ABSTRACT
Purpose: Engulfment and cell motility 1 (ELMO1), is a candidate gene responsible for cell motility and phagocytosis. However, its role in the development and progression of nephropathy attributed to T2D is still unknown. Kidney injury molecule-1 (KIM-1) plays a significant role in renal regeneration processes. The current study aimed to evaluate the association between kidney injury molecule-1 levels, ELMO1 gene polymorphism (rs741301, and rs1345365) as well as DN in an Egyptian population with T2D. Methods: In this study, we enrolled 89 participants from the internal medicine outpatient clinic, 23 T2DM without DN, 22 with DN, and 44 control subjects. They were genotyped by real-time PCR. Serum level of KIM-1 was detected by ELISA. Results: Serum KIM-1 level was correlated with DM duration, HbA1C, and UACR (P value <0.001) in T2D. There was no significant difference in the allelic and genotypic frequencies of rs741301 and rs1345365 between participants with DM who presented with albuminuria and those without. Results showed that rs1345365A/rs741301T and rs1345365G/rs741301C haplotypes were more common in patients with T2D than in HCs. However, the difference was not statistically significant (P = 0.262 and 0.414, respectively). Conclusions: KIM-1 can be a useful non-invasive biomarker for detecting early DN. The association between ELMO1 gene polymorphisms and the risk of DN in patients with T2D was not validated. Therefore, further studies with a larger sample size must be conducted.
ABSTRACT
BACKGROUND: There is considerable inter-individual variability in warfarin dosages necessary to achieve target therapeutic anticoagulation. Polymorphisms in genes, which master warfarin pharmacokinetics and pharmacodynamics, might influence warfarin dose variation. Genes encoding drug transporters, such as human multidrug resistance (MDR1), as well as epoxide hydrolase 1 (EPHX1), which is a putative subunit of the vitamin K epoxide reductase, and Protein Z (PZ), which is a vitamin K-dependent plasma glycoprotein, are among those candidate genes. OBJECTIVE: The purpose of this study was to investigate the contribution of MDR1 C3435T, EPHX1 H139R and PZ A-13G gene polymorphisms in warfarin dose variation in a cohort of the Egyptian population. METHODS: Eighty-four patients whose international normalized ratio (INR) was in the range of 2-3, 41 males and 43 females, with a mean (±SD) age of 40.9 (13.3) years were recruited into this study. MDR1 C3435T, EPHX1 H139R and PZ A-13G gene polymorphisms were detected by polymerase chain reaction-restriction fragment length polymorphism. Primarily, linear regression analysis, including the variables age, gender, MDR1 C3435T, EPHX1 H139R and combined MDR1 C3435T, EPHX1 H139R and PZ A-13G genotypes, was used to assess the effective factors for warfarin maintenance dose. Secondly, the previously examined cytochrome P450 (CYP) 2C9 A1075C and vitamin K epoxide reductase complex subunit 1 (VKORC1) C1173T were added to the regression analysis. RESULTS: Warfarin dose/week was not influenced by each of the MDR1 C3435T, EPHX1 H139R, and PZ A-13G gene polymorphisms when examined separately. However, when these single nucleotide polymorphisms (SNPs) were combined, MDR1 TT/EPHX1 RH,RR/PZ AA subjects showed statistically significant increase in warfarin dose/week when compared with MDR1 CC/EPHX1 RH,RR/PZ AA subjects [median (25th-75th percentiles): 49.0 (42.0-59.5) vs. 35.0 (24.5-42.0) mg/week, respectively] (p = 0.014). In contrast, in the presence of wild-type EPHX1 HH, there was a decrease in warfarin dose/week in MDR1 TT subjects when compared with CT and CC subjects [median (25th-75th percentiles): 22.0 (17.5-30.6), 42.0 (35.0-49.0) and 42.0 (28.0-54.3) mg/week, respectively] (p = 0.005 and 0.030, respectively). Age had a significant contribution (p = 0.048) to the overall variability in warfarin dose. Calculated weekly dose = 52.928 - (0.289 × age) + (9.709 × combined genotype). The multivariate linear regression equation of warfarin maintenance dose accounted for about 8 % of variation in dose (R (2) = 0.079), age accounted for 5 % of variation, while combined genotypes added the extra 3 %. However, the new regression equation accounted for 20.9 % of variation in dose. Age accounted for 5 %, while VKORC1 C1173T accounted for an extra 13 % of variation and MDR1 C3435T accounted for the remaining 3 % of variation. Calculated dose = 64.909 - (0.282 × age) - (13.390 × VKORC1) - (7.164 × MDR1). Correlation analysis showed a close and significant relationship between the calculated and actual warfarin dose (r = 0.457; p < 0.0005). CONCLUSION: Warfarin dose/week was significantly influenced by the combined MDR1 C3435T and EPHX1 H139R gene polymorphism since no polymorphism of PZ A-13G SNP was detected in our studied Egyptian population. Future studies with larger sample size will be needed to confirm our findings before definitive conclusions can be made.
