Evaluation of Single Nucleotide Polymorphism in MDR ABCC1 Gene in Type 2 Diabetic patients from Khyber Pakhtunkhwa Pakistan

Abstract

ABCC1 is a multidrug resistance ATP-Binding cassette transporter commonly known as multidrug resistance-associated protein 1 (MRP1). It is a full-length transporter and is located on chromosome number 16p13.1. Physiologically, it exports xenobiotics and toxins out of the cell, thereby providing a shielding mechanism for the cell. During stress conditions, ABCC1 overexpression causes in an efflux of drugs and creating a hurdle in the treatment of various diseases. Several studies have reported the implication of the ABCC1 genetic polymorphism among cancer patients in different populations. However, studies related to ABCC1 polymorphism in diabetic patients are rare reported, especially from Pakistan. The present study was therefore conceived to genetically screen the ABCC1 gene (exon 22 and flanking intron) in diabetic patients (n=100) from Mardan region of Pakistan. The PCR-SSCP analysis followed by DNA sequencing identified variations in 06 subjects followed by sequencing. A total of 10 genetic variations were identified in diabetic subjects. Among these, 9 were novel including 7 non-synonymous, 1 synonymous, and 1 intronic variant. In addition, rs3851716 (A1009G) is identified as a reported variant in dbSNP and the 1000 Genome project. LD analysis revealed a high degree of linkage for region 16111304-16111721 with African populations. Furthermore, the intronic variant 16111592 G/A is reported in association with diabetes in American and African populations. Furthermore, the structural effect of deleterious variants was also analyzed using homology modelling. The variants were identified in TMD2 regions and exhibit drastic differences in interactions with nearby residues when compared to the wild-type protein, which may affect the binding properties of ABCC1. This study for the first time reports genetic variations (SNPs) of the ABCC1 gene and its effect on structural modifications in proteins in diabetic patients from District Mardan, Khyber Pakhtunkhwa, Pakistan.