Gene-gene interactions of drug metabolizing enzymes and transporter protein in the risk of upper aerodigestive tract cancers among Indians.
BACKGROUND
The combined genetic effects of single nucleotide polymorphisms may additively or synergistically contribute to the increased cancer risk. The interactions associated with xenobiotic metabolizing enzymes and transporter protein involved in the biotransformation and transport of xenobiotics could determine the functional outcomes over the independent effects of a single susceptibility gene in the risk of upper aerodigestive tract cancers.


METHODS
The hospital-based case-control study evaluated CYP1A1 (*2A and *2C), CYP2E1 (*1B, *5B, and *6), GST (M1, T1, and P1) and ABCB1 3435C>T polymorphisms among 408 histopathologically confirmed cases and 220 controls using polymerase chain reaction based methods in an Indian population.


RESULTS
The multivariate logistic regression analyses demonstrated potentially high risk gene-gene interactions with the concurrent deletions of the GSTT1 and GSTM1 genes and GSTP1 variant genotypes (OR 5.81; 95% CI 1.01-40.28), the deletions of GSTT1 and GSTM1 genotypes with variant genotypes of CYP1A1*2A (OR 8.21; 95% CI 1.91-49.48), GSTT1 and GSTM1 deficient genotypes along with CYP2E1*1B variant genotypes (OR 6.73; 95% CI 1.32-22.81), the polymorphic genotypes of ABCB1 and deficient GSTT1 (OR 6.08; 95% CI 2.21-16.76) and an enhanced risk with the combined variant genotypes of CYP1A1*2A, GSTT1 and ABCB1 (OR 11.14; 95% CI 2.70-46.02).


CONCLUSIONS
The findings indicate that the interactions associated with various drug metabolizing enzymes and transporter protein exhibit high risk for UADT cancers than that ascribed to a single susceptible gene. This was particularly established among the polymorphic carriers of CYP1A1*2A, GSTT1 and ABCB1 genes in the population investigated.
Sam
Soya Sisy
SS
Department of Pharmacology, Jawaharlal Institute of Post-graduate Medical Education and Research, Pondicherry 605 006, India. soyasoya@rediffmail.com
Thomas
Vinod
V
Reddy
Kanipakapatanam Sathyanarayana
KS
Surianarayanan
Gopalakrishnan
G
Chandrasekaran
Adithan
A
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics* / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics* / Q000378:metabolism; D004843:Epistasis, Genetic; D005260:Female; D020022:Genetic Predisposition to Disease; D005982:Glutathione Transferase / Q000235:genetics* / Q000378:metabolism; D006258:Head and Neck Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007194:India; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007527:Isoenzymes; D019392:Cytochrome P-450 CYP2E1; D019363:Cytochrome P-450 CYP1A1; D005982:Glutathione Transferase