ABCC8 p.Ala1166Cys
Predicted by SNAP2: | C: N (93%), D: N (66%), E: N (78%), F: N (82%), G: N (87%), H: N (87%), I: N (97%), K: N (87%), L: N (87%), M: N (87%), N: N (87%), P: N (87%), Q: N (87%), R: N (82%), S: N (93%), T: N (97%), V: N (97%), W: N (61%), Y: N (82%), |
Predicted by PROVEAN: | C: N, D: D, E: D, F: N, G: N, H: D, I: N, K: D, L: N, M: N, N: D, P: D, Q: D, R: D, S: N, T: N, V: N, W: D, Y: N, |
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[hide] Understanding the genetic basis for adverse drug e... Pharmacotherapy. 2010 Feb;30(2):195-209. Bai JP, Lesko LJ, Burckart GJ
Understanding the genetic basis for adverse drug effects: the calcineurin inhibitors.
Pharmacotherapy. 2010 Feb;30(2):195-209., [PMID:20099993]
Abstract [show]
The calcineurin inhibitors-cyclosporine and tacrolimus-are the mainstay of immunosuppressive therapy in solid organ transplantation. These drugs produce severe adverse drug effects (ADEs) such as nephrotoxicity, posttransplantation diabetes mellitus, and hypertension. Accumulated evidence suggests that the development of type 2 diabetes, hypertension, and renal failure may be associated with specific DNA genotypes. In this review, the genes involved with the development of these disease processes are compared with those implicated in calcineurin inhibitor-induced ADEs. The renin-angiotensin system genes, cytokine-encoding genes, and plasminogen activator inhibitor type 1 genes have been implicated in calcineurin inhibitor-induced nephrotoxicity, as well as in development of renal failure. A number of genes are implicated in contributing to diabetes, and these include the vitamin D receptor gene, VDR; hepatocyte nuclear factor genes, HNF; transcription factor 7-like 2 gene, TCF7L2; angiotensin-converting enzyme gene, ACE; cytokines; peroxisome proliferator-activated receptor gamma gene, PPARG; and others. Studies have suggested that the VDR, PPARG, HNF1A, and adenosine 5'-triphosphate-binding cassette ABCC8 (which encodes the sulfonylurea receptor) genes are associated with calcineurin inhibitor-induced diabetes. The genes encoding for the angiotensin-converting enzyme, endothelial constitutive nitric oxide synthase, and cytochrome P450 3A isoenzyme have been involved in the development of hypertension and in calcineurin inhibitor-induced hypertension. The genetic study of disease states can be the stepping stones for thoroughly understanding the genetic basis of ADEs. Gene polymorphisms are implicated in the development of diseases and corresponding disease-like ADEs. The disease-associated genes provide candidate genes for exploring ADEs and may provide genomic biomarkers for assessing the risk for developing severe calcineurin inhibitor-related ADEs as well as for developing preventive strategies.
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65 (continued) Risk Factors ACE (rs4340) D/D (+) (RR 5.28, 95% CI 2.48-11.24, p<0.0001) AGT (rs5051) (-), AGTR1 (rs5186) (-) TGF-beta protein expression significantly higher in those with acute cyclosporine toxicity than those with acute rejection or chronic allograft nephropathy (p<0.05) Tissue factor expression (+) (p=0.0026 for 18 transplant recipients with cyclosporine nephrotoxicity vs 6 patients with normal kidneys) -657 4G allele (rs1799889) (+) (p=0.0189) (exponential coefficient of survival regression 3.35, 95% CI 1.22-9.22) ACE I/D (rs4340) (-) AGT M235T T allele (rs 699) (+) (OR 1.33, 95% CI 1.04-1.70, p=0.02) AGTR1 C allele and CC (rs5186) (+) C allele (OR 1.87, 95% CI 1.49-2.35, p<0.0001) ACE (rs4340) (-) D allele (OR 0.92, 95% CI 0.70-1.20, p=0.59) ACE D allele (rs4340) (+) (OR 1.34, 95% CI 1.07-1.69, p=0.01) AGT M235T (rs699) (+) (OR 0.74, 95% CI 0.59-0.94, p=0.01) AGTR1 A1166C (rs388915) (-) TNF -308 AA, AG, GG (rs1088629) (-) TGFB1 (codon 10) TT (rs1800470) (+) (OR 5.31, 95% CI 3.77-7.02, p<0.001) IL10 (-1082) GG (rs1800896) (+) (OR 2.35, 95% CI 1.67-3.15, p<0.01) Hyperuricemia: TGFB1 G/G (rs1800471) (+) (p=0.0013) TGFB1 (codon 10) (rs1800470) (-) IL10 AG (-1082) (rs1800896) (+) (p=0.0022) Type 2 or steroid-induced diabetes mellitus: IFNG (+874 AA) (rs2430561) (+) (p=0.0127) IL10 (-1082 A/G) (rs1800896) (-) IL1RN 2-repeat allele (VNTR 2 copies ) (+) (OR 1.46, 95% CI 1.19-1.78, p<0.01) IL1B (-511) (rs16944) (-) tacrolimus group had decreased insulin secretion.27 The exact mechanism of calcineurin inhibitor-induced toxicity to the beta cell is unknown.
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ABCC8 p.Ala1166Cys 20099993:65:896
status: NEW