A new potential mode of cardiorenal protection of KLOTHO gene variability in type 1 diabetic adolescents

Abstract

As the KL-VS haplotype alters secretion and activity of KLOTHO and uric acid (UA) is associated with endothelial dysfunction and inflammation, their mutual links may contribute to microalbuminuria (MA) in patients with type 1 diabetes (T1D). Therefore, we hypothesize that KL-VS polymorphism could be associated with the prevalence of MA in T1D patients, and KL-VS polymorphism could modify physiological functions and pathogenic potential of UA. We have examined 350 patients with T1D. The analysis concerned KL-VS polymorphism along with the concentrations of serum inflammatory markers, indicators of renal function, blood pressure, and lipid profile. The incidence of KL-VS genotype was lower in a group with MA in comparison to patients without this condition. Moreover, KL-VS carriers had improved indicators of renal function, lower concentrations of pro-inflammatory cytokines, and higher levels of anti-inflammatory markers. Simultaneously, among KL-VS carriers serum UA was negatively correlated with HbA1c, albumin excretion rate, ACR, CRP, TNF-α, total cholesterol, LDL-C and triglycerides, and positively correlated with HDL-C. Moreover, among wild-type KLOTHO carriers serum, UA was in positive correlation with creatinine, blood pressure, IL-12 and MCP-1, and in negative correlation with IL-10 and eGFR. Findings of our study suggest that the functional KL-VS polymorphism is independently associated with MA and the KL-VS genotype protects from the development of MA, and KL-VS polymorphism may modify physiological functions and pathogenic potential of UA by altering the levels of HbA1c, inflammatory biomarkers, indicators of renal function, blood pressure, and lipid profile. Key messages • We analyzed the KL-VS polymorphism and the UA serum level in patients with T1D. • The KL-VS polymorphism is independently associated with microalbuminuria. • The KL-VS alleles protect from the development of microalbuminuria. • KL-VS polymorphism may modify physiological functions and pathogenic potential of uric acid.

Identification of candidate biomarkers and pathways associated with type 1 diabetes mellitus using bioinformatics analysis

“…Furthermore, we investigated the biological functions of these DEGs by using online website, and GO and pathway enrichment analysis. Husemoen et al 51 , Zhang et al 52 , Hartz et al 53 , Słomiński et al 54 , Johansson et al 55 , Pan et al 56 , Lopez-Sanz et al 57 , Grant 58 , Słomiński et al 59 , Galán et al 60 , Jordan et al 61 , Winkler et al 62 , Yip et al 63 , Crookshank et al 64 , Lempainen et al 65 , Qu and Polychronakos 66 , Morrison et al 67 , Zhang et al 68 , Gerlinger-Romero et al 69 , Belanger et al 70 , Dieter et al 71 , Wanic et al 72 , Ushijima Wanic et al 73 , Guo et al 74 , Davis et al 75 , Elbarbary et al 76 , Villasenor et al 77 , Zhang et al 78 , Lee et al 79 , Zhi et al 80 , Li Calzi et al 81 , Sebastiani et al 82 , Cherney et al 83 , Doggrell 84 and Yanagihara et al 85 studied the clinical and prognostic values of FLG (filaggrin), FGF21, PEMT (phosphatidylethanolamine N -methyltransferase) KL (klotho), CEL (carboxyl ester lipase), FOSL2, STAT1, TCF7L2, TP53, EGFR (epidermal growth factor receptor), ETS1, KCNJ8, DEAF1, GCG (glucagon), IKZF4, OAS1, IRS1, ABCG2, FBXO32, PTBP1, BACH2, CNDP2, KLF11, MT1E, DPP4, SLC29A3, RGS16, MAS1, GCGR (glucagon receptor), HLA-C, VASP (vasodilator stimulated phosphoprotein), CCR2, PTGS2, GLP1R and JMJD6 in patients with T1DM. Vassilev et al 86 , Qin et al 87 , Ma et al 88 , West et al 89 , Hoffmann et al 90 , Deary et al 91 , Belangero et al 92 , Jung et al 93 , Tang et al 94 , Goodier et al 95 , Petyuk et al 96 , Roux et al 97 , Castrogiovanni et al…”

Identification of candidate biomarkers and pathways associated with type 1 diabetes mellitus using bioinformatics analysis

“…Furthermore, we investigated the biological functions of these DEGs by using online website, and GO and pathway enrichment analysis. Husemoen et al [52], Zhang et al [53], Hartz et al [54], Słomiń ki et al [55], Johansson et al [56], sPan et al [57], Lopez-Sanz et al [58], Grant, [59], Słomiń i et al [60], Galán et al sk [61], Jordan et al [62], Winkler et al [63], Yip et al [64], Crookshank et al [65], Lempainen et al [66], Qu and Polychronakos, [67], Morrison et al [68], Zhang et al [69], Gerlinger-Romero et al [70], Belanger et al [71], Dieter et al [72], Wanic et al [73], Ushijima Wanic et al [74], Guo et al [75], Davis et al [76], Elbarbary et al [77], Villasenor et al [78], Zhang et al [79], Lee et al [80], Zhi et al [81], Li Calzi et al [82], Sebastiani et al [83], Cherney et al [84], Doggrell, [85] and Yanagihara et al [86] found that FLG (filaggrin), FGF21, PEMT (phosphatidylethanolamine N-methyltransferase) KL (klotho), CEL (carboxyl ester lipase), FOSL2, STAT1, TCF7L2, TP53, EGFR (epidermal growth factor receptor), ETS1, KCNJ8, DEAF1, GCG (glucagon), IKZF4, OAS1, IRS1, ABCG2, FBXO32, PTBP1, BACH2, CNDP2, KLF11, MT1E, DPP4, SLC29A3, RGS16, MAS1, GCGR (glucagon receptor), HLA-C, VASP (vasodilator stimulated phosphoprotein), CCR2, PTGS2, GLP1R and JMJD6 are involved in the progression of T1DM. Vassilev et al [87], Qin et al [88], Ma et al [89], West et al [90], Hoffmann et al [91], Deary et al [92], Belangero et al [93], Jung et al [94], Tang et al [95], Goodier et al [96], Petyuk et al [97], Roux et al [98], Castrogiovanni et al [99], Suleiman et al [100], Haack et al [101], Kwiatkowski et al [102], Pinacho et al [103], Luo et al [104], He et al [105], Moudi et al [106], Thevenon et al [107], Li et al [108], Reitz et al [109], Jenkins and Escayg [110], Letronne et al [111], Ma et al [112<...>…”