Effect of MTHFR C677T genotype on survival in type 2 diabetes patients with end-stage diabetic nephropathy

Böger, Carsten A.; Stubanus, Mike; Haak, Thomas; Götz, Andrea; Christ, Jacob; Hoffmann, Ute; Riegger, Günter A.J.; Krämer, Bernhard K.

doi:10.1093/ndt/gfl512

Cited by 26 publications

(18 citation statements)

References 30 publications

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“…Although disequilibrium may arise from inbreeding, we were not aware of any consanguinity within the population as we recruited the subjects from a large urban area. As previously suggested, a deviation could be a consequence of the recruiting strategy despite the fact that the other tested polymorphism did not deviate from the Hardy-Weinberg equilibrium (Böger et al, 2005(Böger et al, , 2007Kim et al, 2010). A potential explanation is a sampling bias because all subjects were male.…”

Section: Abcg2 Haplotypes On Rosuvastatin Pharmacokineticsmentioning

confidence: 88%

Marked Alteration of Rosuvastatin Pharmacokinetics in Healthy Chinese with ABCG2 34G>A and 421C>A Homozygote or Compound Heterozygote

Wan

Guo

et al. 2015

J Pharmacol Exp Ther

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Rosuvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor used to lower blood low-density lipoprotein cholesterol, is a substrate of the membrane ABCG2 exporter. ABCG2 variants have been shown to alter rosuvastatin disposition. The objective of this study is to determine the impact of ABCG2 34/421 compound haplotypes on rosuvastatin pharmacokinetics in healthy Chinese volunteer subjects. Eight hundred healthy Chinese males were genotyped by polymerase chain reaction-pyrosequencing for ABCG2 34G.A, ABCG2 421C.A, SLCO1B1 521T.C, and CYP2C9*3 variants. Sixty-two male subjects with wild-type SLCO1B1 c.521TT and CYP2C9*3 were recruited for this pharmacokinetic study of rosuvastatin. A single oral dose of 10 mg rosuvastatin was administrated to each subject, and blood samples were collected before and at various time points after drug administration. Plasma concentration of rosuvastatin was determined by high-performance liquid chromatography-tandem mass spectrometry, and pharmacokinetic analysis was carried out using the WinNonlin program. In Chinese males, high allele frequency of ABCG2 c.34G.A (0.275) and c.421C.A (0.282) was observed, resulting in a considerable portion (23.3%) of subjects being ABCG2 34/421 compound heterozygotes. Compared with subjects with ABCG2 wild-type (c.34GG/421CC), plasma rosuvastatin C max and area under the curve, AUC 0-' , were significantly higher, while the apparent oral clearance, CL/F, was significantly lower in subjects with c.34AA, c.421AA, and c.34GA/ 421CA genotypes. Both t 1/2 and T max were similar among subjects with different genotypes. A high frequency of ABCG2 c.34G.A and c.421C.A variants was present in Chinese males, and the disposition of rosuvastatin was significantly affected by both variants. These data suggest that it is advisable to genotype these variants when prescribing rosuvastatin to Chinese subjects, leading to a precise dose for each individual.

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Section: Abcg2 Haplotypes On Rosuvastatin Pharmacokineticsmentioning

confidence: 88%

Marked Alteration of Rosuvastatin Pharmacokinetics in Healthy Chinese with ABCG2 34G>A and 421C>A Homozygote or Compound Heterozygote

Wan

Guo

et al. 2015

J Pharmacol Exp Ther

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“…30 mg per day); the presence of a GFR 6 60 ml/min/1.73 m 2 is not always taken as a criterion defining controls [75] . Cases are mostly those with overt proteinuria (defined mostly as 1 300 mg per day) and/or ESRD in the absence of other possible causes of ESRD [76][77][78] . The presence of diabetic retinopathy is required by some studies [15,75] since this makes the diagnosis of diabetic nephropathy more likely.…”

Section: Definition Of Kidney Traits and Study Designmentioning

confidence: 99%

Chronic Kidney Disease: Novel Insights from Genome-Wide Association Studies

Böger¹,

Heid²

2011

Kidney Blood Press Res

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Chronic kidney disease (CKD) is common, affecting about 10% of the general population, and causing significant morbidity and mortality. Apart from the risk conferred by traditional cardiovascular risk factors, there is a strong genetic component. The method of a genome-wide association study (GWAS) is a powerful hypothesis-free approach to unravel this component by association analyses of CKD with several million genetic variants distributed across the genome. Since the publication of the first GWAS in 2005, this method has led to the discovery of novel loci for numerous human common diseases and phenotypes. Here, we review the recent successes of meta-analyses of GWAS on renal phenotypes. UMOD, SHROOM3, STC1, LASS2, GCKR, ALMS1, TFDP2, DAB2, SLC34A1, VEGFA, PRKAG2, PIP5K1B, ATXN2/SH2B3, DACH1, UBE2Q2, and SLC7A9 were uncovered as loci associated with estimated glomerular filtration rate (eGFR) and CKD, and CUBN as a locus for albuminuria in cross-sectional data of general population studies. However, less than 1.5% of the total variance of eGFR and albuminuria is explained by the identified variants, and the relative risk for CKD is modified by at most 20% per locus. In African Americans, much of the risk for end-stage nondiabetic kidney disease is explained by common variants in the MYH9/APOL1 locus, and in individuals of European descent, variants in HLA-DQA1 and PLA₂R1 implicate most of the risk for idiopathic membranous nephropathy. In contrast, genetic findings in the analysis of diabetic nephropathy are inconsistent. Uncovering variants explaining more of the genetically determined variability of kidney function is hampered by the multifactorial nature of CKD and different mechanisms involved in progressive CKD stages, and by the challenges in elucidating the role of low-frequency variants. Meta-analyses with larger sample sizes and analyses of longitudinal renal phenotypes using higher-resolution genotyping data are required to uncover novel loci associated with severe renal phenotypes.

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“…Studies were conducted in populations of various ethnicity: eight involved Caucasians (Bluthner et al 1999;Makita et al 2003;Moczulski et al 2003;Boger et al 2007;Ksiazek et al 2004;Shcherbak et al 1999;Smyth et al 1999), five East Asians Fujita et al 1999;Odawara and Yamashita 1999;Neugebauer et al 1998;Yoshioka et al 2004), one a mixed population (Shpichinetsky et al 2000), and one Arabs (Mtiraoui et al 2007). Eleven studies involved cases with type 2 diabetes (Shpichinetsky et al 2000;Sun et al 2004;Bluthner et al 1999;Fujita et al 1999;Odawara and Yamashita 1999;Moczulski et al 2003;Boger et al 2007;Ksiazek et al 2004;Neugebauer et al 1998;Mtiraoui et al 2007;Yoshioka et al 2004), and four type 1 diabetes (Bluthner et al 1999;Makita et al 2003;Shcherbak et al 1999;Smyth et al 1999). One study provided data for males and females separately .…”

Section: Eligible Studiesmentioning

confidence: 99%

“…One study (Bluthner et al 1999) did not specify what proportion of cases had microalbuminuria. Sensitivity analyses were performed for studies that may involve cases with microalbuminuria (Shcherbak et al 1999;Bluthner et al 1999;Shpichinetsky et al 2000;Sun et al 2004;Mtiraoui et al 2007), and for studies involving cases with chronic renal failure (CRF) and/or end stage renal disease (ESRD) (Makita et al 2003;Moczulski et al 2003;Mtiraoui et al 2007;Boger et al 2007). A list of details abstracted from the studies included in the metaanalysis is provided in Table 1.…”

Section: Eligible Studiesmentioning

confidence: 99%

Methylenetetrahydrofolate reductase gene polymorphism as a risk factor for diabetic nephropathy: a meta-analysis

et al. 2007

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Investigations into the association between diabetic nephropathy (DN) and MTHFR C677T gene polymorphism in several case-control studies has yielded contradictory results. To shed light on these inconclusive findings, a meta-analysis of all available studies relating the C677T polymorphism to the risk of developing DN was conducted. The PubMed database was searched, and casecontrol studies investigating the association between MTHFR C677T gene polymorphism and DN were included in the meta-analysis. The meta-analysis included 15 studies, of which 8 involved Caucasians and 5 East Asians; 11 studies involved subjects with type 2 diabetes and 4 with type 1 diabetes. The main analysis (all studies) revealed significant heterogeneity between the studies (P Q \ 0.01) and a marginal association between the 677T allele and the risk of developing DN; the random effects (RE) pooled odds ratio (OR) was 1.30 (1.03-1.64). However, the sensitivity analysis (exclusion of studies not in Hardy-Weinberg equilibrium) produced non-significant results. The recessive model derived significant results in main analysis [fixed effects (FE) OR = 1.32 (1.10-1.58), P Q = 0.27], and in type 2 diabetes [FE OR = 1.30 (1.06-1.60), P Q = 0.38]. The additive model produced significant association in main analysis [RE OR = 1.65 (1.13-2.42), P Q \ 0.01] in Caucasians [FE OR = 1.48 (1.11-1.98), P Q = 0.17] and in type 2 diabetes [RE OR = 1.65 (1.03-2.67), P Q \ 0.01]. However, sensitivity analysis diminished the significant results in type 2 diabetes. There is no differential magnitude of effect in large versus small studies. In conclusion, although there is some evidence of association between MTHFR C677T gene polymorphism and DN, the above findings reinforce the need for further and more rigorous association studies.

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Effect of MTHFR C677T genotype on survival in type 2 diabetes patients with end-stage diabetic nephropathy

Cited by 26 publications

References 30 publications

Marked Alteration of Rosuvastatin Pharmacokinetics in Healthy Chinese with ABCG2 34G>A and 421C>A Homozygote or Compound Heterozygote

Marked Alteration of Rosuvastatin Pharmacokinetics in Healthy Chinese with ABCG2 34G>A and 421C>A Homozygote or Compound Heterozygote

Chronic Kidney Disease: Novel Insights from Genome-Wide Association Studies

Methylenetetrahydrofolate reductase gene polymorphism as a risk factor for diabetic nephropathy: a meta-analysis

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