Predictive role of polymorphic variants of phase II drug metabolising enzyme in modulating toxicity in North Indian lung cancer patients undergoing chemotherapy
Creators: name: Walia, Harleen
name: Sharma, Parul
name: Singh, Navneet
name: Sharma, Siddharth
Publisher: name: Taylor & Francis
Year: 2022
Subjects: subject: Medicine
subject: Genetics
subject: FOS: Biological sciences
subject: Pharmacology
subject: 59999 Environmental Sciences not elsewhere classified
subject: FOS: Earth and related environmental sciences
subject: 39999 Chemical Sciences not elsewhere classified
subject: FOS: Chemical sciences
subject: 69999 Biological Sciences not elsewhere classified
subject: Cancer
subject: 60506 Virology

description: Genetic polymorphism of drug-metabolising enzymes such as <i>NQO1, SULT1A1, EPHX1</i>, and <i>NAT2</i> alters its activity which hampers the detoxification and disposal of chemotherapeutic compounds. Thus, in the present study, we have comprehensively investigated the associations between SNPs of the Phase II detoxifying genes and its relationship towards platinum-induced toxicity of lung cancer patients.<i>NQO1</i> (609 C &gt; T), <i>SULT1A1</i> (Arg<sup>213</sup> His), <i>EPHX1</i> (Tyr<sup>113</sup>His, His<sup>139</sup>Arg), and <i>NAT2</i> (481 C &gt; T, 803 A &gt; G, 590 G &gt; A, 857 G &gt; A) were evaluated in our study for their associated adverse events caused due to the administration of platinum-based chemotherapy to the lung cancer patients.For <i>NQO1</i> 609 C &gt; T polymorphism, the <i>TT</i> genotype showed reduced risk of constipation (OR = 0.10, <i>p</i> = 0.04) and anorexia (OR = 0.15, <i>p</i> = <b>0.03</b>). For <i>SULT1A1 Arg<sup>213</sup>His,</i> heterozygous genotype (<i>Arg/His</i>) (AOR = 0.38, <i>p</i> =<b> 0.006</b>) and combined genotype (<i>Arg/His + His/His</i>) were not associated with increased risk of nephrotoxicity (AOR = 0.38, <i>p</i> =<b> 0.004</b>). For <i>NAT2,</i> heterozygous (<i>NAT2*4/*6</i>) and combined genotypes (<i>NAT2*4/*4+*4/*6</i>) for <i>NAT2*6</i> polymorphism exhibit 2.4 folds (<i>p</i> =<b> 0.005</b>), and two-folds (<i>p</i> = <b>0.01</b>) increased risk of hematological toxicity. The heterozygous (AOR = 0.45, <i>p</i> = <b>0.004</b>) and variant genotype (AOR = 0.39, <i>p</i> = <b>0.02</b>) for <i>NAT2*5C</i> had decreased risk for hematological toxicity. The heterozygous genotype for <i>NAT2*7</i> polymorphism showed two-fold increased risk for developing thrombocytopenia.This study provides association of <i>NAT2</i> polymorphic variants in predicting haematological toxicity. Genetic polymorphism of drug-metabolising enzymes such as <i>NQO1, SULT1A1, EPHX1</i>, and <i>NAT2</i> alters its activity which hampers the detoxification and disposal of chemotherapeutic compounds. Thus, in the present study, we have comprehensively investigated the associations between SNPs of the Phase II detoxifying genes and its relationship towards platinum-induced toxicity of lung cancer patients. <i>NQO1</i> (609 C &gt; T), <i>SULT1A1</i> (Arg<sup>213</sup> His), <i>EPHX1</i> (Tyr<sup>113</sup>His, His<sup>139</sup>Arg), and <i>NAT2</i> (481 C &gt; T, 803 A &gt; G, 590 G &gt; A, 857 G &gt; A) were evaluated in our study for their associated adverse events caused due to the administration of platinum-based chemotherapy to the lung cancer patients. For <i>NQO1</i> 609 C &gt; T polymorphism, the <i>TT</i> genotype showed reduced risk of constipation (OR = 0.10, <i>p</i> = 0.04) and anorexia (OR = 0.15, <i>p</i> = <b>0.03</b>). For <i>SULT1A1 Arg<sup>213</sup>His,</i> heterozygous genotype (<i>Arg/His</i>) (AOR = 0.38, <i>p</i> =<b> 0.006</b>) and combined genotype (<i>Arg/His + His/His</i>) were not associated with increased risk of nephrotoxicity (AOR = 0.38, <i>p</i> =<b> 0.004</b>). For <i>NAT2,</i> heterozygous (<i>NAT2*4/*6</i>) and combined genotypes (<i>NAT2*4/*4+*4/*6</i>) for <i>NAT2*6</i> polymorphism exhibit 2.4 folds (<i>p</i> =<b> 0.005</b>), and two-folds (<i>p</i> = <b>0.01</b>) increased risk of hematological toxicity. The heterozygous (AOR = 0.45, <i>p</i> = <b>0.004</b>) and variant genotype (AOR = 0.39, <i>p</i> = <b>0.02</b>) for <i>NAT2*5C</i> had decreased risk for hematological toxicity. The heterozygous genotype for <i>NAT2*7</i> polymorphism showed two-fold increased risk for developing thrombocytopenia. This study provides association of <i>NAT2</i> polymorphic variants in predicting haematological toxicity.