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Association of the Q121 variant of ENPP1 gene with decreased kidney function among patients with type 2 diabetes.

ABSTRACT: Insulin resistance has a role in diabetic kidney complications. The K121Q (lysine to glutamine substitution at amino acid 121, encoded by single-nucleotide polymorphism rs1044498) variant of the ectonucleotide pyrophosphatase/phosphodiesterase gene (ENPP1) has been associated with insulin resistance and related vascular complications in patients with type 2 diabetes (T2D) in many, although not all, studies. This study investigated whether the ENPP1 Q121 variant modulates the risk of decreased glomerular filtration rate (GFR) in patients with T2D.Cross-sectional study.2 diabetes units from Italy (in Gargano and Padua) and 1 from the United States (Boston, MA) recruited a total of 1,392 patients with T2D.The ENPP1 Q121 variant.Estimated GFR from serum creatinine, urinary albumin excretion, blood pressure, hemoglobin A(1c), triglycerides, total cholesterol, and high-density lipoprotein cholesterol.Decreased GFRs (ie, estimated GFR <60 mL/min/1.73 m(2)).In the Gargano and Boston populations, according to the dominant model of inheritance, Q121 carriers (ie, individual with either KQ or QQ alleles) had an increased risk of decreased GFR: odds ratios (ORs) of 1.69 (95% confidence interval [CI], 1.1 to 2.6) and 1.50 (95% CI, 1.0 to 2.2), respectively. In the Padua set, the association was in the same direction, but did not reach formal statistical significance (OR, 1.77; 95% CI, 0.7 to 4.5). When the 3 studies were pooled, Q121 carriers showed an increased risk of decreased GFR (OR, 1.58; 95% CI, 1.2 to 2.1; P = 0.002). Also, pooled mean differences in absolute GFRs were different across genotype groups, with Q121 carriers showing lower GFRs compared with KK individuals (P = 0.04).P values not approaching a genome-wide level of significance.Our data suggest that patients with T2D carrying the ENPP1 Q121 variant are at increased risk of decreased GFR.

SUBMITTER: De Cosmo S

PROVIDER: S-EPMC2939986 | biostudies-literature | 2009 Feb

REPOSITORIES: biostudies-literature

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Association of the Q121 variant of ENPP1 gene with decreased kidney function among patients with type 2 diabetes.

De Cosmo Salvatore S Minenna Antonio A Zhang Yuan-Yuan YY Thompson Ryan R Miscio Giuseppe G Vedovato Monica M Rauseo Anna A Saller Alois A Mastroianno Sandra S Pellegrini Fabio F Trevisan Roberto R Fioretto Paola P Doria Alessandro A Trischitta Vincenzo V

American journal of kidney diseases : the official journal of the National Kidney Foundation 20081031 2

<h4>Background</h4>Insulin resistance has a role in diabetic kidney complications. The K121Q (lysine to glutamine substitution at amino acid 121, encoded by single-nucleotide polymorphism rs1044498) variant of the ectonucleotide pyrophosphatase/phosphodiesterase gene (ENPP1) has been associated with insulin resistance and related vascular complications in patients with type 2 diabetes (T2D) in many, although not all, studies. This study investigated whether the ENPP1 Q121 variant modulates the r ...[more]

PMID: 18950909

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Project description:Rationale & objectiveThe association between bariatric surgery, type 2 diabetes, and chronic kidney disease (CKD) is poorly understood. We studied whether remission of type 2 diabetes induced by bariatric surgery influences markers of kidney disease, if CKD is associated with remission of diabetes after bariatric surgery, and if baseline levels of gut hormones and peptides modify these associations.Study designProspective observational study.Study participants737 bariatric surgery patients with type 2 diabetes who participated in a multicenter cohort study for up to 5 years.PredictorsDemographics, blood pressure, medications, type of bariatric surgery, anthropometrics, markers of kidney disease, and circulating levels of gut hormones and peptides.OutcomesEstimated glomerular filtration rate (eGFR), urinary albumin excretion, prognostic risk for CKD, and remission of diabetes.Analytical approachLinear mixed models for eGFR; generalized linear mixed models with logit link for albuminuria, prognostic risk for CKD, and diabetes remission.ResultsRemission of diabetes at 5 years post-bariatric surgery was not independently associated with eGFR but was associated with lower risk for moderate/severe increase in albuminuria (risk ratio, 0.66; 95% CI, 0.48-0.90) and stabilization in prognostic risk for CKD. These findings were modified by baseline ghrelin level. Lower preoperative eGFR and greater prognostic risk for CKD were independently associated with reduced likelihood of diabetes remission. The association with preoperative GFR was modified by C-peptide level. Higher baseline circulating ghrelin level was independently associated with a lower prognostic risk for CKD.LimitationsA minority of participants had baseline CKD; lack of comparison group; no information on duration of diabetes, other clinical end points, or kidney biopsy results.ConclusionsRemission of type 2 diabetes 5 years after bariatric surgery was associated with improvements in albuminuria and stabilized prognostic risk for CKD, but not with eGFR. Lower kidney function and greater prognostic risk at the time of bariatric surgery was linked to a lower likelihood of diabetes remission. These results highlight the need to identify the mechanisms through which bariatric surgery may delay the long-term progression of CKD in type 2 diabetes.

Project description:ObjectiveThis study aimed to evaluate whether the M420del variants of SLC22A1 (rs72552763) is associated with metformin treatment response in Ethiopian patients with type 2 diabetes mellitus (T2DM).Patients and methodsA prospective observational cohort study was conducted on 86 patients with T2DM who had been receiving metformin monotherapy for <1 year. Patients showing ≥0.5% reduction in HbA1c levels from baseline within 3 months and remained low for at least another 3 months were defined as responders while those patients with <0.5% reduction in HbA1c levels and/or those whom started a new class of glucose-lowering drug(s) because of unsatisfactory reduction were defined as non-responders. In addition, good glycemic control was observed when HbA1c ≤7.0%, and the above values were regarded as poor. Genotyping of rs72552763 SNP was performed using TaqMan® Drug Metabolism Enzyme Genotyping Assay and its association with metformin response and glycemic control were assessed by measuring the change in HbA1c and fasting blood glucose levels using Chi-square, logistic regression and Mann-Whitney U-test. Statistical significance was set at p <0.05.ResultsThe minor allele frequency of the rs72552763 SNP of SLC22A1 was 9.3%. Metformin response was significantly higher in deletion_GAT (del_G) genotypes as compared to the wild-type GAT_GAT (G_G) genotypes. Furthermore, a significantly lower median treatment HbA1 level was found in del_G genotypes as compared to G_G genotypes. However, the association of rs72552763 with metformin response was not replicated at the allele level. In contrast, the minor del_allele was significantly associated with good glycemic control compared to the G_allele, though not replicated at del_G genotypes level.ConclusionThis study demonstrated that metformin response was significantly higher in study participants with a heterozygous carrier of M420del variants of SLC22A1 as compared to the wild-type G_G genotypes after 3 months of treatment.

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Association of the Q121 variant of ENPP1 gene with decreased kidney function among patients with type 2 diabetes.

Publications

Association of the Q121 variant of ENPP1 gene with decreased kidney function among patients with type 2 diabetes.

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