RESUMEN
BACKGROUND: Therapy with anti-cancer drugs remain the cornerstone of treating cancer. The effectiveness and safety of anti-cancer drugs vary significantly among individuals due to genetic factors influencing the drug response and metabolism. Data on the pharmacogenomic variations in Sri Lankans related to anti-cancer therapy is sparse. As current treatment guidelines in Sri Lanka often do not consider local pharmacogenomic variants, this study aimed to explore the diversity of pharmacogenomic variants in the Sri Lankan population to pave the way for personalized treatment approaches and improve patient outcomes. METHODS: Pharmacogenomic data regarding variant-drug pairs of genes CYP2D6, DPYD, NUDT15, EPAS1, and XRCC1 with clinical annotations labelled as evidence levels 1A-2B were obtained from the Pharmacogenomics Knowledgebase database. Their frequencies in Sri Lankans were obtained from an anonymized database that was derived from 541 Sri Lankans who underwent exome sequencing at the Human Genetics Unit, Faculty of Medicine, University of Colombo. Variations in DPYD, NUDT15, and EPAS1 genes are related to increased toxicity to fluoropyrimidines, mercaptopurines, and sorafenib respectively. Variations in CYP2D6 and XRCC1 genes are related to changes in efficacy of tamoxifen and platinum compounds, respectively. Minor allele frequencies of these variants were calculated and compared with other populations. RESULTS: MAFs of rs1065852 c.100 C > T (CYP2D6), rs3918290 c.1905 + 1G > A (DPYD), rs56038477 c.1236G > A (DPYD), rs7557402 c.1035-7 C > G (EPAS1), rs116855232 c.415 C > T (NUDT15*3), and rs25487 c.1196 A > G (XRCC1) were: 12.9% [95%CI:10.9-14.9], 1.5% [95%CI:0.8-2.2], 1.2% [95%CI:0.5-1.8], 37.7% [95%CI:34.8-40.6], 8.3% [95%CI:6.7-10.0], and 64.0% [95%CI:61.1-66.8], respectively. Frequencies of rs1065852 c.100 C > T (CYP2D6), rs7557402 c.1035-7 C > G (EPAS1), and rs25487 (XRCC1) were significantly lower in Sri Lankans, while frequencies of rs116855232 c.415 C > T (NUDT15*3) and rs56038477 c.1236G > A (DPYD) were significantly higher in Sri Lankans when compared to some Western and Asian populations. CONCLUSION: Sri Lankans are likely to show lower toxicity risk with sorafenib (rs7557402 c.84,131 C > G) and, higher toxicity risk with fluoropyrimidines (rs56038477 c.1236G > A) and mercaptopurine (rs116855232 c.415 C > T), and reduced effectiveness with tamoxifen (rs1065852 c.100 C > T) and platinum compounds (rs25487). These findings highlight the potential contribution of these genetic variations to the individual variability in anti-cancer dosage requirements among Sri Lankans.
Asunto(s)
Antineoplásicos , Variantes Farmacogenómicas , Humanos , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Pueblo Asiatico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Citocromo P-450 CYP2D6/genética , Frecuencia de los Genes , Neoplasias/genética , Neoplasias/tratamiento farmacológico , Hidrolasas Nudix , Farmacogenética , Pirofosfatasas/genética , Sri Lanka , Proteína 1 de Reparación por Escisión del Grupo de Complementación Cruzada de las Lesiones por Rayos X/genética , Personas del Sur de AsiaRESUMEN
Introduction: Chronic kidney disease (CKD) is a major complication of diabetes mellitus and it contributes to increased hospital mortality and morbidity. Microalbumin test is used to identify the first sign of deteriorating kidney function but it is an expensive test. Alternatively, measurement of urine total protein-to-creatinine ratio (TPCR) is a simple and inexpensive method. Objective: To find whether the urine TPCR can predict the presence of microalbuminuria in patients with diabetic nephropathy. Method: A cross sectional study was performed on 216 patients with diabetes mellitus at General Hospital, Ampara over a period of 4 weeks. Urine albumin, urine creatinine and urine total protein were analysed on first voided urine samples and urine albumin to creatinine ratio (ACR) and total-protein-to-creatinine ratio were calculated. Regression analysis and Spearman's rank correlation were used to study the linear relationship between two variables. Results: Among 216 patients, 56 (26.1%) were males and 160 (73.9%) were females. The mean urine total-protein-to-creatinine ratio was 89.3 ± 231.6 mg/g and albumin to creatinine ratio was 43.1±76.3 mg/g. Sixty four (29%) patients were newly detected as having microalbuminuria (n=61; 28%,) or macroalbuminuria (n=3; 1%,). There was a significant correlation between urine total-protein-to-creatinine ratio and urine albumin to creatinine ratio (R2 = 0.824, ACR = [TPCR + 18.421]/ 2.5026) in the total sample (p < 0.001). The total-protein-to-creatinine ratio showed a significant correlation with urine albumin to creatinine ratio in the range of microalbuminuria (30-300 mg/g creatinine) (R2 = 0.798; p < 0.001). The regression equation was ACR = [TPCR 5.0491]/1.2633. Conclusion: The urine total-protein-to-creatinine ratio showed a positive significant correlation with urine albumin to creatinine ratio, which is clinically important to identify early stage of diabetic nephropathy. This can be used in rural areas as it is inexpensive.