We analyzed the association between MDR1 polymorphism and ARV drug induced hepatotoxicity. MDR1 encodes for the ATP- dependent membrane efflux transporter (14). P-glycoproteins are substrate for the genetic variant that impact patient drugs. The occurrence of MDR1 polymorphism changes from population to population . We analyzed the MDR1 genotypes and haplotypes among the individuals with ARV drug induced hepatotoxicity and those without hepatotoxicity.
We found that the occurrence of MDR1 3435C/T polymorphism in our healthy control population is identical to the investigations done in European, North Indian, Turkish, and Asian populations [30–35] and contrasted with the similar studies done in the Chinese, Iranian and Thailand populations [27, 33, 36]. Also, the genotypic dispersal of MDR1 1236C/T polymorphism in our healthy individuals was almost alike to the similar investigations in the North Indian population . However, it contrasted from the Mexican, Chinese and South African populations [18, 31, 38, 39]. We have done a genotype-phenotype analysis and found that the individuals with MDR11236TT genotype were at increased risk for severity of hepatotoxicity (OR=1.37, P=0.57). However, due to the small number of ARV drug induced hepatotoxicity cases, the risk could not reach statistical significance. The low phenotypic expression was linked with polymorphisms in P-gp. People with 3435TT genotype were found to have lower levels of P-gp than CC and CT genotypes. Also, MDR1 3435C/T polymorphism was associated with the reduced risk of NNRTI-induced liver toxicity .
We also studied the gene-gene interactions to understand the synergistic impact of MDR1 polymorphism on ARV drug induced hepatotoxicity. The gene-gene interactions are known to have greater effects on gene expression than a single gene . In our investigation, individuals possessing haplotype TC were more prone to a severe ARV drug induced hepatotoxicity (OR=1.96, P=0.06); and the ones with TT and CC haplotypes may have reduced risk for acquiring of ARV drug induced hepatotoxicity OR=0.16, P=0.006; OR=0.46, P=0.06; OR=0.09, P=0.003; OR=0.34, P=0.03).
Likewise, we analyzed the association between the MDR1 genotypes and the stage of HIV infection. In our investigation, the incidence of MDR1 genotypes did not vary significantly among individuals of various stages of HIV infection as well as the healthy population. MDR1 1236CT, 1236TT, and 3435CT genotypes have been shown to be correlated with the HIV disease progression, haven’t been found to regulate the susceptibility to HIV-1 infection . Additionally, the patients with 3435 TT genotype had an increase in the CD4+ counts, following a treatment for half an year .
An analysis of the gene-environment interaction helps to know its impact on the disease etiology [42, 43]. We did a case-only analysis to study the gene-environment interaction. We did not rather go for a case-control analysis in light of the fact that a case-control investigation, requires a coordination of cases with the control population . HIV infected individuals who are naïve to ARV therapy and consume alcohol have been found to have a reduction in the CD4+ cell count . Also, in the HIV infected women who consume tobacco, a diminished response to ARV therapy has been observed . In our study, in ARV drug induced hepatotoxicity cases, who consume alcohol, MDR11236TT genotype exposed a risk for severe hepatotoxicity (OR=1.50, P=0.88). Among the individuals those without hepatotoxicity and used alcohol, the incidence of 3435CT genotype posed a higher risk of acquisition of ARV drug induced hepatotoxicity (OR=2.47, P=0.12) because of combined effect of gene and environment. Among the ARV drug induced hepatotoxicity cases on nevirapine, presence of MDR1 1236TT genotype was likely to be associated with the higher risk of severe hepatotoxicity (OR= 2.11, P=0.55). Whereas among individuals those without hepatotoxicity on nevirapine, MDR1 1236CT, 1236TT genotypes exposed a higher risk of acquisition of ARV drug induced hepatotoxicity (OR=1.66, P=0.45; OR=1.96, P=0.55). In individuals with ARV drug induced hepatotoxicity on nevirapine who consume, MDR1 1236TT genotype exposed a higher susceptibility to severe hepatotoxicity (OR=2.21, P=0.55) because of combined effect of gene and environment.
In the individuals those without hepatotoxicity, who consume alcohol, MDR1 3435CT genotype showed a susceptibility to acquisition of ARV drug induced hepatotoxicity (OR=2.04, P=0.23). This suggests that individuals with MDR1 1236TT and 3435CT genotypes with or without ARV drug induced hepatotoxicity may have a combined effect on acquisition and severity of hepatotoxicity. Also, individuals on nevirapine, possessing 3435T allele has a reduced risk of hepatotoxicity . Individuals with MDR1 1236T and 1235T alleles have been associated with a diminished plasma NNRTI concentration, influencing the virological response to HAART . Haas et al., (2005) have not found any significant association between ABCB1 variations and plasma EFV concentrations .
The fact that this work can just assess the association and does not indicate causation, is one of the limiting points of the study. Also, the present investigation was planned to constitute a 1:4 proportion of cases versus controls but this couldn’t be accomplished and we recruited them in 1:3 proportion which may be sufficient.