A pooled investigation of Toll-like receptor gene variants and risk of non-Hodgkin lymphoma

Toll-like receptors (TLRs) may influence the development ofnon-Hodgkin lymphoma (NHL) given their important roles in recognizingmicrobial pathogens and stimulating multiple immune pathways.We conducted an investigation of TLR gene variants in a pooledanalysis including three population-based case–controlstudies of NHL (1946 cases and 1808 controls). Thirty-six tagsingle-nucleotide polymorphisms (SNPs) in TLR2, TLR4 and theTLR10–TLR1–TLR6 gene cluster were genotyped. TwoTLR10–TLR1–TLR6 variants in moderate linkage disequilibriumwere significantly associated with NHL: rs10008492 [odds ratiofor CT genotype (OR_CT) 1.12, 95% confidence interval (CI) 0.97–1.30;OR_TT 1.40, 95% CI 1.15–1.71; P_trend = 0.001] and rs4833103(OR_AC 0.75, 95% CI 0.64–0.88; OR_AA 0.74, 95% CI 0.62–0.90;P_trend = 0.002; P_dominant = 0.0002). Associations with theseSNPs were consistent across all the three studies and did notappreciably differ by histologic subtype. We found little evidenceof association between TLR2 variation and all NHL, althoughthe rare variant rs3804100 was significantly associated withmarginal zone lymphoma (MZL), both overall (OR_CT/CC 1.89, 95%CI 1.27–2.81; P_dominant = 0.002) and in two of the threestudies. No associations with TLR4 variants were observed. Thispooled analysis provides strong evidence that variation in theTLR10–TLR1–TLR6 region is associated with NHL riskand suggests that TLR2 variants may influence susceptibilityto MZL. Abbreviations: CI, confidence interval; CLL, chronic lymphocytic leukemia; DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; LD, linkage disequilibrium; MALT, mucosa-associated lymphoid tissue; MZL, marginal zone lymphoma; NCI, National Cancer Institute; NHL, non-Hodgkin lymphoma; NSW, New South Wales; OR, odds ratio; SEER, Surveillance Epidemiology and End Results; SLL, small lymphocytic lymphoma; SNP, single-nucleotide polymorphism; TLR, Toll-like receptor Received August 13, 2008; revised October 16, 2008; accepted November 18, 2008.     

Exposure to solvents and risk of non-Hodgkin lymphoma: clues on putative mechanisms.

Malignant lymphomas are a group of diseases of uncertain etiology. Both environmental factors and genetic susceptibility have been reported as risk factors. We have conducted a population-based case-control study in Italy: all newly diagnosed cases of malignant lymphoma, in males and females ages 20 to 74 years in the 1991 to 1993 period, were identified; the control group was comprised of a random sample of the general population resident in each of the areas under study, stratified by sex and 5-year age groups. Overall, 1,428 non-Hodgkin lymphoma (NHL) cases and 1,530 controls were interviewed. Experts from each geographic area examined questionnaire data and assigned a level of probability and intensity of exposure to a range of chemical groups and individual chemicals. For those in the medium/high level of exposure, there was an increased risk of NHL for exposure to benzene, xylene, and toluene. We have examined the hypothesis that the effect of solvents is related to their immunotoxicity by analyzing the interaction with a previous history of autoimmune disease. We have found an apparent, though not statistically significant, increased risk of NHL in those with both exposure to benzene and a history of autoimmune disease (odds ratio, 16.3; 95% confidence interval, 0.8-321). In addition, an odds ratio of 29.8 (95% confidence interval, 1.4-650.2, based on nine exposed cases) was associated with high-level exposure to benzene in those with a positive family history of malignant hematologic neoplasms. Both hypotheses (i.e., the interaction with autoimmune diseases and with familial predisposition) indirectly suggest that an immunologic mechanism could be involved in lymphomagenesis from solvents.     

肿瘤坏死因子α-308基因多态性与非霍奇金淋巴瘤易感性的Meta分析

目的 探讨肿瘤坏死因子α(TNF-α)-308G＞A基因多态性与非霍奇金淋巴瘤(NHL)易感性的关系.方法 在PubMed、中国知网、万方数据知识服务平台等数据库,检索淋巴瘤(或lymphoma)和肿瘤坏死因子(tumor necrosis factor或TNF)、基因多态性(polymorphism或SNP或variant或mutation),获取相关文献,采用固定效应模型或随机效应模型进行数据合并统计.发表偏移的评估采用Begg漏斗图和Egger检验.结果 共纳入15篇文献,包含9 738例NHL患者和10 854例对照人群.对入选文献数据进行综合分析,纯合子基因模型(AA比GG:OR=1.55,95％CI 1.30 ～ 1.86,I2=42.4％)和隐性基因模型(AA比AG+GG:OR=1.53,95％CI 1.27～1.83,I2=41.8％)的统计结果显示,TNF-α-308 AA基因可能增加NHL的发病风险.按种族来源不同进行分层分析,结果表明A等位基因可增加高加索人群罹患NHL的风险(A比G、AA比GG、AG比GG、AA比AG+GG、AA+AG比GG),但可降低亚裔人群的发病风险(A比G、AG比GG、AA+AG比GG).结论 TNF-α-308 G＞A基因多态性与NHL的发病风险相关.     

Organochlorines and risk of non-Hodgkin lymphoma

Organochlorine chemicals and polychlorinated biphenyls (PCBs) have been suspected as possible risk factors for non-Hodgkin lymphoma (NHL). We investigated PCBs and organochlorine pesticides and risk of NHL in a population-based case-control study in British Columbia, Canada. Congeners of PCBs (including dioxinlike congeners) and pesticides or pesticide metabolites were measured in plasma of 422 pretreatment cases and 460 control subjects. This is so far the largest study to examine organochlorines in plasma to date. Several dioxin-like PCB congeners were associated with increased risk of NHL, including dioxin-like PCB nos. 118 and 156 with odds ratios (OR) for the highest versus lowest quartile between 1.6 and 1.8. Several non-dioxin-like congeners also showed significant associations. The PCB congener with the strongest association was no. 180 with an OR for the highest versus the lowest quartile of 1.83 (95% confidence interval = 1.18-2.84). Six pesticide analytes also showed a significant association with NHL; beta-hexachlorocyclohexane, p,p'-DDE, hexachlorobenzene, mirex, oxychlordane and trans-nonachlor. The strongest association was found for oxychlordane, a metabolite of the pesticide chlordane (highest vs. lowest quartile OR = 2.68, 95% confidence interval = 1.69-4.24). Our results provide further evidence that organochlorines contribute to NHL risk.     

Single nucleotide polymorphism in 5'-flanking region of BCL6 is not associated with increased risk of non-Hodgkin's lymphoma

Mutations in the 5'-regulatory region of BCL6 were suggested to play a role in non-Hodgkin's lymphoma (NHL) progression and in the transformation of follicular lymphoma to more aggressive diffuse large B-cell type. The aim of this study was to explore association between polymorphism G397C in the 5'-region of BCL6 and both incidence and progression of NHL in 154 NHL cases and 362 controls. Neither frequencies of the rare BCL6 allele 397C nor particular genotypes differed significantly between NHL cases and controls. There was no significant association of histological type of NHL and clinical characteristics with this polymorphism.     

Interaction between organochlorines and the AHR gene, and risk of non-Hodgkin lymphoma

Background

Plasma organochlorines have been implicated to increase the risk of non-Hodgkin lymphoma (NHL), and interaction with the aryl hydrocarbon receptor gene (AHR) may modify this risk.

Methods

In this case–control study conducted in British Columbia, Canada, five single nucleotide polymorphisms (SNPs) of AHR were genotyped in 422 NHL cases and 459 controls to measure the association between individual SNPs, haplotypes, and risk of NHL. Pre-chemotherapy organochlorine levels were measured and gene–environment interaction analysis was performed.

Results

The IVS1 + 4640G/A SNP was significantly associated with NHL risk, with an odds ratio of 1.32 (95% CI = 1.05–1.65) for G/A or A/A genotypes compared to the G/G genotype. Interactions were observed with PCB 118, a known inducer of AHR, and chlordane-related analytes oxychlordane and trans-nonachlor, although no interactions were statistically significant after controlling for multiple comparisons. The observed interactions were consistent across NHL subtypes.

Conclusion

Results suggest that the AHR gene may play a role in determining the risk of NHL with exposure to organochlorines, and highlight the importance of understanding gene-environment interactions.     

Glucose-6-phosphate dehydrogenase polymorphism and lymphoma risk

AIMS AND BACKGROUND: Evidence linking the glucose-6-phosphate dehydrogenase (G6PD) polymorphism and risk of non-Hodgkin's lymphoma is conflicting. Risk of non-Hodgkin's lymphoma was increased in subjects expressing the G6PD deficient phenotype, whereas subjects under medication with statins, a lipid-lowering class of drugs partially mimicking G6PD deficiency, seemed to enjoy a protective effect. METHODS: We conducted a case-control study on lymphoma risk associated with the self-reported G6PD deficient phenotype in 122 lymphoma male cases and 116 male controls in Sardinia, Italy. The association with the GdMed+ genotype, the most frequent variant expressing a deficient enzyme activity, was also tested in 49 male lymphoma cases and 31 controls. The WHO classification was used to identify lymphoma subentities. RESULTS: Neither self-reported G6PD deficient phenotype nor the GdMed+ genotype showed an association with lymphoma risk or its subentities. CONCLUSIONS: Our results do not confirm an association either positive or negative between the G6PD polymorphism and lymphoma risk.     

Occupation and the risk of non-Hodgkin lymphoma.

Although thus far no occupational agents have been classified as established causes of non-Hodgkin lymphoma (NHL), employment as a farmer, teacher, dry cleaner, meat worker, printer, or wood worker has been associated with elevated risk in the peer-reviewed literature. We conducted several meta-analyses to assess risk in these occupations and industries from articles published in MEDLINE up to August 1, 2006. The summary risk estimates suggest a homogeneous excess risk for NHL among workers in the printing industry [relative risk (RR), 1.86; 95% confidence interval (95% CI), 1.37-2.52] and wood workers (RR, 1.15; 95% CI, 1.00-1.31). Considerable heterogeneity but elevated risks were found for farmers (RR, 1.11; 95% CI, 1.05-1.17), especially in animal husbandry (RR, 1.31; 95% CI, 1.08-1.60), and teaching (RR, 1.47; 95% CI, 1.34-1.61). An increased risk was absent for employment in the meat processing industry (RR, 0.99; 95% CI, 0.77-1.29). These results suggest that although excess risk is found for employment in the printing industry, wood processing industry, teaching, and farming, it is unlikely that occupation represents a major risk factor for NHL in most populations. At present, no conclusive evidence of causal relations between occupations and increased NHL risk exists; this can be ascribed to methodologic problems in studying the link between NHL risk and occupation, including heterogeneity of disease and exposure circumstances and low statistical power. Implementing state-of-the-art exposure assessment technologies, including biomarker-based assessment, and aiming to identify susceptible subgroups can increase the statistical power enough to analyze etiologically relevant NHL subtypes and provide clues on possible causal agents in future studies. These goals can be best attained within the framework of large-scale, international collaborative projects.     

Meat intake and risk of non-Hodgkin lymphoma

We conducted a population-based, case-control study to test the hypothesis that consumption of meat and meat-related mutagens increases the risk of non-Hodgkin lymphoma (NHL), and whether the associations are modified by N-acetyltransferase (NAT) 1 and 2. Participants (336 cases and 460 controls) completed a 117-item food frequency questionnaire. The risk of NHL was associated with a higher intake of red meat (OR?=?1.5; CI, 1.1-2.2), total fat (OR?=?1.4; CI, 1.0-2.1), and oleic acid (OR?=?1.5; CI, 1.0-2.2). NHL risk was also associated with a higher intake of very well-done pork (OR?=?2.5; 95?% CI, 1.4-4.3) and the meat-related mutagen MeIQx (OR?=?1.6; 95?% CI, 1.1-2.3). Analyses of the major NHL histologic subtypes showed a positive association between diffuse large B cell lymphoma (DLBCL) and higher intake of red meat (OR?=?2.1; 95?% CI, 1.1-3.9) and the association was largely due to meat-related mutagens as a positive association was observed for higher intakes of both MeIQx (OR?=?2.4; 95?% CI, 1.2-4.6) and DiMeIQx (OR?=?1.9; 95?% CI, 1.0-3.5). Although the OR for follicular lymphoma (FL) was also increased with a higher red meat intake (OR?=?1.9; 95?% CI, 1.1-3.3), the association appeared to be due to increased oleic acid (OR?=?1.7; 95?% CI: 0.9-3.1). We found no evidence that polymorphisms in NAT1 or NAT2 modify the association between NHL and meat-related mutagens. Our results provide further evidence that red meat consumption is associated with an increase in NHL risk, and new evidence that the specific components of meat, namely fat and meat-related mutagens, may be impacting NHL subtype risk differently.     

A polymorphism in the BCL-6 gene is associated with follicle center lymphoma

Follicle center lymphoma (FCL) accounts for approximately 40% of all non-Hodgkin's lymphomas (NHL). The genetic-environmental interactions involved in the etiology and pathogenesis of this disease are unknown. In our previous study a single nucleotide polymorphism (SNP) (397C) in the regulatory untranslated first intron region of the BCL-6 gene was found in four of the eight FCL patients but in none of the 10 healthy controls. To further evaluate the potential association between the 397C allele of the BCL-6 gene and FCL, we performed a case-control study. Genomic DNA was isolated from 85 FCL patients, from 98 control cases without a previous history of malignancy, treated at Stanford University Medical Center for non-malignant disorders and from 90 samples from the DNA Polymorphism Discovery Resource. The 397G and the 397C polymorphic alleles were identified by a PCR-RFLP method. To evaluate the possible effect of this polymorphism on gene expression, BCL-6 mRNA levels in nine FCL tumors with the 397G-G genotype and in nine FCL tumors with the 397G-C genotype were measured by quantitative real-time RT-PCR. The 397C polymorphic allele was found in 32 FCL cases (37.6%), in 20 controls (20.4%) and in 17 (18.9%) samples from the DNA Polymorphism Discovery Resource. The prevalence of the 397G-C and 397C-C genotypes was significantly higher in FCL cases than in control group (p = 0.01). No difference in BCL-6 gene expression was observed between FCL cases with 397G-G and 397G-C genotypes. The present study demonstrates a possible association between the 397C allele of the BCL-6 proto-oncogene and FCL. The similar levels of BCL-6 mRNA expression in 397G-G and in 397G-C FCL cases suggests that any possible oncogenic effect of the polymorphic allele would not simply be related to a direct effect on BCL-6 gene expression and suggests the existence of other FCL susceptibility genes that are in linkage disequilibrium with the 397C allele of the BCL-6 gene.     

Sun exposure, vitamin D receptor gene polymorphisms and risk of non-Hodgkin lymphoma

Objective Recent findings suggest that ultraviolet (UV) radiation exposure may reduce risk of developing non-Hodgkin lymphoma (NHL), but the biologic basis for this relationship remains unclear. We analyzed data from our US population-based case–control study of NHL to investigate whether our previously reported inverse association with sun exposure was dependent upon variants in the vitamin D receptor gene (IVS10 + 283G > A (BsmI), Ex11 + 32T > C (TaqI)), and genes linked to UV-induced immune modulation (IL4, IL10, IL12A, IL12B, TNF). Methods UV exposure data was collected from an in-person interview with 551 cases and 462 controls. We calculated odds ratios (OR) and 95% confidence intervals (CI) for sun exposure measures for joint variant-exposure effects. Results The association with NHL risk for time in the midday sun within the last decade was dependent upon Ex11 + 32 T > C genotype. Compared to TT carriers who reported < 7 h/week of sun exposure, CC subjects with < 7 h/week of sun exposure had an increased risk of NHL (OR = 1.9, 95% CI 0.8–4.4, P_interaction = 0.16), while the relative risks for other CC carriers approached unity with increasing level of sun exposure. This pattern of effects was especially apparent for follicular lymphoma (for CC genotype and < 7 h/week of exposure: OR 6.3, 95% CI 1.9–22, P_interaction = 0.004), and was consistently observed across measures of reported sun exposure for different periods of life. As IVS10 + 283G > A is correlated with Ex11 + 32T > C in our population (r ² = 0.95), results were equivalent for those with the IVS10 + 283 AA genotype. No evidence of interaction with cytokine gene variants was observed. Conclusions Our results suggest that the inverse association between UV exposure and NHL risk may be mediated by the vitamin D pathway. Further investigation of this finding in other studies is warranted. The U.S. Government's right to retain a non-exclusive, royalty-free license in and to any copyright is acknowledged.     

Household endotoxin levels and the risk of non-Hodgkin lymphoma

Objective

Endotoxin, a component of the outer membrane of gram-negative bacteria, elicits a strong innate and inflammatory immune response associated with the secretion of proinflammatory cytokines, including tumor necrosis factor-alpha (TNF-α). Because TNF-α polymorphisms that increase TNF-α production are associated with an increased risk of non-Hodgkin lymphoma (NHL), we hypothesized that increased levels of household endotoxin would be associated with an increased NHL risk.

Methods

We evaluated this association in the National Cancer Institute/Surveillance, Epidemiology and End Results (NCI/SEER) NHL multicenter population-based case–control study. Used vacuum cleaner bags were collected from participants during a home interview. Dust samples from the bags of 594 cases and 442 controls were analyzed for endotoxin [endotoxin unit (EU)/mg of dust] using the kinetic chromogenic Limulus amebocyte lysate assay. Multivariable logistic regression was used to estimate the effect of endotoxin on NHL risk adjusted for age, sex, race, education, study center, and farm exposure.

Results

Endotoxin was not associated with NHL overall [odds ratio (OR) for highest quartile of endotoxin levels = 0.81, 95 % confidence interval (CI) = 0.55, 1.20; p for trend = 0.35] or with diffuse large B-cell lymphoma (OR = 0.63, 95 % CI = 0.34, 1.16; p = 0.31) or follicular lymphoma (OR = 1.07, 95 % CI = 0.61, 1.89; p = 0.73) subtypes. Both working and living on a farm were associated with higher household endotoxin levels compared to never working (p = 0.009) or living (p = 0.01) on a farm. Excluding farmers from the analysis did not change the results.

Conclusions

We found no evidence of a role for household endotoxin in NHL etiology.     

Benzene exposure and risk of non-Hodgkin lymphoma.

Exposure to benzene, an important industrial chemical and component of gasoline, is a widely recognized cause of leukemia, but its association with non-Hodgkin lymphoma (NHL) is less clear. To clarify this issue, we undertook a systematic review of all case-control and cohort studies that identified probable occupational exposures to benzene and NHL morbidity or mortality. We identified 43 case-control studies of NHL outcomes that recognized persons with probable occupational exposure to benzene. Forty of these 43 (93%) studies show some elevation of NHL risk, with 23 of 43 (53%) studies finding statistically significant associations between NHL risk and probable benzene exposure. We also identified 26 studies of petroleum refinery workers reporting morbidity or mortality for lymphomas and all neoplasms and found that in 23 (88%), the rate of lymphoma morbidity or mortality was higher than that for all neoplasms. A substantial healthy-worker effect was evident in many of the studies and a comprehensive reevaluation of these studies with appropriate adjustments should be undertaken. Numerous studies have also reported associations between benzene exposure and the induction of lymphomas in mice. Further, because benzene is similar to alkylating drugs and radiation in producing leukemia, it is plausible that it might also produce lymphoma as they do and by similar mechanisms. Potential mechanisms include immunotoxicity and the induction of double-strand breaks with subsequent chromosome damage resulting in translocations and deletions. We conclude that, overall, the evidence supports an association between occupational benzene exposure and NHL.     

No association between the TP53 codon 72 polymorphism and risk or prognosis of Hodgkin and non-Hodgkin lymphoma

The role of the TP53 gene's R72P polymorphism in non-Hodgkin lymphoma (NHL) has been analyzed in several studies but it has not been studied in Hodgkin lymphoma (HL). We have evaluated the role of R72P in 340 NHL and 298 HL patients. There was no difference in the R72P frequency between analyzed lymphoma cases and 749 controls. We found no association of R72P with the risk of NHL and HL development [OR_{ArgPro/ProPro} = 0.9 (95% CI 0.7-1.2) and 1.2 (95% CI 0.9-1.5), respectively] or with survival. Our results support the evidence that R72P is not a prognostic factor in Caucasian NHL patients, and they indicate its irrelevance for HL development or prognosis.