Genetic Polymorphisms of Candidate Genes with Thiazolidinedione-associated Peripheral Edema
Date Issued
2009
Date
2009
Author(s)
Liang, Yi-Chih
Abstract
Context. hiazolidinedione (TZDs), synthetic insulin-sensitizing drugs that include rosiglitazone and pioglitazone, are highly effective in the treatment of type 2 diabetes. TZDs are believed to mediate their antidiabetic effect via activation of peroxisome proliferator-activated receptor γ (PPARγ). However, fluid retention, presented as rapid weight gain, and peripheral and pulmonary edema in 10-15% patients have emerged as the most common and serious side effects of TZDs. According to the previous studies, these drugs may cause renal fluid reabsorption directly by affecting tubular transport, renal sodium retention, and vascular hyperpermeability or indirectly by affecting renal hemodynamics or processes. Rosiglitazone increased whole kidney protein abundance of the bumetanide-sensitive Na-K-2Cl cotransporter (SLC12A1), the sodium hydrogen exchanger 3 (NHE3), the aquaporin 2 (AQP2) and aquaporin 3 (AQP3) in mice. Pioglitazone increased SCNN1G mRNA (encoding the epithelial sodium channel γ, ENaCγ) expression in inner medullary collecting ducts (IMCDs) through a PPARγ-dependent pathway. According to the evidence above, renal mechanisms play a major role in TZD-induced fluid retention.bjective. ince a direct role for PPARγ in kidney function has now been identified, the identification of its target genes will allow the initiation of genetic studies that may help identify individuals susceptible to develop edema. The objective of the present study is to investigate if genetic variations in selected candidate genes are associated with the risk of fluid retention and peripheral edema in type 2 diabetic patients treated with TZDs. esign. he genes of peroxisom proliferator-activated receptor γ(PPARG), arginine vasopressin receptor 2 (AVPR2) and the genes of major renal sodium and water transporters and channel proteins (SLC12A1, Na-K-2Cl cotransporter；NHE3, sodium hydrogen exchanger 3；SCNN1G, epithelial sodium channel γ；AQP2, aquaporin 2 and AQP3, aquaporin3) are selected into the candidate genes. The 29 tag single nucleotide polymorphisms (tag-SNPs) of these 7 candidate genes were performed by Applied Biosystems SNPlexTM assays. And genomic DNA was obtained from 328 type 2 diabetic patients receiving with TZDs since 2001. According to the inclusion and exclusion criteria, we plan to conduct a case-control study to test the association between SNPs in certain candidate genes and TZDs related peripheral edema.esults. NPs of AQP2, SCNN1G and SLC12A1 are associated with TZD-related edema. AQP2.1 (rs296766, C/T；odds ratio 2.67, p=0.0003). The odds ratio was 2.67 for the AQP2.1 risk allele compared with the non-risk allele, corresponding to a population attributable risk fraction of 29.75%. SCNN1G.4 (rs4401050, C/T；odds ratio 1.88, p=0.0496). The odds ratio was 1.88 for the SCNN1G.4 risk allele compared with the non-risk allele, corresponding to a population attributable risk fraction of 11.49%. SLC12A1.4 (rs12904216, A/G；odds ratio 1.73, p=0.0096). The odds ratio was 1.73 for the SLC12A1.4 risk allele compared with the non-risk allele, corresponding to a population attributable risk fraction of 18.79%. Other risk factors included female gender (odds ratio 3.59, p<0.001) and age (66.82±11.66 vs. 62.64± 10.85, p=0.011).onclusion. he female gender and age are well known clinical risk factors for TZD-induced edema. The polymorphisms in AQP2, SCNN1G and SLC12A1 genes may be used as clinically relevant pharmacogenetic risk markers for edema in patients with TZDs therapy.ey words：Type 2 diabetes, PPARγ, Thiazolidinediones (TZDs), Fluid retention, Edema, AQP2
Subjects
Type 2 diabetes
PPARγ
Thiazolidinediones (TZDs)
Fluid retention
Edema
AQP2
SDGs
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