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1.  A genome-wide association study of marginal zone lymphoma shows association to the HLA region 
Vijai, Joseph | Wang, Zhaoming | Berndt, Sonja I. | Skibola, Christine F. | Slager, Susan L. | de Sanjose, Silvia | Melbye, Mads | Glimelius, Bengt | Bracci, Paige M. | Conde, Lucia | Birmann, Brenda M. | Wang, Sophia S. | Brooks-Wilson, Angela R. | Lan, Qing | de Bakker, Paul I. W. | Vermeulen, Roel C. H. | Portlock, Carol | Ansell, Stephen M. | Link, Brian K. | Riby, Jacques | North, Kari E. | Gu, Jian | Hjalgrim, Henrik | Cozen, Wendy | Becker, Nikolaus | Teras, Lauren R. | Spinelli, John J. | Turner, Jenny | Zhang, Yawei | Purdue, Mark P. | Giles, Graham G. | Kelly, Rachel S. | Zeleniuch-Jacquotte, Anne | Ennas, Maria Grazia | Monnereau, Alain | Bertrand, Kimberly A. | Albanes, Demetrius | Lightfoot, Tracy | Yeager, Meredith | Chung, Charles C. | Burdett, Laurie | Hutchinson, Amy | Lawrence, Charles | Montalvan, Rebecca | Liang, Liming | Huang, Jinyan | Ma, Baoshan | Villano, Danylo J. | Maria, Ann | Corines, Marina | Thomas, Tinu | Novak, Anne J. | Dogan, Ahmet | Liebow, Mark | Thompson, Carrie A. | Witzig, Thomas E. | Habermann, Thomas M. | Weiner, George J. | Smith, Martyn T. | Holly, Elizabeth A. | Jackson, Rebecca D. | Tinker, Lesley F. | Ye, Yuanqing | Adami, Hans-Olov | Smedby, Karin E. | De Roos, Anneclaire J. | Hartge, Patricia | Morton, Lindsay M. | Severson, Richard K. | Benavente, Yolanda | Boffetta, Paolo | Brennan, Paul | Foretova, Lenka | Maynadie, Marc | McKay, James | Staines, Anthony | Diver, W. Ryan | Vajdic, Claire M. | Armstrong, Bruce K. | Kricker, Anne | Zheng, Tongzhang | Holford, Theodore R. | Severi, Gianluca | Vineis, Paolo | Ferri, Giovanni M. | Ricco, Rosalia | Miligi, Lucia | Clavel, Jacqueline | Giovannucci, Edward | Kraft, Peter | Virtamo, Jarmo | Smith, Alex | Kane, Eleanor | Roman, Eve | Chiu, Brian C. H. | Fraumeni, Joseph F. | Wu, Xifeng | Cerhan, James R. | Offit, Kenneth | Chanock, Stephen J. | Rothman, Nathaniel | Nieters, Alexandra
Nature Communications  2015;6:5751.
Marginal zone lymphoma (MZL) is the third most common subtype of B-cell non-Hodgkin lymphoma. Here we perform a two-stage GWAS of 1,281 MZL cases and 7,127 controls of European ancestry and identify two independent loci near BTNL2 (rs9461741, P=3.95 × 10−15) and HLA-B (rs2922994, P=2.43 × 10−9) in the HLA region significantly associated with MZL risk. This is the first evidence that genetic variation in the major histocompatibility complex influences MZL susceptibility.
Marginal zone lymphoma (MZL) is a common subtype of B-cell non-Hodgkin lymphoma. Here the authors carry out a two-stage genome-wide association study in over 8,000 Europeans and identify two new MZL risk loci at chromosome 6p, implicating the major histocompatibility complex in the disease for the first time.
doi:10.1038/ncomms6751
PMCID: PMC4287989  PMID: 25569183
2.  Environmental determinants of polychlorinated biphenyl concentrations in residential carpet dust 
Environmental science & technology  2013;47(18):10405-10414.
Polychlorinated biphenyls (PCBs), banned in the United Sates in the late 1970s, are still found in indoor and outdoor environments. Little is known about the determinants of PCB levels in homes. We measured concentrations of 5 PCB congeners (105, 138, 153, 170, 180) in carpet dust collected between 1998–2000 from 1,187 homes in four sites: Detroit, Iowa, Los Angeles, and Seattle. Home characteristics, occupational history, and demographic information were obtained by interview. We used a geographic information system to geocode addresses and determine distances to the nearest major road, freight route, and railroad, percentage of developed land, number of industrial facilities within 2 km of residences, and population density. Ordinal logistic regression was used to estimate the associations between the covariates of interest and the odds of PCB detection in each site separately. Total PCBs levels (all congeners < maximum practical quantitation limit [MPQL] vs. at least one congener ≥ MPQL to < median concentration vs. at least one congener >median concentration) were positively associated with either percentage of developed land (ORrange: 1.01-1.04 for each percentage increase) or population density (OR: 1.08 for every 1,000/mi2) in each site. The number of industrial facilities within 2 km of a home was associated with PCB concentrations; however, facility type and the direction of the association varied by site. Our findings suggest that outdoor sources of PCBs may be significant determinants of indoor concentrations.
doi:10.1021/es401447w
PMCID: PMC4076890  PMID: 23952055
3.  Association of Dietary Quercetin with Reduced Risk of Proximal Colon Cancer 
Nutrition and Cancer  2012;64(3):351-360.
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.
doi:10.1080/01635581.2012.658950
PMCID: PMC3329181  PMID: 22429001
diet; quercetin; distal colon cancer; proximal colon cancer; epidemiological
4.  Family history of cancer and non-malignant diseases and risk of childhood acute lymphoblastic leukemia: A Children's Oncology Group Study 
Cancer epidemiology  2011;36(1):45-51.
Background
Studies of family history of cancer and non-malignant diseases in childhood acute lymphoblastic leukemia (ALL) show inconsistent findings. Most studies show no increased risk with family history of cancer. Non-malignant diseases such as allergic diseases, autoimmune diseases, birth defects and thyroid diseases have been reported to be associated with ALL.
Methods
We conducted a case-control study of family history of cancer and selected non-malignant conditions (allergic diseases, autoimmune diseases, birth defects, and thyroid diseases). ALL cases were obtained from Children's Cancer Group institutions from January 1989 to June 1993. Controls were recruited via random digit dialing. Family history for first degree relatives and grandparents of ALL cases and controls was collected by structured telephone questionnaires. Conditional logistical regression was used to calculate odds ratios adjusting for potential confounders.
Results
We found a borderline association of ALL and having a family member with a history of cancer in cases (n = 1842) compared to controls (n = 1986) (OR = 0.98, 95%CI = 0.93, 1.00) and an inverse association for esophageal cancer based on small numbers. Family history of food and drug allergies demonstrated a modestly reduced risk (OR = 0.83, 95%CI = 0.73, 0.95) as did family history of rheumatoid arthritis (OR = 0.79, 95%CI = 0.65, 0.96). There were no associations with family history of any autoimmune diseases, immunodeficiencies, birth defects, thyroid diseases and risk of childhood ALL.
Conclusions
These results show no association of overall family history of cancer with childhood ALL, while providing additional evidence for an inverse association with family history of allergic disease. Two potentially new associations of ALL with family history of esophageal cancer and rheumatoid arthritis require confirmation in other studies and validation with medical records.
doi:10.1016/j.canep.2011.06.004
PMCID: PMC3962042  PMID: 22018949
Pediatric; Cancer; Acute lymphoblastic leukemia; Case–control study; Autoimmune; Allergies; Family history
5.  Blood Transfusion, Anesthesia, Surgery and Risk of Non-Hodgkin Lymphoma in a Population-Based Case-Control Study 
The incidence of NHL has increased dramatically since at least the 1950s, and during this timeframe there has been a major increase in the use of blood transfusions, invasive surgical procedures, and anesthesia, all of which can impact immune function. We evaluated these factors with NHL risk in a population-based study of 759 cases and 589 frequency-matched controls. Risk factor data were collected during in-person interviews. Unconditional logistic regression was used to estimate ORs and 95% CIs, adjusted for the matching factors. History of transfusion was associated with a 26% higher risk of NHL (95% CI 0.91–1.73), and the elevated risk was specific to transfusions first given 5–29 years before the reference date (OR=1.69; 95% CI 1.08–2.62) and transfusions given for a medical condition (OR=2.09; 95% CI 1.03–4.26). The total number of surgeries and dental procedures (OR=1.53 for 26+ surgeries compared to 0–6; 95% CI 1.02–2.29) and to a lesser extent the total number of exposures to general or local/regional anesthesia (OR=1.35 for 24+ times compared to 0–6; 95% CI 0.91–2.02) were positively associated with risk of NHL. Inclusion of transfusion and surgery or transfusion and anesthesia in the same model did not attenuate these associations. All results were broadly consistent for both DLBCL and follicular subtypes. Blood transfusions were associated with NHL risk, but appear to be a marker for underlying medical conditions. Multiple surgical procedures and/or repeated administration of anesthesia have not been previously reported to be associated with risk of NHL and these exposures warrant further evaluation.
doi:10.1002/ijc.23561
PMCID: PMC3913466  PMID: 18506687
anesthesia; blood transfusion; non-Hodgkin lymphoma; surgery
6.  Partial Associations of Dietary Iron, Smoking and Intestinal Bacteria with Colorectal Cancer Risk 
Nutrition and cancer  2013;65(2):169-177.
Smoking and high red meat intake have been associated with colorectal cancer (CRC) risk. Increased iron exposure may be a common factor, favoring the colonization of certain bacterial pathogens that preferentially grow in an iron-rich luminal environment. We analyzed the data from a population-based case-control study of CRC and measured antibody levels against flagelin of Salmonella (FliC), one of the irontrophic bacteria, in two independent blood collections. The risk of CRC synergistically increased by combined exposures to heme iron intake and pack-years (PY) of cigarette smoking (P-value for the interaction = 0.039 on the continuous scale). There was a marginally significant interaction between heme iron intake and PY in increasing FliC antibody in the US control subjects (P=0.055), although no iron or smoking data were available for Dutch samples. Furthermore, FliC antibody levels were significantly higher in patients with colorectal polyps and cancer than in controls in both Dutch (3.93 vs. 2.23) (P=0.014) and US samples (6.65 vs. 4.37) (P<0.001). Potential roles of iron from cigarette smoking and dietary heme in CRC through altering irontrophic luminal bacterial population may warrant further investigation.
doi:10.1080/01635581.2013.748922
PMCID: PMC3655765  PMID: 23441604
smoking; iron; intestinal bacteria; colorectal cancer; Salmonella
7.  Genome-wide Association Study Identifies Multiple Risk Loci for Chronic Lymphocytic Leukemia 
Berndt, Sonja I. | Skibola, Christine F. | Joseph, Vijai | Camp, Nicola J. | Nieters, Alexandra | Wang, Zhaoming | Cozen, Wendy | Monnereau, Alain | Wang, Sophia S. | Kelly, Rachel S. | Lan, Qing | Teras, Lauren R. | Chatterjee, Nilanjan | Chung, Charles C. | Yeager, Meredith | Brooks-Wilson, Angela R. | Hartge, Patricia | Purdue, Mark P. | Birmann, Brenda M. | Armstrong, Bruce K. | Cocco, Pierluigi | Zhang, Yawei | Severi, Gianluca | Zeleniuch-Jacquotte, Anne | Lawrence, Charles | Burdette, Laurie | Yuenger, Jeffrey | Hutchinson, Amy | Jacobs, Kevin B. | Call, Timothy G. | Shanafelt, Tait D. | Novak, Anne J. | Kay, Neil E. | Liebow, Mark | Wang, Alice H. | Smedby, Karin E | Adami, Hans-Olov | Melbye, Mads | Glimelius, Bengt | Chang, Ellen T. | Glenn, Martha | Curtin, Karen | Cannon-Albright, Lisa A. | Jones, Brandt | Diver, W. Ryan | Link, Brian K. | Weiner, George J. | Conde, Lucia | Bracci, Paige M. | Riby, Jacques | Holly, Elizabeth A. | Smith, Martyn T. | Jackson, Rebecca D. | Tinker, Lesley F. | Benavente, Yolanda | Becker, Nikolaus | Boffetta, Paolo | Brennan, Paul | Foretova, Lenka | Maynadie, Marc | McKay, James | Staines, Anthony | Rabe, Kari G. | Achenbach, Sara J. | Vachon, Celine M. | Goldin, Lynn R | Strom, Sara S. | Lanasa, Mark C. | Spector, Logan G. | Leis, Jose F. | Cunningham, Julie M. | Weinberg, J. Brice | Morrison, Vicki A. | Caporaso, Neil E. | Norman, Aaron D. | Linet, Martha S. | De Roos, Anneclaire J. | Morton, Lindsay M. | Severson, Richard K. | Riboli, Elio | Vineis, Paolo | Kaaks, Rudolph | Trichopoulos, Dimitrios | Masala, Giovanna | Weiderpass, Elisabete | Chirlaque, María-Dolores | Vermeulen, Roel C H | Travis, Ruth C. | Giles, Graham G. | Albanes, Demetrius | Virtamo, Jarmo | Weinstein, Stephanie | Clavel, Jacqueline | Zheng, Tongzhang | Holford, Theodore R | Offit, Kenneth | Zelenetz, Andrew | Klein, Robert J. | Spinelli, John J. | Bertrand, Kimberly A. | Laden, Francine | Giovannucci, Edward | Kraft, Peter | Kricker, Anne | Turner, Jenny | Vajdic, Claire M. | Ennas, Maria Grazia | Ferri, Giovanni M. | Miligi, Lucia | Liang, Liming | Sampson, Joshua | Crouch, Simon | Park, Ju-hyun | North, Kari E. | Cox, Angela | Snowden, John A. | Wright, Josh | Carracedo, Angel | Lopez-Otin, Carlos | Bea, Silvia | Salaverria, Itziar | Martin, David | Campo, Elias | Fraumeni, Joseph F. | de Sanjose, Silvia | Hjalgrim, Henrik | Cerhan, James R. | Chanock, Stephen J. | Rothman, Nathaniel | Slager, Susan L.
Nature genetics  2013;45(8):868-876.
doi:10.1038/ng.2652
PMCID: PMC3729927  PMID: 23770605
8.  Household endotoxin levels and the risk of non-Hodgkin lymphoma 
Cancer causes & control : CCC  2013;24(2):357-364.
Objective
Endotoxin, a component of the outer membrane of gram-negative bacteria, elicits a strong innate and inflammatory immune response associated with secretion of pro-inflammatory 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 Result (NCI/SEER) NHL multi-center 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= 0.1.07, 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.
doi:10.1007/s10552-012-0121-9
PMCID: PMC3800025  PMID: 23277417
Endotoxin; Non-Hodgkin lymphoma; Epidemiology; Farming; Risk; Case-control
9.  Variations in Chromosomes 9 and 6p21.3 with Risk of Non–Hodgkin Lymphoma 
Background
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.
Methods
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.
Results
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).
Conclusions
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.
Impact
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
doi:10.1158/1055-9965.EPI-10-0638
PMCID: PMC3817834  PMID: 21148756
10.  Inherited genetic variation and overall survival following follicular lymphoma 
American Journal of Hematology  2012;87(7):724-726.
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.
doi:10.1002/ajh.23184
PMCID: PMC3392094  PMID: 22473939
follicular lymphoma; genetic variation; survival; tag SNP; case-control study
11.  The relationship between combination inhaled corticosteroid and long-acting beta-agonist use and severe asthma exacerbations in a diverse population 
Background
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.
Objective
To estimate the effect ICS therapy and fixed-dose ICS/LABA combination therapy on severe asthma exacerbations in a racially diverse population.
Methods
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).
Results
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.
Conclusion
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.
doi:10.1016/j.jaci.2011.12.974
PMCID: PMC3340459  PMID: 22281166
Long-acting beta-agonist; inhaled corticosteroid; severe asthma exacerbation; safety; racially and ethnically diverse population; observational study
12.  Risk factors for non-Hodgkin lymphoma subtypes defined by histology and t(14;18) in a population-based case–control study 
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.
doi:10.1002/ijc.25717
PMCID: PMC3125462  PMID: 20949561
lymphoma; non-Hodgkin; case–control studies; translocation; follicular lymphoma; diffuse large B-cell lymphoma; etiology
13.  Genetic variation in Th1/Th2 pathway genes and risk of non-Hodgkin lymphoma: A pooled analysis of three population-based case-control studies 
British journal of haematology  2011;153(3):341-350.
The balance between Th1 and Th2 activity is critical in lymphoid cell development and differentiation. Immune dysfunction underlies lymphomagenesis, so an alteration in the regulation of key Th1/Th2 cytokines may lead to the development of non-Hodgkin lymphoma (NHL). To study the impact of polymorphism in Th1/Th2 cytokines on NHL risk, we analyzed 145 tag single nucleotide polymorphisms (SNPs) in 17 Th1/Th2 cytokine and related genes in three population-based case-control studies (1,946 cases and 1,808 controls). Logistic regression was used to compute odds ratios (OR) for NHL and four major NHL subtypes in relation to tag SNP genotypes and haplotypes. A gene-based analysis adjusting for the number of tag SNPs genotyped in each gene showed significant associations with risk of NHL combined and one or more NHL subtypes for Th1 (IL12A and IL12RB1) and Th2 (IL4, IL10RB, and IL18) genes. The strongest association was for IL12A rs485497, which plays a central role in bridging the cellular and humoral pathways of innate resistance and antigen-specific adaptive immune responses (allele risk OR=1.17; P(trend)=0.00099). This SNP was also associated specifically with risk of follicular lymphoma (allele risk OR=1.26; P(trend)=0.0012). These findings suggest that genetic variation in Th1/Th2 cytokine genes may contribute to lymphomagenesis.
doi:10.1111/j.1365-2141.2010.08424.x
PMCID: PMC3075370  PMID: 21418175
Non-Hodgkin lymphoma; single nucleotide polymorphisms; immunogenetics; case-control study
14.  Variation in Effects of Non-Hodgkin Lymphoma Risk Factors According to the Human Leukocyte Antigen (HLA)-DRB1*01:01 Allele and Ancestral Haplotype 8.1 
PLoS ONE  2011;6(11):e26949.
Genetic variations in human leukocyte antigens (HLA) are critical in host responses to infections, transplantation, and immunological diseases. We previously identified associations with non-Hodgkin lymphoma (NHL) and the HLA-DRB1*01:01 allele and extended ancestral haplotype (AH) 8.1 (HLA-A*01-B*08-DR*03-TNF-308A). To illuminate how HLA alleles and haplotypes may influence NHL etiology, we examined potential interactions between HLA-DRB1*01:01 and AH 8.1, and a wide range of NHL risk factors among 685 NHL cases and 646 controls from a United States population-based case-control study. We calculated odds ratios and 95% confidence intervals by HLA allele or haplotype status, adjusted for sex, age, race and study center for NHL and two major subtypes using polychotomous unconditional logistic regression models. The previously reported elevation in NHL risk associated with exposures to termite treatment and polychlorinated biphenyls were restricted to individuals who did not possess HLA-DRB1*01:01. Previous associations for NHL and DLBCL with decreased sun exposure, higher BMI, and autoimmune conditions were statistically significant only among those with AH 8.1, and null among those without AH 8.1. Our results suggest that NHL risk factors vary in their association based on HLA-DRB1*01:01 and AH 8.1 status. Our results further suggest that certain NHL risk factors may act through a common mechanism to alter NHL risk. Finally, control participants with either HLA-DRB1*01:01 or AH 8.1 reported having a family history of NHL twice as likely as those who did not have either allele or haplotype, providing the first empirical evidence that HLA associations may explain some of the well-established relationship between family history and NHL risk.
doi:10.1371/journal.pone.0026949
PMCID: PMC3212525  PMID: 22096508
15.  Human Leukocyte Antigen Class I and II Alleles and Overall Survival in Diffuse Large B-Cell Lymphoma and Follicular Lymphoma 
TheScientificWorldJournal  2011;11:2062-2070.
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.
doi:10.1100/2011/373876
PMCID: PMC3217596  PMID: 22125456
human leukocyte antigen; tumor necrosis factor; diffuse large B-cell lymphoma; follicular lymphoma; survival
16.  APOE and FABP2 Polymorphisms and History of Myocardial Infarction, Stroke, Diabetes, and Gallbladder Disease 
Cholesterol  2011;2011:896360.
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.
doi:10.1155/2011/896360
PMCID: PMC3175690  PMID: 21941641
17.  Birth Order and Risk of Non-Hodgkin Lymphoma—True Association or Bias? 
American Journal of Epidemiology  2010;172(6):621-630.
There is inconsistent evidence that increasing birth order may be associated with risk of non-Hodgkin lymphoma (NHL). The authors examined the association between birth order and related variables and NHL risk in a pooled analysis (1983–2005) of 13,535 cases and 16,427 controls from 18 case-control studies within the International Lymphoma Epidemiology Consortium (InterLymph). Overall, the authors found no significant association between increasing birth order and risk of NHL (P-trend = 0.082) and significant heterogeneity. However, a significant association was present for a number of B- and T-cell NHL subtypes. There was considerable variation in the study-specific risks which was partly explained by study design and participant characteristics. In particular, a significant positive association was present in population-based studies, which had lower response rates in cases and controls, but not in hospital-based studies. A significant positive association was present in higher-socioeconomic-status (SES) participants only. Results were very similar for the related variable of sibship size. The known correlation of high birth order with low SES suggests that selection bias related to SES may be responsible for the association between birth order and NHL.
doi:10.1093/aje/kwq167
PMCID: PMC2950815  PMID: 20720098
birth order; case-control studies; lymphoma, non-Hodgkin; selection bias; social class
18.  Dietary fatty acids, luminal modifiers, and risk of colorectal cancer 
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.
doi:10.1002/ijc.25103
PMCID: PMC2891322  PMID: 19998336
Fatty acids; colorectal cancer; case-control study; calcium; fiber
19.  Smoking, Alcohol Use, Obesity, and Overall Survival from Non-Hodgkin Lymphoma: A Population-Based Study 
Cancer  2010;116(12):2993-3000.
BACKGROUND
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.
METHODS
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.
RESULTS
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.
CONCLUSIONS
NHL patients who smoked, consumed alcohol or were obese prior to diagnosis had a poorer overall and lymphoma-specific survival.
doi:10.1002/cncr.25114
PMCID: PMC2889918  PMID: 20564404
alcohol; non-Hodgkin lymphoma; obesity; smoking; survival
20.  Functional polymorphisms to modulate luminal lipid exposure and risk of colorectal cancer 
Cancer epidemiology  2010;34(3):291-297.
PURPOSE
Fat absorption may play a crucial role in colorectal carcinogenesis by determining intra-colonic exposure to potentially carcinogenic lipid metabolites.
METHODS
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.
RESULTS
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.
CONCLUSIONS
These results suggest that these SNPs may not be useful in predicting colorectal cancer risk in populations with high fat intake.
doi:10.1016/j.canep.2010.02.010
PMCID: PMC2905870  PMID: 20308031
Colorectal cancer; Case-control study; Lipid absorption; Single nucleotide polymorphism (SNP)
21.  GWAS of Follicular Lymphoma Reveals Allelic Heterogeneity at 6p21.32 and Suggests Shared Genetic Susceptibility with Diffuse Large B-cell Lymphoma 
PLoS Genetics  2011;7(4):e1001378.
Non-Hodgkin lymphoma (NHL) represents a diverse group of hematological malignancies, of which follicular lymphoma (FL) is a prevalent subtype. A previous genome-wide association study has established a marker, rs10484561 in the human leukocyte antigen (HLA) class II region on 6p21.32 associated with increased FL risk. Here, in a three-stage genome-wide association study, starting with a genome-wide scan of 379 FL cases and 791 controls followed by validation in 1,049 cases and 5,790 controls, we identified a second independent FL–associated locus on 6p21.32, rs2647012 (ORcombined = 0.64, Pcombined = 2×10−21) located 962 bp away from rs10484561 (r2<0.1 in controls). After mutual adjustment, the associations at the two SNPs remained genome-wide significant (rs2647012:ORadjusted = 0.70, Padjusted = 4×10−12; rs10484561:ORadjusted = 1.64, Padjusted = 5×10−15). Haplotype and coalescence analyses indicated that rs2647012 arose on an evolutionarily distinct haplotype from that of rs10484561 and tags a novel allele with an opposite (protective) effect on FL risk. Moreover, in a follow-up analysis of the top 6 FL–associated SNPs in 4,449 cases of other NHL subtypes, rs10484561 was associated with risk of diffuse large B-cell lymphoma (ORcombined = 1.36, Pcombined = 1.4×10−7). Our results reveal the presence of allelic heterogeneity within the HLA class II region influencing FL susceptibility and indicate a possible shared genetic etiology with diffuse large B-cell lymphoma. These findings suggest that the HLA class II region plays a complex yet important role in NHL.
Author Summary
Earlier studies have established a marker rs10484561, in the HLA class II region on 6p21.32, associated with increased follicular lymphoma (FL) risk. Here, in a three-stage genome-wide association study of 1,428 FL cases and 6,581 controls, we identified a second independent FL–associated marker on 6p21.32, rs2647012, located 962 bp away from rs10484561. The associations at two SNPs remained genome-wide significant after mutual adjustment. Haplotype and coalescence analyses indicated that rs2647012 arose on an evolutionarily distinct lineage from that of rs10484561 and tags a novel allele with an opposite, protective effect on FL risk. Moreover, in an analysis of the top 6 FL–associated SNPs in 4,449 cases of other NHL subtypes, rs10484561 was associated with risk of diffuse large B-cell lymphoma. Our results reveal the presence of allelic heterogeneity at 6p21.32 in FL risk and suggest a shared genetic etiology with the common diffuse large B-cell lymphoma subtype.
doi:10.1371/journal.pgen.1001378
PMCID: PMC3080853  PMID: 21533074
23.  OCCUPATION/INDUSTRY AND RISK OF NON HODGKIN LYMPHOMA IN THE UNITED STATES 
Aims
To identify occupations and industries associated with non-Hodgkin lymphoma in a large population-based case-control study in the United States.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1136/oem.2007.036723
PMCID: PMC3051169  PMID: 18805886
Non Hodgkin lymphoma; occupation; industry
24.  A Case–Control Study of Occupational Exposure to Trichloroethylene and Non-Hodgkin Lymphoma 
Environmental Health Perspectives  2010;119(2):232-238.
Background
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).
Objectives
We investigated the association between occupational TCE exposure and NHL within a population-based case–control study using detailed exposure assessment methods.
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.
Results
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).
Conclusions
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.
doi:10.1289/ehp.1002106
PMCID: PMC3040611  PMID: 21370516
cancer; non-Hodgkin lymphoma; occupational; solvents; trichloroethylene
25.  Degreasing and risk of non-Hodgkin lymphoma 
Objective
To investigate the relationship between selected solvent-related workplace tasks (degreasing, painting, gluing, stripping paint, staining) and risk of non-Hodgkin lymphoma (NHL).
Methods
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.
Results
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.
Conclusion
Findings from this case-control analysis of solvent-related tasks suggest that frequent degreasing work may be associated with an elevated risk of NHL.
doi:10.1136/oem.2008.040386
PMCID: PMC2995288  PMID: 19017696
non-Hodgkin lymphoma; solvents; case-control studies; degreasing

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