Metabolic Gene Variants and Risk of Non-Hodgkin's Lymphoma

Abstract

Genes involved in metabolism of environmental chemical exposures exhibit sequence variability that may mediate the risk of non-Hodgkin's lymphoma. We evaluated associations between non-Hodgkin's lymphoma and 15 variants in AHR, CYP1A1, CYP1A2, CYP1B1, CYP2C9, CYP2E1, GSTP1, GSTM3, EPHX1, NQO1, and PON1. Cases were identified from four Surveillance, Epidemiology, and End Results registries in the United States, and population-based controls were identified through random-digit dialing and Medicare eligibility files. Metabolic gene variants were characterized for the 1,172 (89% of total) cases and 982 (93%) controls who provided biological samples for genotyping. Subjects who were heterozygous or homozygous for the cytochrome P450 gene variant CYP1B1 V432L G allele were at slightly greater risk of non-Hodgkin's lymphoma [odds ratio (OR), 1.27; 95% confidence interval (95% CI), 0.97-1.65]; these results were consistent across B-cell lymphoma subtypes and among both non-Hispanic White and Black subjects, although not statistically significant. The CYP2E1 À1054T allele was associated with decreased risk of non-Hodgkin's lymphoma (CT and TT genotypes combined OR, 0.59; 95% CI, 0.37-0.93), and this pattern was observed among all histologic subtypes. The numbers of cases of particular subtypes were rather small for stable estimates, but we noted that the PON1 L55M AA allele, associated with slightly increased risk of nonHodgkin's lymphoma (variant homozygotes OR, 1.36; 95% CI, 0.96-1.95), was most strongly associated with follicular nonHodgkin's lymphoma and T-cell lymphoma, with ORs for variant homozygotes of 2.12 and 2.93, respectively. There was no overall association with non-Hodgkin's lymphoma for the other gene variants we examined. The modest effects we observed may reflect the context of exposures within the general population represented in our study. (Cancer Epidemiol Biomarkers Prev 2006;15(9):1647 -53)

Vegetables- and antioxidant-related nutrients, genetic susceptibility, and non-Hodgkin lymphoma risk

“…The 3-base deletion in GSTM3 may decrease transcript expression [37] and reduce ability of the enzyme to neutralize ROS. An independent effect of the 3-base deletion was not associated with NHL risk in our study population [12] although higher intake of vegetables and, specifically, cruciferous vegetables was associated with lower risk [9]. The 3-base deletion in GSTM3 has not been well studied and appears to be in linkage disequilibrium with the GSTM1 null allele in exon 4 [37], which we did not investigate.…”

“…The 3-base deletion in GSTM3 has not been well studied and appears to be in linkage disequilibrium with the GSTM1 null allele in exon 4 [37], which we did not investigate. Inheritance of both the GSTM3 3-base deletion and the GSTM1 null allele has been reported to confer increased cancer susceptibility [12]. The functional effect of the GSTP1 (A114V) SNP is unclear [38] and also was not independently associated with NHL risk in our sample [12].…”

“…Exposure categories were classified as above-median intake of the dietary variable using the control group's distribution [9] and as genotypes with ≥1 copies of the variant allele, depending on the genetic model from previous analyses [10][11][12][13]. Statistical significance of effect modification was evaluated with the Wald test in models that included a product term for the dietary variable and the genotype.…”

“…We previously reported inverse associations with NHL from increased intake of all, green leafy, and cruciferous vegetables and the nutrients lutein/zeaxanthin and zinc in a multicentered population-based case-control study of incident NHL [9]. In separate analyses, we also examined NHL risk by inherited differences in polymorphic genes in pathways of ROS neutralization and detoxification [10][11][12] and DNA repair [13]. In these reports [10][11][12][13], allelic variants of the genes encoding nitric oxide synthase 2A (NOS2A), manganese superoxide dismutase (SOD2), N-acetyltransferases (NAT1, NAT2), and X-Ray repair crosscomplementing proteins (XRCC1, XRCC3, XRCC4) were associated with increased NHL risk and a variant in the gene encoding myeloperoxidase (MPO) was associated with decreased risk.…”

“…In separate analyses, we also examined NHL risk by inherited differences in polymorphic genes in pathways of ROS neutralization and detoxification [10][11][12] and DNA repair [13]. In these reports [10][11][12][13], allelic variants of the genes encoding nitric oxide synthase 2A (NOS2A), manganese superoxide dismutase (SOD2), N-acetyltransferases (NAT1, NAT2), and X-Ray repair crosscomplementing proteins (XRCC1, XRCC3, XRCC4) were associated with increased NHL risk and a variant in the gene encoding myeloperoxidase (MPO) was associated with decreased risk. No significant and independent associations were observed between NHL and variation in the genes glutathione-S-transferases (GSTM3, GSTP1), NAD(P)H dehydrogenase quinone 1 (NQO1), CYP1A1, CYP1A2, and glutathione peroxidase 1 (GPX1), 8-oxoguanine DNA glycosylase 1 (OGG1), NOS3 and XRCC2.…”