immune mechanisms in non-hodgkin lymphoma: joint effects of the tnf g308a and il10 t3575a...

2007;67:5042-5054. Cancer Res Sophia S. Wang, Wendy Cozen, James R. Cerhan, et al.

Hodgkin Lymphoma Risk Factors−with Non T3575A PolymorphismsIL10 G308A and TNFEffects of the

Hodgkin Lymphoma: Joint−Immune Mechanisms in Non

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Immune Mechanisms in Non–Hodgkin Lymphoma: Joint Effects

of the TNF G308A and IL10 T3575A Polymorphisms with

Non–Hodgkin Lymphoma Risk Factors

Sophia S. Wang,1Wendy Cozen,

2James R. Cerhan,

3,4Joanne S. Colt,

1Lindsay M. Morton,

1

Eric A. Engels,1Scott Davis,

5Richard K. Severson,

6Nathaniel Rothman,

1

Stephen J. Chanock,1,7and Patricia Hartge

1

1Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, Maryland; 2University of Southern California,Los Angeles, California; 3Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, Minnesota; 4University ofIowa, Iowa City, Iowa; 5Fred Hutchinson Cancer Research Center and the University of Washington, Seattle, Washington; 6KarmanosCancer Institute and Department of Family Medicine, Wayne State University, Detroit, Michigan; and 7Core Genotyping Facility,Advanced Technology Corporation, National Cancer Institute, Gaithersburg, Maryland

Abstract

Two common single nucleotide polymorphisms in immuno-regulatory genes (TNF G308A, rs1800629 and IL10 T3575A,rs1800890) have been recently reported as risk factors fornon–Hodgkin lymphoma (NHL) in a large pooled analysis.We systematically investigated the effects of other establishedNHL risk factors in relation to the tumor necrosis factor(TNF) G308A or interleukin 10 (IL10) T3575A genotypes. Wecalculated odds ratios (OR) and 95% confidence intervals(95% CI) from 1,172 cases and 982 population-based controlsin a U.S. multicenter study. We investigated NHL overall andtwo common subtypes [diffuse large B-cell lymphoma(DLBCL) and follicular lymphoma]. NHL risks were increasedamong those with both an autoimmune condition and theTNF G308A GA/AA (ORNHL, 2.1; 95% CI, 1.0–4.2) or the IL10T3575A TA/AA genotype (ORNHL, 1.6; 95% CI, 0.9–2.6)compared with individuals without an autoimmune condi-tion and with the common TNF G308A GG or IL10 T3575ATT genotype, respectively; results were similar for DLBCL andfollicular lymphoma. We found that elevated DLBCL riskassociated with last-born status was more pronouncedamong those with TNF G308A GA/AA (ORDLBCL, 2.7; 95% CI,1.1–6.4) or IL10 T3575A TA/AA (ORDLBCL, 2.9; 95% CI, 1.6–5.2). Similarly, elevated DLBCL risk associated with obesity(body mass index, z35 versus <25 kg/m2) was observed onlyamong those with TNF G308A GA/AA (ORDLBCL, 2.5; 95% CI,1.1–5.7) or IL10 T3575A TA/AA genotypes (ORDLBCL, 2.0; 95%CI, 1.1–3.5). These exploratory results require replication butprovide evidence that autoimmune conditions, late birthorder, and obesity act partly through a common inflamma-tory pathway, posing a greater risk to individuals withvariant TNF and IL10 genotypes than those with wild-typealleles. [Cancer Res 2007;67(10):5042–54]

Introduction

Immune alteration is a major risk factor for non–Hodgkinlymphoma (NHL), but the specific immune mechanisms respon-sible remain unresolved. Immunologic response is often driven byspecific environmental/infectious agents that are influenced byinherited human genetic variation and the host’s capacity to elicitimmunologic memory. As evidence mounts for inherited geneticvariations and other risk factors in NHL, evaluation of their jointeffects should provide clues to the specific immune pathwayscritical for lymphomagenesis.NHL risk is increased in the presence of autoimmune

conditions (e.g., Sjogren’s syndrome and lupus; ref. 1), certaininfectious agents (e.g., HIV, Helicobacter pylori , human Tlymphotropic virus I, human herpesvirus 8, and hepatitis C virus;refs. 2–6), and family history of lymphoma (7). Recent pooledanalyses within the International Lymphoma EpidemiologyConsortium (InterLymph) have also showed increased NHL riskwith smoking (8) and decreased NHL risk with alcohol intake (9).A growing body of evidence indicates that organochlorinepesticides (10, 11) and other organochlorines increase NHL risk(12), and that sunlight decreases risk (13). Evidence for decreasedNHL risk with atopic conditions (e.g., allergies and asthma; refs.14–16) and vitamin B6 (17) and increased risk with obesity, height(18), and later birth order (14) has also been reported, but theseassociations require further replication.In a large consortial study within InterLymph, we recently

showed an increased risk for NHL, especially the major lymphomasubtype diffuse large B-cell lymphoma (DLBCL), with geneticvariations in the tumor necrosis factor (TNF) and interleukin 10(IL10) immunoregulatory cytokines that mediate inflammation(19–21). There is laboratory-based evidence that the TNF G308Apromoter polymorphism elevates expression of the TNFa protein(22), whereas the IL10 T3575A polymorphism results in lowerproduction of IL-10 (23). Because IL-10 is a potent down-regulatorof TNFa, decreased IL-10 may suppress TNFa levels less efficiently,resulting in an overall elevated expression of TNFa. Bothpolymorphisms are therefore hypothesized to increase TNFa levelsand thus contribute to a shift in the Th1/proinflammatory immuneresponse. As TNFa activates the nuclear factor-nB pathway, acentral mechanism for inflammation (24), it is plausible that thesegenetic factors contribute to further chronic inflammation thatultimately lead to lymphomagenesis (20).To probe the specific immune mechanisms relevant for

NHL, we evaluated jointly the TNF G308A and IL10 T3575A

Note: Written informed consent was obtained from all participants in accordancewith U.S. Department of Health and Human Services guidelines. This study wasapproved by the institutional review boards at the NIH and at each participatingSurveillance Evaluation, Epidemiology, and End Results site (Iowa, Seattle, LosAngeles, and Detroit).

Requests for reprints: Sophia S. Wang, Division of Cancer Epidemiology andGenetics, National Cancer Institute, 6120 Executive Boulevard, EPS MSC# 7234,Bethesda, MD 20892-7234. Phone: 301-402-5374; Fax: 301-402-0916; E-mail:[email protected].

I2007 American Association for Cancer Research.doi:10.1158/0008-5472.CAN-06-4752

Cancer Res 2007; 67: (10). May 15, 2007 5042 www.aacrjournals.org

Research Article




Table 1. Risk factor distribution by TNF G308A and IL10 T3575A genotypes among controls in the National Cancer Institute-Surveillance Evaluation, Epidemiology, and End Results NHL multicenter case-control study (associations are adjusted for thefollowing study design variables: age, education, sex, race, and study center)

Risk factor TNF G308A IL10 T3575A

GG, n (%) GA/AA, n (%) OR (95% CI) TT, n (%) TA/AA, n (%) OR (95% CI)

Study design variables

SexFemale 323 (46.4) 111 (49.3) 1.0 (reference) 166 (43.8) 262 (49.3) 1.0 (reference)

Male 373 (53.6) 114 (50.7) 0.9 (0.7-1.2) 213 (56.2) 269 (50.7) 0.8 (0.6-1.0)

RaceWhite 556 (79.9) 188 (83.6) 1.0 (reference) 294 (77.6) 438 (82.5) 1.0 (reference)

Other/Unknown 140 (20.1) 37 (16.4) 0.8 (0.5-1.2) 85 (22.4) 93 (17.5) 0.7 (0.5-1.0)

Age (y)

<45 116 (16.7) 27 (12.0) 1.0 (reference) 64 (16.9) 79 (14.9) 1.0 (reference)45-64 293 (42.1) 103 (45.8) 1.5 (0.9-2.4) 169 (44.6) 221 (41.6) 1.1 (0.7-1.6)

z65 287 (41.2) 95 (42.2) 1.4 (0.9-2.3) 146 (38.5) 231 (43.5) 1.3 (0.9-1.9)

P trend 0.3 0.1

Education (y)<12 69 (9.9) 20 (8.9) 1.0 (reference) 38 (10.0) 50 (9.4) 1.0 (reference)

12-15 416 (59.8) 124 (55.1) 1.0 (0.6-1.8) 215 (56.7) 319 (60.1) 1.1 (0.7-1.8)

>15 211 (30.3) 81 (36.0) 1.3 (0.8-2.3) 126 (33.2) 162 (30.5) 1.0 (0.6-1.6)P trend 0.1 0.6

Study site

Detroit 118 (16.9) 41 (18.2) 1.0 (reference) 68 (17.9) 87 (16.4) 1.0 (reference)

Iowa 189 (27.2) 68 (30.2) 1.0 (0.7-1.6) 83 (21.9) 171 (32.2) 1.6 (1.1-2.4)Los Angeles 192 (27.6) 44 (19.6) 0.7 (0.4-1.1) 113 (29.8) 123 (23.2) 0.8 (0.6-1.3)

Seattle 197 (28.3) 72 (32.0) 1.0 (0.7-1.6) 115 (30.3) 150 (28.2) 1.0 (0.7-1.5)

Family and medical historyFamily history of NHL

No 646 (97.1) 205 (94.9) 1.0 (reference) 350 (96.7) 490 (96.5) 1.0 (reference)

Yes 19 (2.9) 11 (5.1) 1.7 (0.8-3.8) 12 (3.3) 18 (3.5) 1.0 (0.5-2.1)

Autoimmune conditionsNo 655 (94.2) 212 (94.6) 1.0 (reference) 354 (93.4) 502 (94.9) 1.0 (reference)

Yes 40 (5.8) 12 (5.4) 0.9 (0.5-1.7) 25 (6.6) 27 (5.1) 0.8 (0.4-1.3)

AsthmaYes 47 (12.3) 12 (9.1) 1.0 (reference) 27 (12.9) 34 (11.2) 1.0 (reference)

No 335 (87.7) 120 (90.9) 1.3 (0.7-2.6) 182 (87.1) 270 (88.8) 1.2 (0.7-2.0)

Allergy

Yes 190 (61.5) 59 (64.1) 1.0 (reference) 108 (63.9) 137 (61.7) 1.0 (reference)No 119 (38.5) 33 (35.9) 1.0 (0.6-1.7) 61 (36.1) 85 (38.3) 1.1 (0.7-1.8)

Surgeries (total number)

0-6 76 (19.9) 21 (15.9) 1.0 (reference) 41 (19.6) 56 (18.4) 1.0 (reference)

7-11 76 (19.9) 28 (21.2) 1.2 (0.6-2.4) 45 (21.5) 59 (19.4) 0.9 (0.5-1.6)12-17 83 (21.7) 20 (15.1) 0.8 (0.4-1.6) 39 (18.7) 63 (20.7) 1.0 (0.6-1.9)

18-25 65 (17.0) 34 (25.8) 1.7 (0.8-3.3) 39 (18.7) 60 (19.7) 1.0 (0.5-1.8)

z26 82 (21.5) 29 (22.0) 1.1 (0.5-2.1) 45 (21.5) 66 (21.7) 0.9 (0.5-1.7)P trend 0.6 0.9

Transfusion

No 582 (84.1) 185 (84.1) 1.0 (reference) 307 (82.1) 453 (86.0) 1.0 (reference)

Yes 110 (15.9) 35 (15.9) 1.0 (0.6-1.5) 67 (17.9) 74 (14.0) 0.6 (0.4-0.9)Birth order

First/Middle 212 (73.87) 82 (78.1) 1.0 (reference) 113 (72.0) 180 (77.2) 1.0 (reference)

Last 75 (26.1) 23 (21.9) 0.8 (0.4-1.3) 44 (28.0) 53 (22.7) 0.7 (0.5-1.2)

Anthropometrics and diet

BMI (kg/m2)

<25 202 (31.2) 70 (33.3) 1.0 (reference) 105 (29.9) 164 (32.9) 1.0 (reference)25 to <35 386 (59.6) 122 (58.1) 0.9 (0.6-1.3) 215 (61.2) 286 (57.4) 0.8 (0.6-1.2)

(Continued on the following page)

TNF, IL10, and Other NHL Risk Factors

www.aacrjournals.org 5043 Cancer Res 2007; 67: (10). May 15, 2007




Table 1. Risk factor distribution by TNF G308A and IL10 T3575A genotypes among controls in the National Cancer Institute-Surveillance Evaluation, Epidemiology, and End Results NHL multicenter case-control study (associations are adjusted for thefollowing study design variables: age, education, sex, race, and study center) (Cont’d)



z35 60 (9.3) 18 (8.6) 0.9 (0.5-1.6) 31 (8.8) 48 (9.6) 1.0 (0.6-1.7)

P trend 0.5 0.6

Height (in.)<65 189 (28.8) 53 (25.0) 1.0 (reference) 90 (25.4) 149 (29.6) 1.0 (reference)

65-70 302 (46.1) 109 (51.4) 1.5 (1.0-2.3) 173 (48.9) 233 (46.2) 0.9 (0.6-1.3)

z71 164 (25.0) 50 (23.6) 1.5 (0.8-2.6) 91 (25.7) 122 (24.2) 0.9 (0.6-1.6)

P trend 0.2 0.8Smoking status

Never 125 (45.3) 38 (45.2) 1.0 (reference) 68 (45.9) 91 (44.8) 1.0 (reference)Former 107 (38.8) 36 (42.9) 1.1 (0.6-1.9) 58 (39.2) 80 (39.4) 1.0 (0.6-1.7)

Current 44 (15.9) 10 (11.9) 0.8 (0.3-1.8) 22 (14.9) 32 (15.8) 1.1 (0.5-2.1)

P trend 0.7 0.9

Ethanol (g/wk)z60 56 (21.3) 23 (27.4) 1.0 (reference) 36 (25.0) 41 (20.9) 1.0 (reference)

15 to <60 57 (21.7) 9 (10.7) 0.4 (0.1-0.9) 29 (20.1) 36 (18.4) 1.0 (0.5-2.1)

1 to <15 42 (16.0) 22 (26.2) 1.1 (0.5-2.4) 21 (14.6) 41 (20.9) 1.7 (0.8-3.6)<1 108 (41.1) 30 (35.7) 0.5 (0.2-1.0) 58 (40.3) 78 (39.8) 0.8 (0.4-1.6)

P trend 0.2 0.7

B6 (mg)z0.97 130 (49.4) 40 (47.6) 1.0 (reference) 74 (51.4) 91 (46.4) 1.0 (reference)

<0.97 133 (50.6) 44 (52.4) 1.2 (0.7-2.0) 70 (48.6) 105 (53.6) 1.2 (0.8-2.0)

SunlightSun in teens (h/wk)

z28 133 (43.6) 36 (39.1) 1.0 (reference) 68 (40.2) 97 (44.5) 1.0 (reference)

<28 106 (34.7) 31 (33.7) 1.0 (0.6-1.8) 58 (34.3) 74 (33.9) 0.9 (0.5-1.5)

<14 40 (13.1) 12 (13.0) 1.0 (0.4-2.1) 27 (16.0) 24 (11.0) 0.6 (0.3-1.2)

<7 26 (8.5) 13 (14.1) 1.6 (0.7-3.6) 16 (9.5) 23 (10.5) 0.9 (0.4-2.1)P trend 0.4 0.4

Sun in past 10 y (h/wk)z28 38 (12.4) 10 (11.0) 1.0 (reference) 22 (13.0) 25 (11.4) 1.0 (reference)

<28 81 (26.4) 23 (25.3) 0.9 (0.4 2.2) 43 (25.4) 60 (27.4) 1.3 (0.6 2.9)

<14 84 (27.4) 26 (28.6) 0.9 (0.4 2.2) 47 (27.8) 59 (26.9) 1.2 (0.6 2.7)

<7 104 (33.9) 32 (35.2) 0.8 (0.3 2.0) 57 (33.7) 75 (34.2) 1.3 (0.6 2.8)P trend 0.7 0.7

Eye colorGreen/blue-green 36 (11.6) 13 (14.1) 1.0 (reference) 24 (14.2) 23 (10.4) 1.0 (reference)Blue 113 (36.6) 40 (43.5) 0.9 (0.4-1.9) 55 (32.5) 96 (43.2) 2.0 (1.0-4.0)

Hazel 61 (19.7) 17 (18.5) 0.7 (0.3-1.6) 34 (20.1) 43 (19.4) 1.4 (0.7-3.1)

Light brown 32 (10.4) 7 (7.6) 0.6 (0.2-1.9) 17 (10.1) 21 (9.5) 2.1 (0.8-5.5)Dark brown 67 (21.7) 15 (16.3) 0.6 (0.2-1.5) 39 (23.1) 39 (17.6) 1.5 (0.7-3.4)

P trend 0.2 0.8

Environmental exposuresTermite treatment <1988

Not treated <1988 466 (67.0) 163 (72.8) 1.0 (reference) 236 (62.6) 384 (72.3) 1.0 (reference)

None or DK 112 (16.1) 31 (13.8) 0.9 (0.6-1.4) 71 (18.8) 72 (13.6) 0.7 (0.5-1.0)

z1 117 (16.8) 30 (13.4) 0.8 (0.5-1.3) 70 (18.6) 75 (14.1) 0.7 (0.5-1.1)

P trend 0.4 0.04a-Chlordane (dust; ng/g)

ND 211 (61.2) 75 (66.4) 1.0 (reference) 119 (62.0) 167 (63.7) 1.0 (reference)

20.8-60.1 57 (16.5) 24 (21.2) 1.2 (0.7-2.1) 34 (17.7) 45 (17.2) 0.9 (0.5-1.5)60.3-5,870 77 (22.3) 14 (12.4) 0.5 (0.3-1.0) 39 (20.3) 50 (19.1) 0.8 (0.5-1.4)

P trend 0.1 0.4


Cancer Research





polymorphisms and other risk factors associated with NHL in aU.S.-based multicenter case-control study. Specifically, we assessed(a) which risk factors are themselves related to the polymorphisms,(b) the effects of these factors on NHL risk according to thepresence or absence of the polymorphisms, and (c) the joint effectsbetween key risk factors and polymorphisms on NHL risk.

Materials and Methods

Study PopulationThe study population has previously been described in detail (25). We

included 1,321 newly diagnosed NHL cases identified in four Surveillance,

Epidemiology, and End Results registries (Iowa; Detroit, MI; Los Angeles,CA; and Seattle, WA) ages 20 to 74 years between July 1998 and June 2000

without evidence of HIV infection; 1,057 population controls were identified

by random digit dialing (<65 years) and from Medicare eligibility files (z65

years). Overall participation rates were 76% in cases and 52% in controls;overall response rates were 59% and 44%, respectively. Written informed

consent was obtained from each participant before interview.

HistopathologyEach registry provided NHL pathology and subtype information derived

from abstracted reports by the local diagnosing pathologist. All cases were

histologically confirmed and have been coded according to the International

Classification of Diseases for Oncology, 2nd Edition (ICD-O-2; ref. 26) andupdated to the WHO/ICD-O-3. We evaluated the histologic subtypes DLBCL

and follicular lymphoma.

Questionnaire DataTo accommodate a large number of questions, we used a split-sample

design, with a core set of questions given to all respondents and the

remainder given to participants in either group A (all African-American

participants and 50% of non–African-American participants) or group B

(50% of non–African-American participants). Before the in-person inter-view, participants were mailed a form for listing residential and job history

and either a family and medical history questionnaire (group A) or a diet

and lifestyle questionnaire (group B). During the home visit, the interviewer

administered a computer-assisted personal interview that included corequestions on demographics, height, weight, occupational history, pesticide

use history, and hair dye use and separate sets of questions for group A and

group B respondents.

From all participants, we queried on family history any first-degree

family member having NHL or lymphoma not otherwise specified (25). We

asked about a history of immune-related disorders including Sjogren’s

syndrome, lupus, Crohn’s disease, ulcerative colitis, rheumatic heart disease,

polymyalgia rheumatica, sarcoidosis, multiple sclerosis, uveitis, myasthenia

gravis, polymyositis, dermatomyositis, and/or celiac disease (1). We also

asked about blood transfusions. We asked about all surgeries since birth,

which we summed for a lifetime total. We asked about birth order and

characterized it as first- or middle-born child compared with last born. We

asked about height and weight and calculated body mass index (BMI) as

weight (kg) divided by height (m) squared (18). Height was categorized

according to tertile cut points in the control group. We asked about termite

treatment via a detailed history of pesticide use in each residence occupied

for 2 years since 1970 (10). The interviewer asked when the termite

treatments occurred and noted particularly whether they occurred before or

after 1988, when the termiticide chlordane was banned in the United States.

We categorized the responses as no treatment before 1988 (reference), one

or more treatments between 1988, or uncertain whether there was

treatment in one or more homes. From group A participants, we asked

about asthma.

From the self-administered diet and lifestyle questionnaire given to

group B participants, we estimated vitamin B6 intake and dichomotomizedit by the median among controls (17). We asked about regular cigarette

smoking for at least 6 months. We asked about alcohol intake, defining

nondrinkers as those who consumed alcohol less than once per month as

an adult. Intensity of ethanol consumption (grams per week) was calculatedby number of servings � ethanol per serving (beer, 12.9 g; wine, 9.3 g; and

liquor, 15.9 g) and categorized as quartiles according to the distribution

among controls. Because of the previously reported protective associationbetween alcohol and NHL, we used the highest level of alcohol intensity

(z60 g/wk) as the reference group. During the interviews with group B

Table 1. Risk factor distribution by TNF G308A and IL10 T3575A genotypes among controls in the National Cancer Institute-Surveillance Evaluation, Epidemiology, and End Results NHL multicenter case-control study (associations are adjusted for thefollowing study design variables: age, education, sex, race, and study center) (Cont’d)



PCB180 (dust; ng/g)

0-20.7 272 (78.8) 87 (77.0) 1.0 (reference) 153 (79.7) 205 (78.2) 1.0 (reference)20.8-44.3 36 (10.4) 13 (11.5) 1.0 (0.5-2.0) 20 (10.4) 28 (10.7) 1.0 (0.5-1.8)

>44.3 37 (10.7) 13 (11.5) 1.0 (0.5-2.0) 19 (9.9) 29 (11.1) 1.2 (0.6-2.2)

P trend 1.0 0.7PCB180 (blood; ng/g)

V28.7 19 (27.9) 6 (21.4) 1.0 (reference) 9 (25.0) 16 (26.7) 1.0 (reference)

>28.7-41.2 16 (23.5) 8 (28.6) 2.6 (0.5-12.3) 8 (22.2) 16 (26.7) 0.8 (0.2-3.6)

>41.2-54.4 16 (23.5) 8 (28.6) 2.9 (0.5-17.3) 8 (22.2) 16 (26.7) 0.7 (0.1-3.6)>54.4 17 (25.0) 6 (21.4) 1.8 (0.3-11.2) 11 (30.6) 12 (20.0) 0.5 (0.1-2.5)

P trend 0.6 0.4

Total furans (blood; mol/g)

V0.057 19 (28.8) 5 (17.9) 1.0 (reference) 11 (32.3) 13 (21.7) 1.0 (reference)>0.057-0.075 21 (31.8) 5 (17.9) 0.8 (0.2-4.3) 7 (20.6) 19 (31.7) 6.1 (1.3-28.2)

>0.075-0.098 10 (15.1) 13 (46.4) 5.2 (1.1-24.1) 9 (26.5) 14 (23.3) 1.9 (0.5-7.6)

>0.098 16 (24.2) 5 (17.9) 0.9 (0.2-5.4) 7 (20.6) 14 (23.3) 4.4 (0.9-21.3)P trend 0.4 0.3

Abbreviations: DK, Don’t know; ND, Not detected.






participants, sunlight exposures also were ascertained, including anestimate of hours per week in teen years and in the past 10 years (27).

Because increased sun was found to decrease NHL risk, we assigned the

highest level as the reference group. In addition, eye color was ascertained

as an indicator of UV susceptibility and categorized as dark brown, lightbrown, hazel, blue, and green/blue-green. We also asked about hay fever and

other allergies to food, animals, insects, medications, dust, and other

triggers. We excluded food allergies as these typically were intolerance

rather than allergy.

Environmental Samplesa-Chlordane and PCB180 were measured from 682 cases and 513

controls from whom dust samples were collected and analyzed (11, 28). A

multiple-imputation procedure was used to assign values to missing data

(29); in the present analyses, we used values from one of the imputations.

Individuals with detectable levels of a-chlordane or PCB180 (ng/g) were

grouped into tertiles based on the control distribution (a-chlordane: notdetectable (reference), 20.8–60.1, 60.3–5,870 ng/g; PCB180: 0–20.7 (refer-

ence), 20.8–44.3, >44.3 ng/g).

Serum SamplesPCB180 and total furans were further evaluated in serum samples in a

subset of 100 untreated cases and 100 controls (12). A multiple-imputationprocedure was also used to assign values to missing data determined to be

below the detection limits; in the present analyses, we used one of the

imputations. Levels for both analyses were categorized as quartiles

according to distribution among controls.

DNA Extraction and GenotypingAll study participants were asked to provide a venous blood or

mouthwash buccal cell sample. Overall, 1,172 cases (89%) and 982 controls

(93%) for whom biological samples were obtained were genotyped. There

was virtually no variation in the availability of DNA between cases and

controls or according to availability of risk factor data, except that most of

the subjects with serum also had DNA that could be genotyped. As

previously described (20), DNA was extracted from blood clots or buffy

coats (BBI Biotech) using Puregene Autopure DNA extraction kits (Gentra

Systems). DNA was extracted from buccal cell samples by phenol-

chloroform extraction methods (30). Genotyping was conducted at the

National Cancer Institute Core Genotyping Facility (Gaithersburg, MD)

using the Taqman platform. Forty replicate samples from two blood donors

each and duplicate samples from 100 participants processed in an identical

fashion were interspersed for all assays and blinded from the laboratory.

Agreement for quality control replicates and duplicates was >99% for all

assays. Successful genotyping was achieved for >99% of DNA samples, and

both TNF G308A and IL10 T3575A were in Hardy-Weinberg equilibrium.

Statistical AnalysisIndependence of risk factors. Among controls, we calculated odds

ratios (OR) and 95% confidence intervals (95% CI) for each risk factor with

dichotomized genotype, comparing the presence of a variant allele with theabsence of the allele (e.g., TNF �308 AA or AG genotypes versus GG; IL10

3575 AA or TA genotypes versus TT; Table 1). For ordinal risk factors with at

least three values, we calculated the P trend for a linear model.

Effects of risk factors by genotype. For all NHL cases and for DLBCL

and follicular lymphoma, we calculated OR and 95% CI for the joint effect of

each risk factor with dichotomized genes as described above (Tables 2

and 3). For these analyses, we report the risk estimates for each risk factor

stratified by genotype. In general, we chose as the reference group the

category with the lowest NHL risk. We calculated P interaction based on the

scored variable for each risk factor and for genotype; in these calculations,

we scored the genotype using the tri-level categorization to assess risk by

each additional risk allele.In the presentation of our results, we have specifically highlighted those

risk factors for which risk is statistically significant only within the variant

TNF G308A or IL10 T3575A genotypes or where risk elevation within the

variant TNF G308A or IL10 T3575A genotypes is equivalent or greater thanthat reported in the original manuscript.

Joint effects. For selected risk factors, we also calculated risk estimateswith a common reference group so that the risk factor category and

genotype that confers the least NHL risk is the singular reference group.

All risk estimates are adjusted for the following study design variables:

sex, age (<45, 45–64, z65 years), race (White, other/unknown), education(<12, 12–15, >15 years), and study center (Detroit, Iowa, Los Angeles,

Seattle). All logistic regression models were unconditional and conducted

using SAS 9.1.3 (SAS Institute).

Results

We evaluated the independence of all risk factors from TNFG308A and IL10 T3575A genotypes among the controls (Table 1).No consistent statistically significant associations were observedbetween any risk factor and the TNF G308A or IL10 T3575Agenotypes. However, we note a moderate, albeit not statisticallysignificant, association between family history and TNF G308A(OR, 1.7; 95% CI, 0.8–3.8). We also note no association betweeneither genotype with the presence of an autoimmune condition orwith obesity. Other elevated but not statistically significant ORswere observed for age, height, and PCB180 as measured from bloodwith TNF G308A and for eye color and total furans as measuredfrom blood with IL10 T3575A genotypes.Effects stratified by TNF genotype. We evaluated the risk for

NHL, DLBCL, and follicular lymphoma for all risk factors by TNFG308A genotypes (Table 2). Of the family and medical historyvariables evaluated, autoimmune conditions and status as last-born showed evidence of conveying differential risk by genotype.We observed elevated NHL risks with autoimmune conditions onlyamong those with the TNF GA/AA genotype (OR, 1.7; 95% CI, 0.8–3.5); this risk elevation was consistent for both DLBCL (OR, 1.5; 95%CI, 0.6–3.9) and follicular lymphoma (OR, 3.0; 95% CI, 1.1–8.5). Wefound elevated NHL risk among those with TNF GA/AA genotypesbut not TNF GG genotype for being the last born (OR, 2.0; 95% CI,1.1–3.8; Table 2). This elevated risk for late birth order among TNFGA/AA genotypes was statistically significant for DLBCL (OR, 2.7;95% CI, 1.1–6.4) but not follicular lymphoma.Of the anthropometric and diet variables evaluated, BMI showed

the most notable effect. We observed elevated NHL risk amongTNF GA/AA genotypes but not GG genotypes for BMI of z35 kg/m2

compared with <25 kg/m2 (OR, 1.8; 95% CI, 0.9–3.4). Risk seemedspecific for DLBCL (OR, 2.5; 95% CI, 1.1–5.7) and was not observedfor follicular lymphoma.Elevated NHL risks among TNF GA/AA genotypes but not GG

genotypes was also evident for eye color for NHL, DLBCL, andfollicular lymphoma. Risk increased with darker eye color and washighest for those with dark brown eyes (ORNHL, 3.7; 95% CI, 1.2–11.0;ORDLBCL, 2.4; 95% CI, 0.6–10.1; ORfollicular, 7.3; 95% CI, 1.2–44.5).All other risk factors associations with NHL were either present

only among those with the TNF GG genotype ( family history,surgeries, B6 intake, termite treatment, PCB180 in dust or blood)or no different between TNF GG or GA/AA genotypes (asthma,allergies, transfusion, height, smoking, ethanol, sunlight, a-chordane, total furans). On balance, those patterns suggest noevidence of further risk increase or modification for these riskfactors due to the presence of the TNF G308A GA/AA genotype.Joint effects with TNF. Compared with individuals without an

autoimmune condition and with the common TNF genotype, risksfor NHL, DLBCL, and follicular lymphoma were highest amongthose with both the TNF GA/AA genotype and autoimmuneconditions (ORNHL, 2.1; 95% CI, 1.0–4.2; ORDLBCL, 2.4; 95% CI, 1.0–5.8; ORfollicular, 2.4; 95% CI, 1.0–6.2; Table 4). Similarly, highest risks

Cancer Research





Table 2. Associations (OR and 95% CI) for NHL, DLBCL, and follicular lymphoma for NHL-relevant risk factors, stratified byTNF G308A genotypes and adjusted for age, education, sex, race, and study center

Risk factor All NHL DLBCL Follicular

GG GA/AA P* GG GA/AA P* GG GA/AA P*

n OR (95% CI) n OR (95% CI) n OR (95% CI) n OR (95% CI) n OR (95% CI) n OR (95% CI)

Family and medical history

Family history of NHL

No 729 1.0 (reference) 308 1.0 (reference) 217 1.0 (reference) 108 1.0 (reference) 178 1.0 (reference) 67 1.0 (reference)

Yes 32 1.4 (0.8-2.5) 16 0.8 (0.4-1.9) 0.58 8 1.2 (0.5-2.9) 6 1.0 (0.3-2.7) 0.90 10 1.8 (0.8-4.1) 5 1.3 (0.4-4.2) 0.73Autoimmune conditions


Yes 47 1.0 (0.7-1.6) 27 1.7 (0.8-3.5) 0.58 8 0.6 (0.3-1.3) 9 1.5 (0.6-3.9) 0.29 11 1.0 (0.5-2.0) 8 3.0 (1.1-8.5) 0.44Asthma

Yes 43 1.0 (reference) 17 1.0 (reference) 14 1.0 (reference) 3 1.0 (reference) 10 1.0 (reference) 6 1.0 (reference)

No 413 1.2 (0.8-1.9) 161 0.9 (0.4-2.1) 0.71 113 1.0 (0.5-2.0) 49 1.8 (0.4-7.2) 0.71 94 1.3 (0.6-2.7) 29 0.4 (0.1-1.3) 0.33

AllergyYes 198 1.0 (reference) 95 1.0 (reference) 53 1.0 (reference) 43 1.0 (reference) 60 1.0 (reference) 18 1.0 (reference)

No 139 1.1 (0.8-1.5) 60 1.1 (0.6-1.9) 0.57 54 1.6 (1.0-2.6) 21 0.7 (0.3-1.6) 0.30 31 0.8 (0.5-1.4) 21 2.3 (0.9-5.7) 0.20


0-6 51 1.0 (reference) 25 1.0 (reference) 15 1.0 (reference) 8 1.0 (reference) 5 1.0 (reference) 4 1.0 (reference)7-11 97 1.9 (1.2-3.1) 23 0.6 (0.3-1.4) 32 2.2 (1.1-4.6) 5 0.4 (0.1-1.5) 21 4.3 (1.5-12.2) 2 0.4 (0.1-2.4)

12-17 102 1.7 (1.0-2.8) 46 1.5 (0.7-3.6) 30 2.1 (1.0-4.6) 16 1.6 (0.5-5.0) 22 3.8 (1.3-10.9) 12 2.5 (0.6-10.4)

18-25 100 2.2 (1.3-3.7) 36 0.8 (0.4-1.8) 21 1.9 (0.8-4.2) 10 0.6 (0.2-2.1) 28 5.9 (2.1-16.8) 10 1.4 (0.3-6.1)z26 105 1.8 (1.1-3.1) 48 1.3 (0.5-3.0) 0.19 29 2.2 (1.0-4.9) 13 1.0 (0.3-3.4) 0.41 28 4.5 (1.6-12.9) 7 1.3 (0.3-6.3) 0.29

Transfusion


Yes 115 1.0 (0.7-1.3) 54 1.1 (0.6-1.7) 0.85 31 1.0 (0.6-1.5) 18 0.9 (0.5-1.8) 0.73 31 1.0 (0.6-1.6) 14 1.3 (0.6-2.7) 0.85Birth order

First/

middle

248 1.0 (reference) 92 1.0 (reference) 61 1.0 (reference) 24 1.0 (reference) 60 1.0 (reference) 24 1.0 (reference)

Last 108 1.2 (0.8-1.7) 43 2.0 (1.1-3.8) 0.53 40 2.0 (1.2-3.3) 16 2.7 (1.1-6.4) 0.85 25 1.1 (0.6-1.9) 7 1.5 (0.5-4.6) 0.64


BMI (kg/m2)<25 257 1.0 (reference) 87 1.0 (reference) 68 1.0 (reference) 29 1.0 (reference) 69 1.0 (reference) 19 1.0 (reference)

25-<35 411 0.8 (0.6-1.0) 183 1.2 (0.8-1.8) 126 1.0 (0.7-1.4) 60 1.2 (0.7-2.1) 93 0.8 (0.5-1.1) 46 1.5 (0.8-3.0)

z35 72 0.9 (0.6-1.3) 41 1.8 (0.9-3.4) 0.32 30 1.6 (0.9-2.7) 18 2.5 (1.1-5.7) 0.55 16 0.7 (0.4-1.4) 3 0.6 (0.1-2.3) 0.31

Height (in.)<65 185 1.0 (reference) 77 1.0 (reference) 53 1.0 (reference) 27 1.0 (reference) 45 1.0 (reference) 14 1.0 (reference)

65-70 367 1.2 (0.9-1.7) 145 0.9 (0.5-1.4) 108 1.1 (0.7-1.7) 43 0.8 (0.4-1.5) 91 1.6 (1.0-2.5) 30 1.0 (0.4-2.3)

z71 195 1.2 (0.8-1.8) 91 1.2 (0.6-2.3) 0.59 64 1.1 (0.6-2.0) 38 1.9 (0.8-4.8) 0.25 42 1.8 (1.0-3.4) 24 2.0 (0.7-5.6) 0.39

SmokingNever 134 1.0 (reference) 67 1.0 (reference) 46 1.0 (reference) 31 1.0 (reference) 37 1.0 (reference) 14 1.0 (reference)

Former 97 0.9 (0.6-1.3) 46 0.6 (0.3-1.2) 35 1.0 (0.6-1.7) 16 0.5 (0.2-1.1) 22 0.8 (0.4-1.4) 13 0.9 (0.3-2.8)

Current 59 1.1 (0.7-1.8) 20 0.9 (0.3-2.2) 0.89 15 0.9 (0.4-1.7) 8 0.7 (0.2-2.4) 0.92 16 1.1 (0.5-2.2) 6 1.9 (0.4-8.0) 0.99

Ethanol (g/wk)z60 54 1.0 (reference) 28 1.0 (reference) 15 1.0 (reference) 10 1.0 (reference) 15 1.0 (reference) 5 1.0 (reference)

15-<60 50 0.9 (0.5-1.6) 15 1.3 (0.4-4.0) 18 1.2 (0.5-2.8) 7 1.2 (0.3-5.1) 13 0.7 (0.3-1.6) 5 2.3 (0.4-13.3)

1-V15 36 0.9 (0.5-1.6) 15 0.7 (0.3-1.7) 16 1.4 (0.6-3.4) 8 0.8 (0.2-2.6) 4 0.3 (0.1-0.9) 4 1.3 (0.2-7.6)<1 151 1.6 (1.0-2.6) 71 3.0 (1.3-6.8) 0.81 47 2.2 (1.1-4.5) 31 3.3 (1.1-9.6) 0.97 44 1.4 (0.7-2.8) 18 5.1 (1.2-20.5) 0.85

Vitamin B6 (mg)

z0.97 111 1.0 (reference) 51 1.0 (reference) 33 1.0 (reference) 19 1.0 (reference) 31 1.0 (reference) 13 1.0 (reference)

<0.97 180 1.6 (1.1-2.2) 78 1.1 (0.6-2.0) 0.60 63 1.9 (1.2-3.2) 37 1.2 (0.6-2.7) 0.72 45 1.4 (0.8-2.4) 19 1.1 (0.4-3.0) 0.58

Sunlight

Sun in teens (h/wk)

z28 134 1.0 (reference) 58 1.0 (reference) 39 1.0 (reference) 24 1.0 (reference) 36 1.0 (reference) 18 1.0 (reference)<28 112 1.0 (0.7-1.5) 57 1.5 (0.8-3.0) 38 1.3 (0.8-2.3) 26 1.4 (0.6-3.2) 30 0.9 (0.5-1.7) 9 1.1 (0.3-3.3)







were observed for those with both the TNF GA/AA genotype andstatus as last-born child or a BMI of z35 kg/m2 compared withthose with the TNF GG genotype and status as the first/middlechild or BMI of <25 kg/m2, respectively.Effects stratified by IL10 genotype. Similarly arranged

estimates for all risk factor variables by IL10 T3575A genotypeare shown in Table 3. Of family and medical history variables

evaluated, the presence of an autoimmune condition wasassociated with elevated NHL (OR, 1.5; 95% CI, 0.9–2.4), DLBCL(OR, 1.4; 95% CI, 0.7–2.9), and follicular lymphoma risk (OR, 1.9;95% CI, 0.9–3.9) among IL10 TA/AA genotypes but not IL10 TTgenotypes. Individuals who reported that they were the last-bornalso had elevated risks among IL10 TA/AA genotypes for NHL(OR, 1.7; 95% CI, 1.1–2.5) and DLBCL (OR, 2.9; 95% CI, 1.6–5.2)

Table 2. Associations (OR and 95% CI) for NHL, DLBCL, and follicular lymphoma for NHL-relevant risk factors, stratified byTNF G308A genotypes and adjusted for age, education, sex, race, and study center (Cont’d)


GG GA/AA P* GG GA/AA P* GG GG/AA P*


<14 45 1.2 (0.7-2.0) 25 2.0 (0.8-4.9) 14 1.5 (0.7-3.1) 9 1.4 (0.4-4.3) 11 1.1 (0.5-2.3) 8 2.4 (0.6-9.3)<7 42 1.8 (1.0-3.1) 15 1.0 (0.4-2.7) 0.26 16 2.6 (1.2-5.7) 5 0.7 (0.2-2.3) 0.38 12 1.6 (0.7-3.6) 4 0.8 (0.2-3.5) 0.49

Sun in past 10 yrs (h/wk)z28 41 1.0 (reference) 15 1.0 (reference) 19 1.0 (reference) 10 1.0 (reference) 11 1.0 (reference) 2 1.0 (reference)<28 92 1.2 (0.7-2.1) 31 0.9 (0.3-2.6) 29 0.8 (0.4-1.6) 13 0.6 (0.2-1.9) 19 0.9 (0.4-2.3) 6 2.4 (0.3-19.2)

<14 78 1.0 (0.6-1.8) 49 1.5 (0.5-4.1) 19 0.5 (0.2-1.1) 17 0.6 (0.2-2.2) 25 1.2 (0.5-2.8) 14 6.9 (0.9-54.1)

<7 126 1.3 (0.7-2.2) 60 1.5 (0.5-4.2) 0.83 40 0.9 (0.4-1.8) 24 0.9 (0.3-2.9) 0.58 36 1.4 (0.6-3.3) 17 7.2 (0.9-56.0) 0.89

Eye colorGreen/

blue-

green


Blue 108 1.0 (0.6-1.7) 62 1.9 (0.8-4.9) 35 1.2 (0.5-2.8) 29 2.1 (0.6-7.1) 35 1.2 (0.5-2.6) 15 2.5 (0.6-11.0)

Hazel 51 0.8 (0.5-1.5) 33 2.3 (0.8-6.5) 12 0.8 (0.3-2.0) 13 2.2 (0.6-8.2) 19 1.1 (0.5-2.7) 8 2.7 (0.6-13.6)Light

brown

34 1.1 (0.6-2.2) 12 2.5 (0.7-9.4) 14 2.0 (0.8-5.5) 5 2.3 (0.4-12.6) 7 0.8 (0.3-2.6) 3 4.3 (0.5-39.7)

Dark

brown

106 1.6 (0.9-2.9) 33 3.7 (1.2-11.0) 0.86 36 2.2 (1.0-5.2) 11 2.4 (0.6-10.1) 0.66 19 1.0 (0.4-2.5) 9 7.3 (1.2-44.5) 0.88

Environmental exposures

Termite treatment <1988Not

treated<1988


None or

DK

153 1.2 (0.9-1.6) 53 1.1 (0.7-1.9) 53 1.3 (0.9-2.0) 16 0.9 (0.4-1.8) 37 1.1 (0.7-1.7) 13 1.2 (0.5-2.6)

z1 152 1.3 (1.0-1.8) 42 1.0 (0.6-1.8) 0.87 47 1.6 (1.0-2.5) 15 1.0 (0.5-2.1) 0.90 29 1.0 (0.6-1.6) 8 0.9 (0.3-2.2) 0.84

a-Chlordane (dust; ng/g)ND 249 1.0 (reference) 105 1.0 (reference) 70 1.0 (reference) 42 1.0 (reference) 57 1.0 (reference) 23 1.0 (reference)20.8-60.1 79 1.2 (0.8-1.7) 26 0.8 (0.4-1.5) 23 1.4 (0.8-2.4) 7 0.5 (0.2-1.4) 19 1.3 (0.7-2.4) 6 0.9 (0.3-2.7)

60.3-5,870 108 1.3 (0.9-1.8) 34 1.7 (0.8-3.7) 0.71 34 1.6 (0.9-2.7) 7 0.9 (0.3-2.6) 0.40 24 1.2 (0.7-2.3) 7 1.4 (0.4-4.4) 0.99

PCB180 (dust; ng/g)0-20.7 323 1.0 (reference) 123 1.0 (reference) 100 1.0 (reference) 43 1.0 (reference) 72 1.0 (reference) 27 1.0 (reference)

20.8-44.3 58 1.5 (1.0-2.4) 23 1.4 (0.7-3.1) 16 1.3 (0.7-2.5) 10 1.7 (0.7-4.5) 14 1.6 (0.8-3.2) 3 1.1 (0.3-4.6)>44.3 55 1.5 (0.9-2.3) 19 1.1 (0.5-2.5) 0.70 11 0.9 (0.4-2.0) 3 0.4 (0.1-1.6) 0.92 14 1.6 (0.8-3.3) 6 2.1 (0.6-6.8) 0.81

PCB180 (blood; ng/g)

V28.7 10 1.0 (reference) 5 1.0 (reference)>28.7-41.2 15 2.5 (0.8-8.1) 5 0.6 (0.1-4.7)

>41.2-54.4 10 1.6 (0.5-5.6) 10 1.1 (0.1-8.5)

>54.4 27 5.7 (1.6-20.0) 11 2.2 (0.2-19.5) 0.79

Total furans (blood; mol/g)V0.057 9 1.0 (reference) 5 1.0 (reference)

>0.057-0.075 13 1.9 (0.6-6.3) 6 1.2 (0.1-9.5)

>0.075-0.098 15 5.7 (1.5-21.7) 7 0.7 (0.1-4.4)

>0.098 25 6.3 (1.8-22.8) 13 5.6 (0.7-43.6) 0.31

*P interaction modeled on separate genotypes as scored variable; gray hatchets indicate insufficient numbers to calculate risk estimates.

Cancer Research





Table 3. Associations (OR and 95% Ci) for NHL, DLBCL, and follicular lymphoma for NHL-relevant risk factors, stratified byIL10 T3575A genotypes and adjusted for age, education, sex, race, and center


TT TA/AA P* TT TA/AA P* TT TA/AA P*


Family and medical history

Family history of NHL


Yes 27 1.9 (0.9-3.9) 21 0.8 (0.4-1.6) 0.07 8 2.0 (0.8-5.3) 6 0.7 (0.3-1.9) 0.32 9 2.8 (1.1-7.0) 6 1.0 (0.4-2.6) 0.10Autoimmune conditions


Yes 26 0.9 (0.5-1.6) 48 1.5 (0.9-2.4) 0.36 3 0.3 (0.1-1.1) 14 1.4 (0.7-2.9) 0.04 6 0.8 (0.3-2.1) 13 1.9 (0.9-3.9) 0.42Asthma

Yes 23 1.0 (reference) 35 1.0 (reference) 8 1.0 (reference) 9 1.0 (reference) 7 1.0 (reference) 9 1.0 (reference)

No 231 1.5 (0.8-2.7) 340 1.1 (0.6-1.8) 0.14 61 1.0 (0.4-2.4) 102 1.3 (0.6-2.9) 0.55 46 1.0 (0.4-2.5) 75 0.9 (0.4-2.0) 0.64

AllergyYes 113 1.0 (reference) 178 1.0 (reference) 34 1.0 (reference) 61 1.0 (reference) 28 1.0 (reference) 50 1.0 (reference)

No 74 1.1 (0.7-1.8) 124 1.1 (0.7-1.6) 0.99 29 1.6 (0.8-3.1) 45 1.1 (0.7-1.8) 0.81 16 0.8 (0.3-1.7) 36 1.2 (0.7-2.2) 0.75


0-6 34 1.0 (reference) 37 1.0 (reference) 12 1.0 (reference) 11 1.0 (reference) 2 1.0 (reference) 6 1.0 (reference)7-11 52 1.3 (0.7-2.4) 67 1.6 (0.9-2.7) 15 1.2 (0.5-3.0) 22 1.8 (0.8-4.2) 11 5.6 (1.1-27.5) 12 1.7 (0.6-5.0)

12-17 55 1.6 (0.8-3.2) 93 1.8 (1.0-3.1) 12 1.5 (0.5-4.3) 34 2.2 (1.0-5.1) 14 7.1 (1.4-35.4) 20 2.5 (0.9-7.1)

18-25 53 1.7 (0.9-3.2) 83 1.7 (0.9-3.0) 17 2.0 (0.8-5.1) 15 1.1 (0.4-2.7) 10 5.3 (1.0-26.9) 27 3.5 (1.2-9.6)z26 60 1.6 (0.8-3.2) 93 1.7 (1.0-3.1) 0.91 13 1.5 (0.5-4.4) 29 2.0 (0.8-4.8) 0.41 16 6.9 (1.4-34.9) 19 2.2 (0.8-6.5) 0.91

Transfusion


Yes 55 0.7 (0.4-1.0) 114 1.4 (1.0-1.9) 0.03 15 0.6 (0.3-1.2) 34 1.3 (0.8-2.0) 0.16 15 0.8 (0.4-1.5) 30 1.4 (0.8-2.2) 0.56Birth order

First/

middle


Last 54 1.0 (0.6-1.6) 96 1.7 (1.1-2.5) 0.22 19 1.4 (0.7-2.8) 37 2.9 (1.6-5.2) 0.36 14 1.7 (0.8-3.8) 18 1.0 (0.5-2.0) 0.54


BMI (kg/m2)<25 138 1.0 (reference) 205 1.0 (reference) 40 1.0 (reference) 56 1.0 (reference) 32 1.0 (reference) 56 1.0 (reference)

25-<35 230 0.8 (0.6-1.1) 359 1.0 (0.7-1.3) 70 0.9 (0.6-1.5) 117 1.2 (0.8-1.8) 48 0.7 (0.4-1.2) 89 1.0 (0.7-1.5)

z35 43 1.0 (0.6-1.7) 70 1.1 (0.7-1.7) 0.33 15 1.5 (0.7-3.2) 33 2.0 (1.1-3.5) 0.68 9 0.8 (0.3-1.8) 10 0.6 (0.3-1.3) 0.40

Height (in.)<65 105 1.0 (reference) 155 1.0 (reference) 31 1.0 (reference) 49 1.0 (reference) 20 1.0 (reference) 38 1.0 (reference)

65-70 199 1.0 (0.7-1.5) 311 1.3 (0.9-1.8) 52 0.8 (0.4-1.5) 100 1.3 (0.8-2.1) 41 1.3 (0.6-2.5) 79 1.6 (0.9-2.6)

z71 111 1.1 (0.7-1.9) 173 1.3 (0.8-2.0) 0.43 42 1.3 (0.6-3.0) 59 1.5 (0.8-2.7) 0.60 28 2.2 (0.9-5.4) 38 1.7 (0.9-3.4) 0.32

SmokingNever 84 1.0 (reference) 117 1.0 (reference) 34 1.0 (reference) 43 1.0 (reference) 16 1.0 (reference) 35 1.0 (reference)

Former 46 0.7 (0.4-1.2) 97 0.9 (0.6-1.4) 14 0.5 (0.2-1.2) 37 0.9 (0.5-1.6) 13 0.9 (0.4-2.2) 22 0.9 (0.5-1.7)

Current 29 1.0 (0.5-2.0) 48 1.0 (0.6-1.7) 0.76 8 0.7 (0.3-1.8) 14 0.8 (0.3-1.6) 0.45 8 1.4 (0.5-4.0) 14 1.1 (0.5-2.4) 0.95

Ethanol (g/wk)z60 28 1.0 (reference) 51 1.0 (reference) 6 1.0 (reference) 17 1.0 (reference) 5 1.0 (reference) 15 1.0 (reference)

15-<60 25 1.1 (0.5-2.3) 40 0.9 (0.5-1.8) 9 1.6 (0.5-5.3) 16 1.2 (0.5-2.9) 6 1.4 (0.4-5.5) 12 0.6 (0.2-1.7)

1-<15 19 1.2 (0.5-2.9) 32 0.7 (0.3-1.2) 8 2.3 (0.6-8.1) 16 1.1 (0.4-2.5) 3 0.9 (0.2-4.7) 5 0.3 (0.1-1.0)<1 89 2.1 (1.1-4.1) 134 1.9 (1.1-3.3) 0.85 34 3.8 (1.4-10.5) 45 2.2 (1.0-4.8) 0.73 24 3.2 (1.0-9.8) 38 1.6 (0.7-3.7) 0.75

Vitamin B6 (mg)

z0.97 60 1.0 (reference) 101 1.0 (reference) 18 1.0 (reference) 33 1.0 (reference) 15 1.0 (reference) 29 1.0 (reference)

<0.97 101 1.7 (1.1-2.8) 156 1.2 (0.8-1.7) 0.51 39 2.2 (1.1-4.3) 61 1.4 (0.8-2.4) 0.41 23 1.6 (0.7-3.4) 41 1.1 (0.6-1.9) 0.67

Sunlight

Sun in teens (h/wk)

z28 70 1.0 (reference) 120 1.0 (reference) 22 1.0 (reference) 40 1.0 (reference) 20 1.0 (reference) 34 1.0 (reference)<28 65 1.0 (0.6-1.8) 103 1.2 (0.8-1.8) 23 1.4 (0.7-2.9) 40 1.4 (0.8-2.5) 14 0.8 (0.3-1.8) 25 0.9 (0.5-1.6)







but not among IL10 TT genotypes or for follicular lymphoma(Table 3).For those reporting having had a blood transfusion, mild

elevations in risk for NHL (OR, 1.4; 95% CI, 1.0–1.9) were alsoobserved among IL10 TA/AA genotypes but not IL10 TT genotypes.Although P interaction was statistically significant, we note thedecreased risk among IL10 TT genotypes, which likely contributedto this statistic.

Of anthropometric and diet variables evaluated, elevated DLBCLrisk was observed only among individuals with IL10 TA/AA withBMI z35 kg/m2 (OR, 2.0; 95% CI, 1.1–3.5) compared with BMI <25kg/m2 and not among those with IL10 TT genotypes.Of environmental exposures evaluated, termite treatment

showed differential effects by IL10 genotypes. We observedelevated NHL risks among IL10 TA/AA genotypes but not IL10TT genotypes for those who had termite treatment before 1988

Table 3. Associations (OR and 95% CI) for NHL, DLBCL, and follicular lymphoma for NHL-relevant risk factors, stratified byIL10 T3575A genotypes and adjusted for age, education, sex, race, and center (Cont’d)


TT TA/AA P* TT TA/AA P* TT TA/AA P*


<14 30 1.0 (0.5-2.0) 39 1.5 (0.8-2.8) 11 1.3 (0.5-3.4) 11 1.3 (0.5-3.0) 5 0.6 (0.2-1.9) 14 1.8 (0.8-4.2)

<7 21 1.1 (0.5-2.4) 37 1.7 (0.9-3.3) 0.97 7 1.3 (0.4-3.6) 15 2.3 (1.0-5.2) 0.86 5 0.8 (0.2-2.5) 11 1.6 (0.6-4.1) 0.83

Sun in past 10 yrs (h/wk)z28 19 1.0 (reference) 36 1.0 (reference) 8 1.0 (reference) 20 1.0 (reference) 5 1.0 (reference) 8 1.0 (reference)<28 40 1.2 (0.5-2.7) 83 1.0 (0.5-2.0) 14 1.0 (0.3-3.0) 28 0.6 (0.3-1.3) 6 0.9 (0.2-3.8) 19 1.3 (0.5-3.7)

<14 59 1.6 (0.8-3.6) 68 1.0 (0.5-1.9) 16 1.0 (0.3-3.0) 20 0.4 (0.2-1.0) 17 2.3 (0.7-7.7) 22 1.6 (0.6-4.6)

<7 69 1.5 (0.7-3.2) 115 1.2 (0.6-2.3) 0.72 25 1.3 (0.4-3.6) 38 0.6 (0.3-1.4) 0.83 16 1.6 (0.5-5.4) 37 2.3 (0.8-6.4) 0.56

Eye colorGreen/

blue-

green


Blue 55 2.0 (0.9-4.5) 113 0.7 (0.4-1.3) 19 3.4 (0.9-13.2) 44 0.9 (0.4-2.0) 16 4.9 (1.0-24.5) 34 0.7 (0.3-1.5)

Hazel 30 1.8 (0.8-4.1) 54 0.8 (0.4-1.5) 9 2.6 (0.6-10.7) 16 0.7 (0.3-1.8) 11 4.6 (0.9-23.8) 16 0.7 (0.3-1.7)Light

brown

28 3.6 (1.4-9.1) 18 0.5 (0.2-1.2) 9 5.7 (1.3-25.5) 10 0.9 (0.3-2.6) 87.6 (1.2-45.6) 2 0.2 (0.03-0.9)

Dark

brown

59 3.0 (1.3-6.8) 79 1.3 (0.6-2.5) 0.37 23 5.5 (1.4-21.3) 23 1.2 (0.5-2.9) 0.45 72.5 (0.4-13.9) 21 1.1 (0.4-2.8) 0.12

Environmental exposures

Termite treatment <1988Not

treated

<1988


None or

DK

91 1.0 (0.7-1.4) 114 1.3 (0.9-1.9) 32 1.2 (0.7-2.0) 37 1.3 (0.8-2.0) 16 0.8 (0.4-1.5) 34 1.5 (0.9-2.4)

z1 78 1.0 (0.6-1.5) 112 1.4 (1.0-2.0) 0.54 27 1.3 (0.7-2.4) 34 1.4 (0.8-2.3) 0.14 14 0.8 (0.4-1.6) 22 1.0 (0.6-1.8) 0.40

a-Chlordane (dust; ng/g)ND 136 1.0 (reference) 216 1.0 (reference) 43 1.0 (reference) 68 1.0 (reference) 34 1.0 (reference) 46 1.0 (reference)

20.8-60.1 38 0.9 (0.5-1.6) 67 1.2 (0.8-1.9) 9 0.7 (0.3-1.6) 21 1.3 (0.7-2.5) 10 1.0 (0.5-2.4) 15 1.4 (0.7-2.9)

60.3-5,870 50 1.0 (0.6-1.8) 90 1.6 (1.0-2.4) 0.63 14 0.9 (0.4-2.1) 27 1.6 (0.9-3.0) 0.67 14 1.4 (0.6-3.1) 17 1.3 (0.7-2.7) 0.83PCB180 (dust; ng/g)

0-20.7 177 1.0 (reference) 266 1.0 (reference) 54 1.0 (reference) 88 1.0 (reference) 45 1.0 (reference) 54 1.0 (reference)

20.8-44.3 24 1.2 (0.6-2.4) 56 1.7 (1.0-2.8) 8 1.2 (0.5-3.2) 17 1.6 (0.8-3.2) 6 1.4 (0.5-3.9) 11 1.7 (0.8-3.7)

>44.3 23 1.6 (0.8-3.3) 51 1.5 (0.9-2.5) 0.85 4 0.8 (0.2-2.7) 11 1.0 (0.5-2.2) 0.97 7 2.3 (0.8-6.7) 13 2.0 (0.9-4.3) 0.99PCB180 (blood; ng/g)

V28.7 9 1.0 (reference) 6 1.0 (reference)

>28.7-41.2 8 0.8 (0.1-5.2) 12 2.7 (0.7-9.9)

>41.2-54.4 6 1.0 (0.1-6.0) 13 4.3 (1.1-17.6)>54.4 17 2.6 (0.5-13.7) 20 11.0 (2.4-51.0) 0.60

Total furans (blood; mol/g)

V0.057 7 1.0 (reference) 7 1.0 (reference)

>0.057-0.075 7 2.8 (0.4-17.7) 10 1.0 (0.3-3.9)>0.075-0.098 6 1.1 (0.2-5.8) 16 5.1 (1.1-22.4)

>0.098 20 11.9 (2.0-71.3) 18 4.7 (1.1-20.1) 0.33

*P interaction modeled on separate genotypes as scored variable; gray hatchets indicate insufficient numbers to calculate risk estimates.

Cancer Research





(OR, 1.4; 95% CI, 1.0–2.0) or the highest tertile of a-chlordanelevels from dust (OR, 1.6; 95% CI, 1.0–2.4). Associations fora-chlordane, but not termite treatment, seemed pronounced forDLBCL.All other associations with NHL were either present only among

those with the IL10 T3575A TT genotypes ( family history, vitaminB6, sunlight in past 10 years, eye color) or no different between IL10T3575A TT or TA/AA genotypes (asthma, allergy, surgeries, height,smoking, ethanol, PCB180, total furans), suggesting no further riskincrease or modification in the presence of the IL10 T3575A TA/AAgenotype.Joint effects with IL10. Highest risks were observed for

individuals with both the IL10 TA/AA genotype and autoimmuneconditions (ORNHL, 1.6; 95% CI, 0.9–2.6; ORDLBCL, 1.5; 95% CI, 0.8–3.1;ORfollicular, 2.1; 95% CI, 1.0–4.3) when compared with a commonreference group of IL10 TT genotype and no autoimmune condition(Table 5). Similarly, DLBCL risks were highest for individualswith the IL10 TA/AA genotype and a BMI of z35 kg/m2 (OR, 1.8;95% CI, 1.0–3.2) or with the highest tertile of a-chlordane levels(OR, 1.8; 95% CI, 1.0–3.4) when compared with a common referencegroup of IL10 TT genotype and a BMI of <25 kg/m2 or noa-chlordane exposure, respectively.

Discussion

To our knowledge, this is the first evaluation of recognizedNHL risk factors and (a) their association with TNF G308A or IL10T3575A variant alleles, (b) their risks in the presence and absenceof a chronic inflammatory state resulting from TNF G308A or IL10T3575A variants, and (c) their joint effects. From this broadexploration of the combined effects of genetic and non-geneticfactors, several provocative findings have emerged. Family historyof NHL is of interest because inherited TNF or IL10 variants couldbe a genetic basis for familial risk, but our findings suggest thatneither variant fully explains the family history association with

NHL. On the other hand, history of medical conditions, such asautoimmune conditions and exposure to childhood infections,might be expected to be associated with the variant TNF or IL10alleles, but we found virtually no association between these riskfactors and presence of the variant TNF or IL10 allele among thecontrols.Our evaluation of risk factors, stratified by genotype and acting

jointly with genotypes, suggests that common genetic variants inTNF and IL10 may potentiate the risk associated with autoimmuneconditions, late birth order, and obesity for NHL, specifically in theDLBCL subtype. Different mechanisms could be posited for theserisk factors, but we infer that they act through a common pathwaythat results in chronic antigen stimulation and inflammation.Potential joint effects with termite exposure and a-chlordane wereapparent only with IL10 T3575A variants and NHL, suggesting thatalthough these risk factors may also act on the immunoregulatorypathway, immunosuppression rather than inflammation may be aculpable pathway of interest.Autoimmune conditions are a well-established risk factor for

NHL as shown in this and other studies (1, 31, 32). In the presentanalysis, we find the increased risk restricted to individuals witheither the TNF G308A or IL10 T3575A variant alleles. Althoughassociations between TNF G308A with some autoimmune con-ditions (e.g., rheumatoid arthritis; ref. 33) have been reported, thisvariant was not associated with autoimmune conditions (or anyindividual condition) among our control group. These conditionsentail chronic stimulation and proliferation of lymphocytes (34, 35)and an active Th1/proinflammatory immune response (34, 36); thus,the apparent synergy between an already present chronicinflammatory state as induced by TNF G308A or IL10 T3575Aand the presence of an autoimmune condition that increases NHLrisk strongly suggests that chronic inflammation explains the effectof autoimmune conditions.Birth order has not yet been firmly established as a risk factor

for NHL, although several well-conducted studies recently showed

Table 4. Selected joint effects with TNF for NHL, DLBCL, and follicular lymphoma, adjusted for age, education, sex, race, andstudy center

Genotype Risk factor Controls, n (%) NHL DLBCL Follicular

n (%) OR (95% CI) n (%) OR (95% CI) n (%) OR (95% CI)

TNF Autoimmune conditionsGG No 655 (71.3) 751 (66.5) 1.0 (reference) 228 (65.1) 1.0 (reference) 185 (68.3) 1.0 (reference)

Yes 40 (4.3) 47 (4.2) 1.1 (0.7-1.6) 8 (2.3) 0.6 (0.3-1.3) 11 (4.1) 1.0 (0.5-2.1)

GA/AA No 212 (23.1) 305 (27.0) 1.2 (1.0-1.5) 105 (30.0) 1.5 (1.1-1.9) 67 (24.7) 1.1 (0.8-1.5)

Yes 12 (1.3) 27 (2.4) 2.1 (1.0-4.2) 9 (2.6) 2.4 (1.0-5.8) 8 (2.9) 2.4 (1.0-6.2)TNF Birth order

GG First/middle 212 (54.1) 248 (50.5) 1.0 (reference) 61 (43.3) 1.0 (reference) 60 (51.7) 1.0 (reference)

Last 75 (19.1) 108 (22.0) 1.2 (0.8-1.7) 40 (28.4) 1.9 (1.2-3.2) 25 (21.5) 1.2 (0.7-2.0)

GA/AA First/middle 82 (20.9) 92 (18.7) 0.9 (0.6-1.3) 24 (17.0) 0.9 (0.5-1.7) 24 (20.7) 0.9 (0.5-1.6)Last 23 (5.9) 43 (8.8) 1.6 (0.9-2.7) 16 (11.3) 2.3 (1.1-4.9) 7 (6.0) 1.1 (0.4-2.9)

TNF BMI (kg/m2)

GG <25 202 (23.5) 257 (24.4) 1.0 (reference) 68 (20.5) 1.0 (reference) 69 (28.0) 1.0 (reference)25 to <35 386 (45.0) 411 (39.1) 0.8 (0.6-1.0) 126 (38.1) 1.0 (0.7-1.4) 93 (37.8) 0.7 (0.5-1.1)

z35 60 (7.0) 72 (6.8) 0.9 (0.6-1.3) 30 (9.1) 1.5 (0.9-2.6) 16 (6.5) 0.7 (0.4-1.3)

GA/AA <25 70 (8.2) 87 (8.3) 1.0 (0.7-1.4) 29 (8.8) 1.2 (0.7-2.0) 19 (7.7) 0.7 (0.4-1.3)

25 to <35 122 (14.2) 183 (17.4) 1.1 (0.8-1.5) 60 (18.1) 1.5 (1.0-2.4) 46 (18.7) 1.1 (0.7-1.8)z35 18 (2.1) 41 (3.9) 1.7 (0.9-3.0) 18 (5.4) 3.1 (1.5-6.4) 3 (1.2) 0.4 (0.1-1.6)






that later-born children have the highest risks for NHL (14, 37, 38)and particularly for DLBCL as recently reported in our population(38). A Th2 immune response predominates in utero (39–41) andshifts to a Th1 response in childhood upon exposure to infectiousagents. Because birth order is thought to be a surrogate forgeneral exposure to infectious agents, an individual with a largernumber of older siblings likely would be exposed to infectiousagents earlier in life. The shift to a Th1 immune response earlierin life may thus correspond to a higher likelihood of having life-long chronic B-cell stimulation (38). Our observation of increasedrisk among later-born individuals with TNF or IL10 variantgenotypes supports the hypothesis that longer periods ofprolonged Th1/proinflammatory response or chronic antigenicstimulation, especially early in development, could increase risk ofNHL, and especially DLBCL. Later birth order may mark a specificinfectious agent or general exposure, but there certainly existsevidence for interaction between TNF and IL10 with infectiousagents, including delayed EBV seroconversion and resistance toherpesvirus infection with increased IL10 production (42) andprotection against cytomegalovirus with the TNF G308A poly-morphism (43).The association between obesity as defined by a BMI ofz35 kg/m2

and NHL has been reported (44) and specifically for DLBCL(18, 45). A number of mechanisms have been posited for theobserved associations between obesity and cancer (including NHL).These mechanisms include the effects of obesity on endogenoushormone metabolism, DNA damage via production of reactiveoxygen species, and inflammation (18). Although our observedassociation between obesity and risk only in the presence of TNF

G308A and IL10 T3575A variants does not disprove any of thealternative explanations, it does support the hypothesis that anobesity-related chronic inflammatory response (46) likely plays animportant role in the etiology of NHL and DLBCL. This maycontribute to some of the inconsistency in the literature on obesityand NHL.The previously observed association between termite treatment

before 1988 and a-chlordane with NHL (10) seemed to berestricted to individuals with variant genotypes for IL10 T3575A.The lack of an association among the TNF G308A polymorphismsuggests that these risk factors may not act primarily through aproinflammatory pathway. It has been suggested that chlordanehas immunosuppressing effects (47). We hypothesize that de-creased IL10 expression and exposure to certain termiticides mayhave a synergistic effect that results in immune suppression and areduced capacity for the host to counter other environmentalagents/infections.It is unclear why elevated risks for eye color were present only

among TNF G308A variants, particularly as no consistentassociation was observed with our sunlight exposure variables.For other risk factors, such as smoking and height, we infer thatdifferent mechanisms may be relevant because we did notobserve elevated NHL risks among subjects with variant TNF orIL10 genotypes. Indeed, we recently reported the joint effectbetween the N-acetyltransferase 1 and 2 phenotypes with smokingin follicular lymphoma (48), which supports a role for diaryl-amines or heterocyclic amines in lymphomagenesis. We observedno consistent joint effect between TNF G308A and IL10 T3575Apolymorphisms and those risk factors previously found to

Table 5. Selected joint effects with IL10 for NHL, DLBCL, and follicular lymphoma, adjusted for age, education, sex, race, andcenter

Gene Risk factor Controls, n (%) NHL DLBCL Follicular

n (%) OR (95% CI) n (%) OR (95% CI) n (%) OR (95% CI)

IL10 Autoimmune conditions

TT No 354 (39.0) 419 (37.3) 1.0 (reference) 130 (37.2) 1.0 (reference) 92 (34.2) 1.0 (reference)

Yes 25 (2.7) 26 (2.3) 0.9 (0.5-1.5) 3 (0.9) 0.3 (0.1-1.0) 6 (2.2) 0.8 (0.3-2.1)TA/AA No 502 (55.3) 630 (56.1) 1.0 (0.9-1.3) 202 (57.9) 1.1 (0.8-1.4) 158 (58.7) 1.1 (0.8-1.5)

Yes 27 (3.0) 48 (4.3) 1.6 (0.9-2.6) 14 (4.0) 1.5 (0.8-3.1) 13 (4.8) 2.1 (1.0-4.3)

IL10 Birth orderTT First/middle 113 (29.0) 143 (29.2) 1.0 (reference) 37 (26.2) 1.0 (reference) 25 (21.7) 1.0 (reference)

Last 44 (11.3) 54 (11.0) 1.0 (0.6-1.6) 19 (3.5) 1.4 (0.7-2.8) 14 (12.2) 1.5 (0.7-3.3)

TA/AA First/middle 180 (41.6) 196 (40.1) 0.8 (0.6-1.1) 48 (34.0) 0.7 (0.4-1.2) 58 (50.4) 1.4 (0.8-2.4)

Last 53 (13.6) 96 (19.6) 1.4 (0.9-2.1) 37 (26.2) 2.0 (1.1-3.6) 18 (15.6) 1.5 (0.7-3.1)IL10 BMI (kg/m2)

TT <25 105 (12.4) 138 (13.2) 1.0 (reference) 40 (12.1) 1.0 (reference) 32 (13.1) 1.0 (reference)

25 to <35 215 (25.3) 230 (22.0) 0.8 (0.6-1.1) 70 (21.1) 0.8 (0.5-1.3) 48 (19.7) 0.8 (0.5-1.3)

z35 31 (3.6) 43 (4.1) 1.0 (0.6-1.6) 15 (4.5) 1.3 (0.6-2.7) 9 (3.7) 0.8 (0.3-1.9)TA/AA <25 164 (19.3) 205 (19.6) 0.9 (0.6-1.3) 56 (16.9) 0.9 (0.5-1.4) 56 (22.9) 1.0 (0.6-1.7)

25 to <35 286 (33.7) 359 (34.3) 0.9 (0.7-1.2) 117 (35.3) 1.1 (0.7-1.6) 89 (36.5) 1.0 (0.6-1.7)

z35 48 (5.6) 70 (6.7) 1.0 (0.6-1.6) 33 (10.0) 1.8 (1.0-3.2) 10 (4.1) 0.6 (0.3-1.4)IL10 a-Chlordane (ng/g)

TT ND 119 (26.2) 136 (22.8) 1.0 (reference) 43 (23.6) 1.0 (reference) 34 (25.0) 1.0 (reference)

20.8-60.1 34 (7.5) 38 (6.4) 0.9 (0.6-1.6) 9 (4.9) 0.8 (0.3-1.7) 10 (7.3) 1.0 (0.4-2.3)

60.3-5,870 39 (8.6) 50 (8.4) 1.2 (0.7-2.0) 14 (7.7) 1.1 (0.5-2.2) 14 (10.3) 1.3 (0.6-2.7)TA/AA ND 167 (36.8) 216 (36.2) 1.1 (0.8-1.6) 68 (37.4) 1.1 (0.7-1.8) 46 (33.8) 0.9 (0.5-1.5)

20.8-60.1 45 (9.9) 67 (11.2) 1.4 (0.9-2.2) 21 (11.5) 1.5 (0.8-2.8) 15 (11.0) 1.3 (0.6-2.7)

60.3-5,870 50 (11.0) 90 (15.1) 1.7 (1.1-2.7) 27 (14.8) 1.8 (1.0-3.4) 17 (12.5) 1.3 (0.6-2.6)

Cancer Research





decrease NHL risk, including the Th2-type risk factors (e.g.,asthma and allergy), ethanol, vitamin B6 intake, and sunlight.These results suggest that the mechanisms by which asthma,allergies, sunlight, and other risk factors reduce the risk oflymphomagenesis do not necessarily act through diminution ofinflammation via TNFa or IL10.Strengths of our study include the systematic approach we took

to evaluating the joint effects of two important genetic poly-morphisms with a wide range of other risk factors observed inthe present study (1, 10, 11, 18, 20, 25, 27, 38) that have beenreplicated in large pooled analyses (7–9, 19) or consistent with theliterature (13, 14, 31, 37, 45, 49, 50).The major limitation was low statistical power for estimating

the combined effects of TNF or IL10 polymorphisms and lesscommon risk factors for specific lymphoma subtypes. In thisbroad exploration, we identified an interesting pattern, but theseresults require replication, such as within the InterLymphConsortium. Other limitations include that genetic variability ofinflammatory/immune pathways is not completely explained byTNF or IL10, and that childhood infections and other risk factorswere imperfectly assessed. Finally, our study analyzed twopolymorphisms already identified as risk factors for NHL, but it

is possible that one or both polymorphisms are in linkagedisequilibrium with another variant that could confer theobserved biological effect.In summary, our results provide suggestive evidence that

autoimmune conditions, obesity, and later birth order couldcontribute to lymphomagenesis through an alteration of theproinflammatory pathway, specifically involving common geneticvariants in TNF and IL10 . Furthermore, these data suggest that thispathway may be particularly important for DLBCL. Further studiesare needed to investigate the joint effects between risk factors andcommon genetic variations in these and other genes that regulatethe inflammatory response.

Acknowledgments

Received 12/27/2006; revised 3/1/2007; accepted 3/6/2007.Grant support: Intramural Research Program at the NIH National Cancer Institute

and USPHS contracts N01-PC-65064, N01-PC-67008, N01-PC-67009, N01-PC-67010, andN02-PC-71105.

The costs of publication of this article were defrayed in part by the payment of pagecharges. This article must therefore be hereby marked advertisement in accordancewith 18 U.S.C. Section 1734 solely to indicate this fact.

We thank Lonn Irish (Information Management Services, Inc., Silver Spring, MD)for programming support and Geoffrey Tobias for research assistance.

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immune mechanisms in non-hodgkin lymphoma: joint effects of the tnf g308a and il10 t3575a...

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