Poor metabolizers at the cytochrome P450 2D6 and 2C19 loci are at increased risk of developing adult acute leukaemia.
We have genotyped over 550 cases of acute leukaemia and 950 matched controls from a population-based case-control study, to investigate the impact cytochrome P450s 2D6, 2C19 and 1A1 have on susceptibility to adult acute leukaemia. Analysis included potential associations between polymorphic status and acute myeloid leukaemia (AML), acute lymphoblastic leukaemia (ALL), plus the FAB and cytogenetic subtypes therein. A significant increased risk was found for CYP2D6 poor metabolizer phenotype and acute leukaemia [odds ratio (OR) = 1.69, 95% confidence interval (CI) 1.17-2.43], a risk also found in AML and ALL. No interaction was found with smoking. However, a significant age-related association between CYP2D6 polymorphism and acute myeloid leukaemia implied that the excess risk was confined to persons aged 40 years and over (OR 2.38, 95% CI 1.53-3.71). Amongst AML cases, increased odds ratios were observed in both de-novo (OR 1.54, 95% CI 1.02-2.32) and secondary leukaemia (OR 2.83, 95% CI 0.91-8.77), and among patients with a chromosomal abnormality (OR 2.00, 95% CI 1.11-3.61). An increased risk was found for the CYP2C19 poor metabolizer phenotype (OR 1.68, 95% CI 0.97-2.92) which was also present in AML and ALL. For this CYP450 locus, an increased risk was suggested in secondary leukaemia (OR 2.67, 95% CI 0.44-16.3) and amongst AML cases with a chromosomal abnormality (OR 6.72, 95% CI 2.22-20.4). No difference in CYP1A1 genotype distribution was found for acute leukaemia, AML, ALL or any other diagnostic classification group used. No significant interactions between CYP2D6, CYP2C19 or CYP1A1 were found.
Roddam
P L
PL
Department of Haematology, University of Leeds, UK.
Rollinson
S
S
Kane
E
E
Roman
E
E
Moorman
A
A
Cartwright
R
R
Morgan
G J
GJ
D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D001189:Aryl Hydrocarbon Hydroxylases; D001483:Base Sequence; D016022:Case-Control Studies; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D017931:DNA Primers; D006801:Humans; D007951:Leukemia, Myeloid / Q000201:enzymology*; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics / Q000378:metabolism*; D011110:Polymorphism, Genetic; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000201:enzymology*; D012307:Risk Factors
D017931:DNA Primers; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6