diabetes mellitus (T2DM), who are residents of the Upper Silesia region of Poland. Material and methods: CCR5 gene polymorphism (rs1799987, 59029 A/G) was assessed among consecutive patients with type 2 diabetes mellitus (T2DM) treated in a single outpatient diabetology clinic in Upper Silesia, Poland. Its association with DKD was examined. Additionally, selected clinical and demographic data were included in the analysis. Results: Among 467 eligible study patients, there was no association between examined CCR5 gene polymorphism and the presence of DKD in relation both to the American Diabetes Association definition (p = 0.6) and to the National Kidney Foundation definition (p = 0.3) of this complication. Conclusion: The presented study did not confirm the association between the examined gene polymorphism and the risk of DKD; further studies in this area are needed in order to establish or explicitly exclude this association.

Selected microRNA Expression and Protein Regulator Secretion by Adipose Tissue-Derived Mesenchymal Stem Cells and Metabolic Syndrome

The role of adipose mesenchymal stem cells (Ad-MSCs) in metabolic syndrome remains unclear. We aimed to assess the expression of selected microRNAs in Ad-MSCs of non-diabetic adults in relation to Ad-MSC secretion of protein regulators and basic metabolic parameters. Ten obese, eight overweight, and five normal weight subjects were enrolled: 19 females and 4 males; aged 43.0 ± 8.9 years. Ad-MSCs were harvested from abdominal subcutaneous fat. Ad-MSC cellular expressions of four microRNAs (2−ΔCt values) and concentrations of IL-6, IL-10, VEGF, and IGF-1 in the Ad-MSC-conditioned medium were assessed. The expressions of miR-21, miR-122, or miR-192 did not correlate with clinical parameters (age, sex, BMI, visceral fat, HOMA-IR, fasting glycemia, HbA1c, serum lipids, CRP, and eGFR). Conversely, the expression of miR-155 was lowest in obese subjects (3.69 ± 2.67 × 10−3 vs. 7.07 ± 4.42 × 10−3 in overweight and 10.25 ± 7.05 × 10−3 in normal weight ones, p = 0.04). The expression of miR-155 correlated inversely with BMI (sex-adjusted r = −0.64; p p = 0.03), and serum CRP (r = −0.63; p p = 0.02). Moreover, miR-155 synthesis was associated marginally negatively with Ad-MSC secretion of IGF-1 (r = −0.42; p = 0.05), and positively with that of IL-10 (r = 0.40; p = 0.06). Ad-MSC expression of miR-155 appears blunted in visceral obesity, which correlates with Ad-MSC IGF-1 hypersecretion and IL-10 hyposecretion, systemic microinflammation, and HDL dyslipidemia. Ad-MSC studies in metabolic syndrome should focus on miR-155