There is growing evidence linking genetic variations to non–Hodgkin lymphoma (NHL) etiology. To complement ongoing agnostic approaches for identifying susceptibility genes, we evaluated 488 candidate gene regions and their relation to risk for NHL and NHL subtypes.
We genotyped 6,679 tag single nucleotide polymorphisms (SNPs) in 947 cases and 826 population-based controls from a multicenter U.S. case–control study. Gene-level summary of associations were obtained by computing the minimum P value (“minP test”) on the basis of 10,000 permutations. We used logistic regression to evaluate the association between genotypes and haplotypes with NHL. For NHL subtypes, we conducted polytomous multivariate unconditional logistic regression (adjusted for sex, race, age). We calculated P-trends under the codominant model for each SNP.
Fourteen gene regions were associated with NHL (P < 0.01). The most significant SNP associated with NHL maps to the SYK gene (rs2991216, P-trend = 0.00005). The three most significant gene regions were on chromosome 6p21.3 (RING1/RXRB; AIF1; BAT4). Accordingly, SNPs in RING1/RXRB (rs2855429), AIF1 (rs2857597), and BAT4 (rs3115667) were associated with NHL (P-trends ≤ 0.0002) and both diffuse large B-cell and follicular lymphomas (P-trends < 0.05).
Our results suggest potential importance for SYK on chromosome 9 with NHL etiology. Our results further implicate 6p21.3 gene variants, supporting the need for full characterization of this chromosomal region in relation to lymphomagenesis.
Gene variants on chromosome 9 may represent a new region of interesting for NHL etiology. The independence of the reported variants in 6p21.3 from implicated variants (TNF/HLA) supports the need to confirm causal variants in this region
Safety concerns surround the use of long-acting beta agonists (LABA) for the treatment of asthma, even in combination with inhaled corticosteroids (ICS) and particularly in high-risk subgroups.
To estimate the effect ICS therapy and fixed-dose ICS/LABA combination therapy on severe asthma exacerbations in a racially diverse population.
Inhaled corticosteroid and ICS/LABA exposure was estimated from pharmacy data for patients with asthma age 12 to 56 years who were members of a large health maintenance organization. Inhaled corticosteroid and ICS/LABA use was estimated for each day of follow-up to create a moving window of exposure. Proportional hazard models were used to assess the relationship between ICS and ICS/LABA combination therapy and severe asthma exacerbations (i.e., use of oral corticosteroids, asthma-related emergency department visit, or asthma-related hospitalization).
Among the 1,828 patients who met the inclusion criteria, 37% were African American, 46% were treated with ICS therapy alone, and 54% were treated with an ICS/LABA combination. Models assessing the risk of severe asthma exacerbations among individuals using ICS treatment alone and ICS/LABA combination therapy suggested that the overall protective effect was as good or better for ICS/LABA combination therapy when compared with ICS treatment alone (hazard ratio [HR]=0.65 vs. HR=0.72, respectively). Analyses in several subgroups, including African American patients, showed a similar statistically significant protective association for combination therapy.
Treatment with ICS/LABA fixed combination therapy appeared to perform as well or better than ICS alone in reducing severe asthma exacerbations; this included multiple high-risk subgroups.
Long-acting beta-agonist; inhaled corticosteroid; severe asthma exacerbation; safety; racially and ethnically diverse population; observational study
Quercetin is a flavonol that appears to be protective against several cancers, but its possible role in prevention of colorectal cancer is not yet well studied. We evaluated dietary intakes of quercetin and risk of colorectal cancer in a large case-control study conducted in Metropolitan Detroit, MI (n = 2664). The protective effects of quercetin intake, as assessed by food frequency questionnaire, were confined to risk of proximal colon cancer. Stratified analyses showed that the protective effects of quercetin on risk of proximal colon cancer were significant only when fruit intake or the Healthy Eating Index score were high, or when tea intake was low, with odds ratios (OR) for the highest versus the lowest quartile = 0.49, 0.44, and 0.51, respectively. Increased quercetin intake had no protective effects when tea intake was high. Interestingly, increased intake of quercetin was associated with increased risk of distal colon cancer when total fruit intake was low (OR for the highest versus the lowest quartile = 1.99). These results suggest that quercetin can have disparate effects on colon cancer risk depending on whether dietary intakes of fruit or tea are high, and that quercetin had protective effects only on proximal, not distal, colon cancer.
diet; quercetin; distal colon cancer; proximal colon cancer; epidemiological
The t(14;18) chromosomal translocation is the most common cytogenetic abnormality in NHL, occurring in 70–90% of follicular lymphomas (FL) and 30–50% of diffuse large B-cell lymphomas (DLBCL). Previous t(14;18)-NHL studies have not evaluated risk factors for NHL defined by both t(14;18) status and histology. In this population-based case-control study, t(14;18) status was determined in DLBCL cases using fluorescence in situ hybridization on paraffin-embedded tumor sections. Polytomous logistic regression was used to evaluate the association between a wide variety of exposures and t(14;18)-positive (N=109) and −negative DLBCL (N=125) and FL (N=318), adjusting for sex, age, race and study center. Taller height, more lifetime surgeries, and PCB180 exposure were associated with t(14;18)-positivity. Taller individuals (3rd tertile vs. 1st tertile) had elevated risks of t(14;18)-positive DLBCL [odds ratio (OR)=1.8, 95% confidence interval (CI) 1.1–3.0] and FL (OR=1.4, 95%CI 1.0–1.9) but not t(14;18)-negative DLBCL. Similar patterns were seen for individuals with more lifetime surgeries [13+ versus 0–12 surgeries; t(14;18)-positive DLBCL OR=1.4, 95%CI 0.7–2.7; FL OR=1.6, 95%CI 1.1–2.5] and individuals exposed to PCB180 greater than 20.8 ng/g [t(14;18)-positive DLBCL OR=1.3, 95%CI 0.6–2.9; FL OR=1.7, 95%CI 1.0–2.8]. In contrast, termite treatment and high alpha-chlordane levels were associated with t(14;18)-negative DLBCL only, suggesting that these exposures do not act through t(14;18). Our findings suggest that putative associations between NHL and height, surgeries, and PCB180 may be t(14;18)-mediated and provide support for case-subtyping based on molecular and histologic subtypes. Future efforts should focus on pooling data to confirm and extend previous research on risk factors for t(14;18)-NHL subtypes.
lymphoma; non-Hodgkin; case–control studies; translocation; follicular lymphoma; diffuse large B-cell lymphoma; etiology
Genetic variation in the 6p21 chromosomal region, including human leukocyte antigen (HLA) genes and tumor necrosis factor (TNF), has been linked to both etiology and clinical outcomes of lymphomas. We estimated the effects of HLA class I (A, B, and C), class II DRB1 alleles, and the ancestral haplotype (AH) 8.1 (HLAA*01-B*08-DRB1*03-TNF-308A) on overall survival (OS) among patients with diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) in a population-based study of non-Hodgkin lymphoma. During a median followup of 89 months, 31% (52 of 166) DLBCL and 28% (46 of 165) FL patients died. Using multivariate Cox regression models, we observed statistically significant associations between genetic variants and survival: HLA-Cw*07:01 was associated with poorer OS among DLBCL patients (Hazard ratio [HR] = 1.76, 95% confidence interval [CI] = 1.01–3.05); HLA-A*01:01 was associated with poorer OS (HR = 2.23, 95% CI = 1.24–4.01), and HLA-DRB1*13 (HR = 0.12, 95% CI = 0.02–0.90) and HLA-B Bw4 (HR = 0.36, 95% CI = 0.20–0.63) with better OS among FL patients. These results support a role for HLA in the prognosis of DLBCL and FL and represent a promising class of prognostic factors that warrants further evaluation.
human leukocyte antigen; tumor necrosis factor; diffuse large B-cell lymphoma; follicular lymphoma; survival
Dysfunctional lipid metabolism plays a central role in pathogenesis of major chronic diseases, and genetic factors are important determinants of individual lipid profiles. We analyzed the associations of two well-established functional polymorphisms (FABP2 A54T and APOE isoforms) with past and family histories of 1492 population samples. FABP2-T54 allele was associated with an increased risk of past history of myocardial infarction (odds ratio (OR) = 1.51). Likewise, the subjects with APOE4, compared with E2 and E3, had a significantly increased risk of past history myocardial infarction (OR = 1.89). The OR associated with APOE4 was specifically increased in women for past history of myocardial infarction but decreased for gallstone disease. Interactions between gender and APOE isoforms were also significant or marginally significant for these two conditions. FABP2-T54 allele may be a potential genetic marker for myocardial infarction, and APOE4 may exert sex-dependent effects on myocardial infarction and gallbladder disease.
Inconsistent observations in epidemiologic studies on the association between total fat intake and colorectal cancer may be ascribed to opposing effects of individual fatty acids and the presence of other dietary constituents that modify luminal or systemic lipid exposure. We analyzed the data from a population-based case-control study that included 1163 cases and 1501 controls to examine the effects of individual fatty acid groups on colorectal cancer risk as well as their interactions with calcium and fiber intake. Odds ratios (OR) and 95% confidence intervals (CI) were estimated by unconditional logistic regression model according to quartile levels of energy-adjusted fatty acid intake. In the bivariable analyses, the risk of colorectal cancer increased with trans fatty acid (TFA) intake (OR for top vs bottom quartile =1.46, 95% CI 1.17-1.59, p-value for a trend <0.001 ), but the associations was substantially attenuated in multivariable analyses (p-value for a trend =0.176). However, a significant linear trend in the multivariable OR (p=0.029) for TFA was present for subjects with lower calcium intake. Furthermore, multivariable ORs progressively decreased with increasing both omega-3 and omega-6 polyunsaturated fatty acid intake (P-values for linear trend: 0.033 and 0.011, respectively) for subjects with lower dietary fiber intake. These interactions were also significant or marginally significant (P = 0.085 for TFA, 0.029 for omega-3 and 0.068 for omega-6). Our results suggest that populations with lower intake of luminal modifiers, i.e., calcium and fiber, may have differential risks of colorectal cancer associated with dietary fatty acid intake.
Fatty acids; colorectal cancer; case-control study; calcium; fiber
Smoking, alcohol use, and obesity appear to increase the risk of developing non-Hodgkin lymphoma (NHL), but few studies have assessed their impact on NHL prognosis.
We evaluated the association of pre-diagnosis cigarette smoking, alcohol use, and body mass index (BMI) on overall survival in 1,286 patients enrolled through population-based registries in the United States from 1998–2000. Hazard Ratios (HR) and 95% confidence intervals (CI) were estimated using Cox regression, adjusting for clinical and demographic factors.
Through 2007, 442 patients died (34%), and the median follow-up on living patients was 7.7 years. Compared to never smokers, former (HR=1.59; 95% CI 1.12–2.26) and current (HR=1.50; 95% CI 0.97–2.29) smokers had poorer survival, and poorer survival was positively associated with smoking duration, number of cigarettes smoked per day, pack-years of smoking, and shorter time since quitting (all p-trend<0.01). Alcohol use was associated with poorer survival (p-trend=0.03); compared to non-users, those drinking more than 43.1 grams/week (median of intake among drinkers) had poorer survival (HR=1.55; 95% CI 1.06–2.27) while those drinkers consuming less than this amount showed no survival disadvantage (HR=1.13; 95% CI 0.75–1.71). Greater body mass index was associated with poorer survival (p-trend=0.046), but the survival disadvantage was only seen among obese individuals (HR=1.32 for BMI ≥30 versus 20–24.9 kg/m2; 95% CI 1.02–1.70). These results held for lymphoma-specific survival and were broadly similar for DLBCL and follicular lymphoma.
NHL patients who smoked, consumed alcohol or were obese prior to diagnosis had a poorer overall and lymphoma-specific survival.
alcohol; non-Hodgkin lymphoma; obesity; smoking; survival
Fat absorption may play a crucial role in colorectal carcinogenesis by determining intra-colonic exposure to potentially carcinogenic lipid metabolites.
We conducted a population-based case-control study that included 1163 cases and 1501 controls to examine whether individuals who carry genetic variants associated with lower lipid absorption have a higher risk of colorectal cancer. Using Taqman assay, we determined FABP2 alanine (A)/threonine (T) polymorphism at codon 54 in exon-2 and APOE isoforms. Multivariable odds ratios (OR) and 95% confidence intervals (CI) were calculated by unconditional logistic regression models, assuming FABP2 A54 and APO non-E4 as high risk alleles.
We found no associations with either of the polymorphisms. The OR associated with FABP2 A54 homozygotes compared with the others was 1.01 (95% CI; 0.86–1.45) and that for non-ApoE4 carriers compared with carries was 0.95 (95% CI; 0.80–1.13). However, there was a statistically significant negative interaction between total fat intake and FABP2 AA genotypes (P=0.025), indicating that the risk of colorectal cancer associated with this polymorphism is higher in the subjects with lower fat intake.
These results suggest that these SNPs may not be useful in predicting colorectal cancer risk in populations with high fat intake.
Colorectal cancer; Case-control study; Lipid absorption; Single nucleotide polymorphism (SNP)
To identify occupations and industries associated with non-Hodgkin lymphoma in a large population-based case-control study in the United States.
Cases (n = 1,189) of histologically confirmed malignant NHL ages 20–74 were prospectively identified in four geographic areas covered by the National Cancer Institute SEER Program. Controls (n = 982) were selected from the general population by random digit dialing (< 65 years of age) and from residents listed in Medicare files (65–74 years of age). Odds ratios and 95% confidence intervals for occupations and industries were calculated by unconditional logistic regression analyses, adjusting for age, gender, ethnicity, and study center. Further analyses stratified for gender and histological subtype were also performed.
Risk of NHL was increased for a few occupations and industries. Several white collar occupations, with no obvious hazardous exposures, had elevated risks, including purchasing agents and buyers, religious workers, physical therapists, and information clerks. Occupations with excesses that may have exposures of interest include launderers and ironers, service occupations, food/beverage preparation supervisors, hand packers and packagers, roofing and siding, leather and leather products, transportation by air, nursing and personal care facilities, and specialty outpatient clinics. Significantly decreased risks of NHL were found for a number of occupations and industries including post secondary teachers and chemical and allied products.
The results of this study suggest that several occupations and industries may alter the risk of NHL. Our results support previously reported increased risks among farmers, printers, medical professionals, electronic workers, and leather workers. These findings should be evaluated further in larger studies that have the power to focus on specific exposures and histologic subtypes of NHL.
Non Hodgkin lymphoma; occupation; industry
Previous epidemiologic findings suggest an association between exposure to trichloroethylene (TCE), a chlorinated solvent primarily used for vapor degreasing of metal parts, and non-Hodgkin lymphoma (NHL).
We investigated the association between occupational TCE exposure and NHL within a population-based case–control study using detailed exposure assessment methods.
Cases (n = 1,189; 76% participation rate) and controls (n = 982; 52% participation rate) provided information on their occupational histories and, for selected occupations, on possible workplace exposure to TCE using job-specific interview modules. An industrial hygienist assessed potential TCE exposure based on this information and a review of the TCE industrial hygiene literature. We computed odds ratios (ORs) and 95% confidence intervals (CIs) relating NHL and different metrics of estimated TCE exposure, categorized using tertiles among exposed controls, with unexposed subjects as the reference group.
We observed associations with NHL for the highest tertiles of estimated average weekly exposure (23 exposed cases; OR = 2.5; 95% CI, 1.1–6.1) and cumulative exposure (24 exposed cases; OR = 2.3; 95% CI, 1.0–5.0) to TCE. Tests for trend with these metrics surpassed or approached statistical significance (p-value for trend = 0.02 and 0.08, respectively); however, we did not observe dose–response relationships across the exposure levels. Overall, neither duration nor intensity of exposure was associated with NHL, although we observed an association with the lowest tertile of exposure duration (OR = 2.1; 95% CI, 1.0–4.7).
Our findings offer additional support for an association between high levels of exposure to TCE and increased risk of NHL. However, we cannot rule out the possibility of confounding from other chlorinated solvents used for vapor degreasing and note that our exposure assessment methods have not been validated.
cancer; non-Hodgkin lymphoma; occupational; solvents; trichloroethylene
To investigate the relationship between selected solvent-related workplace tasks (degreasing, painting, gluing, stripping paint, staining) and risk of non-Hodgkin lymphoma (NHL).
We analyzed occupational data from a large population-based case-control study of NHL conducted in the United States. For participants reporting occupations with possible exposure to organic solvents, job-specific interview modules were administered to elicit in-depth information on solvent-related workplace tasks and other exposure-related factors (225 cases, 189 controls). Unconditional logistic regression models were fit to calculate odds ratios (OR) and 95% confidence intervals (CI) for average frequency, maximal frequency and cumulative number of hours having performed each task. Individuals with jobs rated as unexposed to organic solvents in the workplace (180 cases, 213 controls) were used as a reference group.
We observed an increased risk of NHL among subjects in the highest category of maximal degreasing frequency (>520 hours/year: OR 2.1, 95% CI 0.9-4.9, trend test p=0.02). We found similar associations for the highest levels of average frequency and, among men, cumulative number of hours. Other solvent-related tasks were not associated with NHL.
Findings from this case-control analysis of solvent-related tasks suggest that frequent degreasing work may be associated with an elevated risk of NHL.
non-Hodgkin lymphoma; solvents; case-control studies; degreasing
Compare the risk of reproductive and infant outcomes between male childhood cancer survivors and a population-based comparison group.
Retrospective cohort study.
4 U.S. regions.
Cancer registries identified males <20 years old diagnosed with cancer 1973−2000. Linked birth certificates identified first subsequent live offspring (n=470). Comparison subjects were identified from remaining birth certificates, frequency-matched on year and age at fatherhood, and race/ethnicity (n=4150).
Cancer diagnosis prior to age 20.
Pregnancy and infant outcomes identified from birth certificates.
Compared with infants born to unaffected males, offspring of cancer survivors had a borderline risk of birth weight <2500 g (RR 1.43, 95% CI 0.99−2.05), with risk associated most strongly with younger age of cancer diagnosis and exposure to any chemotherapy (RR 1.96, 95% CI 1.22−3.17) or radiotherapy (RR 1.95, 95% CI 1.14−3.35). However, they were not at risk of being born prematurely, small for gestational age, having malformations or an altered male:female sex ratio. Overall, female partners of male survivors were not more likely to have maternal complications recorded on birth records versus the comparison group. However, preeclampsia was associated with some cancers, especially central nervous system tumors (RR 3.36, 95% CI 1.63−6.90).
Most pregnancies resulting in live births among partners of male childhood cancer survivors were not at significantly greater risk of complications versus comparison subjects. The possibility of a paternal component affected by prior cancer history influencing predisposition towards some adverse perinatal outcomes merits further investigation.
male; cancer survivors; pregnancy outcome; low birth weight
To compare birth outcomes among childhood and adolescent female cancer survivors who subsequently bear children, relative to those of women without cancer history.
Retrospective cohort study.
4 U.S. regions.
Cancer registries identified girls <20 years, diagnosed with cancer 1973-2000. Linked birth records identified first live births after diagnosis (n=1898). Comparison subjects were selected from birth records (n=14278). Cervical/genital tract cancer cases were analyzed separately.
Cancer diagnosis <20 years.
Infant low birth weight, preterm delivery, sex ratio, malformations, mortality, delivery method; maternal diabetes, anemia, preeclampsia.
Childhood cancer survivors' infants were more likely to be preterm (relative risk [RR] 1.54, 95% CI 1.30-1.83) and weigh <2500 g (RR 1.31, 95% CI 1.10-1.57). For cervical/genital cancer patients' offspring, estimates were 1.33 (95% CI 1.13, 1.56), and 1.29 (95% CI 1.10-1.53), respectively. There were no increased risks of malformations, infant death, or altered sex ratio, suggesting no increased germ cell mutagenicity. In exploratory analysis, bone cancer survivors had an increased risk of diabetes (RR 4.92, 95% CI 1.60-15.13), and anemia was more common among brain tumor survivors (RR 3.05, 95% CI 1.16-7.98) and childhood cancer survivors with initial treatment of chemotherapy only (RR 2.45, 95% CI 1.16-5.17).
Infants of female childhood and adolescent cancer patients were not at increased risk of malformations or death. Increased occurrence of preterm delivery and low birth weight suggest close monitoring is warranted. Increased diabetes and anemia among sub-groups have not been reported, suggesting areas for study.
cancer survivors; pregnancy outcome; low birth weight; premature birth; congenital abnormalities
We compared long-term survivors of invasive and noninvasive cervical cancer (1) to determine if there are differences in the quality of life (QOL) and (2) to assess the association between self-esteem and QOL.
A sample of cervical cancer survivors diagnosed with invasive and noninvasive cervical cancer during 1995–1996 was drawn from the metropolitan Detroit Surveillance, Epidemiology, and End Results (SEER) cancer registry. There were 145 participating survivors, 42 with invasive and 103 with noninvasive cervical cancer. Data were collected using a structured interview, conducted primarily over the telephone. The outcome measures were the QOL (measured by the Medical Outcomes Study Short Form-36 [SF-36]) summary scales, the Physical Component Summary (PCS) score and the Mental Component Summary (MCS) score. Differences in MCS and PCS between women with invasive and noninvasive cancer were determined using analysis of covariance (ANCOVA). Multivariate analysis was performed to determine the association between self-esteem and MCS and PCS.
There were no differences in either PCS or MCS scores between long-term survivors of invasive and noninvasive cervical cancer. Self-esteem was associated with MCS but not with PCS in women with invasive cancer as well as in women with noninvasive cancer.
The distinctive association of self-esteem with MCS but not PCS indicates that interventions for supporting and improving self-esteem may be more effective by promoting psychological well-being rather than physical well-being. Moreover, women with noninvasive cervical cancer, a group often neglected in cervical cancer studies, should also be targeted for these interventions.
Chromosomal translocations are the hallmark genetic aberration in non-Hodgkin lymphoma (NHL), with specific translocations often selectively associated with specific NHL subtypes. Because many NHL-associated translocations involve cell cycle, apoptosis, and lymphocyte development regulatory genes, we evaluated NHL risk associated with common genetic variation in 20 candidate genes in these pathways. Genotyping of 203 tag single nucleotide polymorphisms (SNPs) was conducted in 1946 NHL cases and 1808 controls pooled from three independent population-based case-control studies. We used logistic regression to compute odds ratios (OR) and 95% confidence intervals (CI) for NHL and four major NHL subtypes in relation to tag SNP genotypes and haplotypes. We observed the most striking associations for tag SNPs in the pro-apoptotic gene BCL2L11 (BIM) and BCL7A, which is involved in a rare NHL-associated translocation. Variants in BCL2L11 were strongly related to follicular lymphoma only, particularly rs3789068 (ORAG=1.41, 95%CI 1.10–1.81; ORGG=1.65, 95%CI 1.25–2.19; p-trend=0.0004). Variants in BCL7A were strongly related to diffuse large B-cell lymphoma only, particularly rs1880030 (ORAG=1.34, 95%CI 1.08–1.68; ORAA=1.60, 95%CI 1.22–2.08; p-trend=0.0004). The associations for both variants were similar in all three studies and supported by haplotype analyses. We also observed notable associations for variants in BCL6, CCND1, and MYC. Our results support the role of common genetic variation in cell cycle, apoptosis, and lymphocyte development regulatory genes in lymphomagenesis, and suggest that effects may vary by NHL subtype. Replication of our findings and further study to identify functional SNPs are warranted.
lymphoma; non-Hodgkin; polymorphism; single nucleotide; apoptosis; cell cycle
Toll-like receptors (TLRs) may influence the development of non-Hodgkin lymphoma (NHL) given their important roles in recognizing microbial pathogens and stimulating multiple immune pathways. We conducted an investigation of TLR gene variants in a pooled analysis including three population-based case–control studies of NHL (1946 cases and 1808 controls). Thirty-six tag single-nucleotide polymorphisms (SNPs) in TLR2, TLR4 and the TLR10–TLR1–TLR6 gene cluster were genotyped. Two TLR10–TLR1–TLR6 variants in moderate linkage disequilibrium were significantly associated with NHL: rs10008492 [odds ratio for CT genotype (ORCT) 1.12, 95% confidence interval (CI) 0.97–1.30; ORTT 1.40, 95% CI 1.15–1.71; Ptrend = 0.001] and rs4833103 (ORAC 0.75, 95% CI 0.64–0.88; ORAA 0.74, 95% CI 0.62–0.90; Ptrend = 0.002; Pdominant = 0.0002). Associations with these SNPs were consistent across all the three studies and did not appreciably differ by histologic subtype. We found little evidence of association between TLR2 variation and all NHL, although the rare variant rs3804100 was significantly associated with marginal zone lymphoma (MZL), both overall (ORCT/CC 1.89, 95% CI 1.27–2.81; Pdominant = 0.002) and in two of the three studies. No associations with TLR4 variants were observed. This pooled analysis provides strong evidence that variation in the TLR10–TLR1–TLR6 region is associated with NHL risk and suggests that TLR2 variants may influence susceptibility to MZL.
Sun exposure and sensitivity, including pigmentation, are associated with risk for non-Hodgkin lymphoma (NHL). One variant in the immune regulatory factor 4 (IRF4) gene (rs12203592) is associated with pigmentation, and a different IRF4 variant (rs12211228) is associated with NHL risk. We evaluated the independent roles of these IRF4 polymorphisms and sun sensitivity in mediating NHL risk and explored whether they are confounded or modified by each other.
Genotyping of tag single nucleotide polymorphisms (SNPs) in the IRF4 gene was conducted in 990 NHL cases and 828 controls from a multi-center US study. Measures of sun sensitivity and exposure were ascertained from computer-assisted personal interviews. We used logistic regression to compute odds ratios (OR) and 95% confidence intervals (CI) for NHL in relation to sun exposures, sun exposures in relation to IRF4 genotypes, and NHL in relation to sun exposures. We further assessed the effects of sun exposures in relation to IRF4 genotypes.
As previously reported, we found significant associations between IRF4 rs12211228 and NHL and between hair and eye color and NHL. The IRF4 rs12203592 polymorphism (CT/TT genotype) was statistically significantly associated with eye color and particularly with hair color (ORLight Blonde = 0.24, 95% CI = 0.11–0.50, overall Chi square p = 0.0002). Analysis of joint effects between eye and hair color with the IRF4 rs12203592 SNP did not reveal statistically significant p-interactions although NHL risk did decline with lighter hair color and presence of the variant IRF4 rs12203592 allele, compared to those without a variant allele and with black/brown hair color.
Our data do not statistically support a joint effect between IRF4 and sun sensitivity in mediating risk for NHL. Further evaluation of joint effects in other and larger populations is warranted.
Electronic supplementary material
The online version of this article (doi:10.1007/s10552-009-9348-5) contains supplementary material, which is available to authorized users.
Non-Hodgkin lymphoma; Interferon regulatory factor-4; Single nucleotide polymorphism; Sunlight; Pigmentation
We previously reported that, although asthma did not increase the risk of non-Hodgkin’s lymphoma (NHL), the risk from pesticide exposures was higher among asthmatics than that among nonasthmatics. To further evaluate this finding, we analyzed data from a population-based case–control study of NHL conducted in Iowa, Detroit, Los Angeles and Seattle. Cases (n = 668) diagnosed with NHL from 1998 to 2000 and controls (n = 543) randomly selected from the same geographical areas as that of the cases were included in this analysis. Odds ratios (OR) for the risk of NHL from potential occupational exposure to pesticides tended to be higher among asthmatics (OR = 1.7; 95% CI 0.3–9.1) when compared with that among nonasthmatics (OR = 0.9; 95% CI 0.6–1.5). The risks of NHL associated with pesticide exposure were also higher among asthmatics who had history of hospitalization (OR = 2.1; 95% CI 0.2–29.0) or daily medication for asthma (OR = infinite) than those among asthmatics who did not have such histories. Our results support the previous finding that the risk of NHL from pesticide exposure may be greater among asthmatics.
asthma; non-Hodgkin’s lymphoma; pesticide exposure
Several previous studies have found non-Hodgkin lymphoma (NHL) risk to be associated with hair dye use, particularly use of permanent, dark colors and use before 1980, when hair dye formulations changed.
We examined NHL risk in relation to reported hair dye use among 1,321 cases and 1,057 controls from a US population-based multicenter study. DNA was extracted from blood or buccal cells to identify genetic variation in N acetyltransferase 1 (NAT1) and 2 (NAT2), which encode enzymes that metabolize aromatic amine compounds found in hair dyes.
Among women, 509 cases and 413 controls reported hair dye use (odds ratio [OR]=1.2,95% confidence interval [CI]=0.9,1.6). Risk estimates were higher for use before 1980 than for use in 1980 or later, particularly for use of permanent, intense tone (black, dark brown, dark blonde) products (<1980: OR=1.6,95%CI 0.9,2.7; ≥1980: OR=0.6,95%CI 0.4,1.1). Risk estimates were increased for women who used permanent, intense tone products before 1980 if they had the rapid/intermediate NAT2 phenotype (OR=3.3, 95%CI 1.3,8.6) or the NAT1*10 allele (OR=2.5,95%CI 0.9,7.6), but not if they were slow NAT2 acetylators (OR=1.5,95%CI 0.6,3.6) or had no copies of the NAT1*10 allele (OR=1.5,95%CI 0.7,3.3). NHL risk was not increased among women who began hair dye use after 1980 or among men.
Our results support previous research demonstrating elevated NHL risk among women who used dark color or intense tone permanent hair dyes before 1980. We present the first evidence suggesting that this risk may differ by genetic variation in NAT1 and NAT2.
Quantitative measurements of environmental factors greatly improve the quality of epidemiologic studies but can pose challenges because of the presence of upper or lower detection limits or interfering compounds, which do not allow for precise measured values. We consider the regression of an environmental measurement (dependent variable) on several covariates (independent variables). Various strategies are commonly employed to impute values for interval-measured data, including assignment of one-half the detection limit to nondetected values or of “fill-in” values randomly selected from an appropriate distribution. On the basis of a limited simulation study, we found that the former approach can be biased unless the percentage of measurements below detection limits is small (5–10%). The fill-in approach generally produces unbiased parameter estimates but may produce biased variance estimates and thereby distort inference when 30% or more of the data are below detection limits. Truncated data methods (e.g., Tobit regression) and multiple imputation offer two unbiased approaches for analyzing measurement data with detection limits. If interest resides solely on regression parameters, then Tobit regression can be used. If individualized values for measurements below detection limits are needed for additional analysis, such as relative risk regression or graphical display, then multiple imputation produces unbiased estimates and nominal confidence intervals unless the proportion of missing data is extreme. We illustrate various approaches using measurements of pesticide residues in carpet dust in control subjects from a case–control study of non-Hodgkin lymphoma.
dust; environmental exposure; imputation; missing data; non-Hodgkin lymphoma; pesticides
Follicular lymphoma (FL) has variable progression and survival, and improved identification of patients at high risk for progression would aid in identifying patients most likely to benefit from alternative therapy. In a sample of 244 FL cases identified during a population-based case-control study of non-Hodgkin lymphoma (NHL), we examined 6,679 tag SNPs in 488 gene regions for associations with overall FL survival. Over a median follow-up of 89 months with 65 deaths in this preliminary study, we identified 5 gene regions (BMP7, GALNT12, DUSP2, GADD45B, and ADAM17) that were associated with overall survival from FL. Results did not meet the criteria for statistical significance after adjustment for multiple hypothesis testing. These results, which support a role for host factors in determining the variable progression of FL, serve as an initial examination that can inform future studies of genetic variation and FL survival. However, they require replication in independent populations, as well as assessment in rituximab-treated patients.
follicular lymphoma; genetic variation; survival; tag SNP; case-control study