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Journal of Clinical Oncology logoLink to Journal of Clinical Oncology
. 2010 Dec 20;29(4):378–385. doi: 10.1200/JCO.2010.30.1515

Racial Differences in Chronic Immune Stimulatory Conditions and Risk of Non-Hodgkin's Lymphoma in Veterans From the United States

Jill Koshiol 1,✉, Tram Kim Lam 1, Gloria Gridley 1, David Check 1, Linda Morris Brown 1, Ola Landgren 1
PMCID: PMC3058284  PMID: 21172877

Abstract

Purpose

To examine underlying etiologic factors that may explain the racial disparity in non-Hodgkin's lymphoma (NHL) incidence patterns.

Patients and Methods

We assessed immune-related conditions and risk of developing NHL among more than 4 million hospitalized US veterans including 9,496 patients with NHL (7,999 white patients and 1,497 black patients) with up to 26 years of follow-up. We used time-dependent Poisson regression to estimate rate ratios (RRs) and 95% CIs for NHL risk among patients with a history of specific autoimmune diseases, infections, and allergies compared with patients without such history, adjusting for attained age, calendar year, race, number of hospital visits, and time between study entry and exit.

Results

Patients with infectious conditions had an increased risk of developing NHL (RR, 1.2; 95% CI, 1.1 to 1.2), particularly for gastrohepatic, genital, and systemic infectious conditions. Patients with autoimmune disease were generally more likely to develop NHL than patients without autoimmune disease, especially for conditions that typically present with detectable autoantibodies with systemic involvement (RR, 2.0; 95% CI, 1.8 to 2.2). Allergies were also associated with increased risk (RR, 1.4; 95% CI, 1.3 to 1.5). Although the risk of NHL was lower for blacks than whites (RR, 0.87; 95% CI, 0.82 to 0.92), blacks had a slightly higher risk of NHL associated with infections than whites (likelihood ratio test, P = .002) and a tendency toward higher risk associated with allergies (likelihood ratio test, P = .05). Risks associated with autoimmune conditions were similar by race (likelihood ratio test, P = .5).

Conclusion

The observed difference in NHL risk by race supports a role for race-related differences in genes regulating immune/inflammatory response.

INTRODUCTION

In 2010, non-Hodgkin's lymphoma (NHL) will account for an estimated 65,540 new cancer cases and 20,210 deaths in the United States.1 NHL has been associated with broadly categorized immune-related conditions,2,3 including immunodeficiency,4 autoimmune diseases,5,6 infections,7 and allergies.8,9 We previously found that the association of infectious conditions with risk of Waldenström macroglobulinemia, a rare B-cell subtype of NHL, was consistently higher for blacks than whites.10

Although the incidence of NHL is somewhat lower among blacks compared with whites,2 blacks have higher rates of the extranodal NHL subtypes peripheral T-cell lymphoma and mycosis fungoides.11 These disparities, coupled with findings that associations between immune system–related gene polymorphisms and NHL vary by race,12 suggest that genetic predisposition may play a role in immune-related NHL. Immune status has been associated with race, with blacks having higher levels of immunoglobulin A and CD8 cell counts than whites.13 Furthermore, several studies observed that whites and blacks living in the same geographical region had different levels of γ-globulin, a marker of immune disruption.14,15

Previous epidemiologic studies on NHL generally have not included many blacks or were limited by small sample size. These studies often adjusted for race in their analyses3 and rarely compared results across racial/ethnic groups. To further examine the role of immune-related conditions in lymphomagenesis and potential differences by race, we investigated the relation between immune-related conditions and risk of developing NHL among a large cohort of more than 4 million adult male military veterans, including more than 800,000 black veterans, admitted to the US Veterans Affairs (VA) hospitals.

PATIENTS AND METHODS

Patients, Outcome, and Exposures

With more than 150 hospitals, the VA medical care system has been used to create a database of inpatient records from more than 4 million US veterans hospitalized between July 1, 1969, and September 30, 1996.16,17 These patients originated from approximately 30 million US veterans eligible for admission to VA hospitals during the study period.18 White or black men age 18 to 100 years who were hospitalized at least once during the study period were included if they were cancer free during the first year of follow-up and survived at least 1 year after the initial visit. Females and males of other ethnicities and ages were excluded because they formed a small proportion of hospitalized veterans. This study was exempt from institutional review board review and informed consent as per the National Institutes of Health Office of Human Subjects Research because it analyzed existing data stripped of personal identifiers and there was no patient contact.

NHL diagnoses were identified using the eighth and ninth revisions of the International Classification of Diseases codes (200, 202) as were the specific autoimmune, infectious, and allergic conditions listed in Tables 2 through 4. Combined categories of bacterial, viral, parasitic, organ site–specific, and total infections also were analyzed, as were autoimmune diseases that typically present with detectable autoantibodies (with either systemic involvement or organ-specific involvement) and those that do not have detectable autoantibodies.

Statistical Analysis

Person-time at risk began 1 year after the first hospital discharge and ended at diagnosis of NHL. Individuals not diagnosed with NHL were censored at first malignancy, death, or the end of follow-up (September 30, 1996), whichever came first. Records were linked to Social Security Administration Death Master File Records to determine dates of death.19 Exposed person-time was calculated for chronic immune stimulatory conditions (autoimmunity, infections, and allergies) by subtracting the date of the first hospital discharge diagnosis for an immune stimulatory condition from the date of first hospital admission for NHL.

Time-dependent Poisson regression20 (AMFIT module in Epicure version 1.4; HiroSoft International, Seattle, WA) was used to calculate rate ratios (RRs) and two-sided 95% CIs for the risk of NHL associated with race and with immune-related conditions in black and white patients. RRs were adjusted for attained age (< 40, 40 to 49, 50 to 59, 60 to 69, 70 to 79, or ≥ 80 years), attained calendar year (1969 to 1974, 1975 to 1979, 1980 to 1984, 1985 to 1989, or 1990 to 1996), race (black or white), number of hospital visits (one to two, three to four, or ≥ five visits), and latency between study entry and exit (2 to 3, 4 to 5, 6 to 9, 10 to 14, or ≥ 15 years). Because estimates based on small numbers are unstable, we present RRs when there are five or more patients with NHL. The likelihood ratio test (LRT) for multiplicative interaction was used to formally test whether race modified the RRs for these conditions.

To assess whether undetected NHL might cause the immune-related conditions (ie, reverse causality), models for infectious, autoimmune, and allergic conditions were stratified by latency (time in the cohort) of 2 to 5 years and more than 5 years. To evaluate whether changes in the definition of NHL over time might affect the results, models were stratified by median calendar time (< 1980 and ≥ 1980 at first visit). We also stratified by age at first visit (< and ≥ 50 years).

RESULTS

We identified 9,496 patients with NHL (7,999 white patients and 1,497 black patients) with a mean follow-up time of 7.9 years (range, 1 to 26 years; Table 1). Overall, blacks had a lower risk of NHL than whites (RR, 0.87; 95% CI, 0.82 to 0.92). Patients with NHL tended to be older at study entry and to have slightly more hospital visits than patients without NHL, and blacks were younger than whites (Table 1).

Table 1.

Demographics and Clinical Characteristics of the Study Cohort: White and Black Male US Veterans With at Least One Hospital Admission Between July 1, 1969, and September 30, 1996, Who Were Observed More Than 1 Year

Characteristic Whites
 Blacks
No NHL NHL No NHL NHL
No. of persons 3661,245 7,999 830,837 1,497
Mean age at study entry, years* 52.1 55.8 47.7 49.6
Mean years of follow-up† 11.7 7.8 11.9 8.6
Person-years at risk† 42,702,434 62,254 9876,557 12,935
Median No. of hospital visits 3 4‡ 3 4‡
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Abbreviation: NHL, non-Hodgkin's lymphoma.

*

Age at first discharge record for inpatient hospitalization at Veterans Affairs hospitals between July 1, 1969, and September 30, 1996.

†

Follow-up started 1 year after the first hospital visit.

‡

Includes visits up to the exit date.

Infections and Risk of NHL

Patients with infectious conditions had an increased risk of developing NHL (RR, 1.2; 95% CI, 1.1 to 1.2; Table 2). The risk was somewhat higher for viral (RR, 1.6; 95% CI, 1.5 to 1.8) and parasitic infections (RR, 1.7; 95% CI, 1.5 to 1.8) than for bacterial infections (RR, 1.2; 95% CI, 1.1 to 1.3). Gastrohepatic, genital, systemic, and arthropod-borne infectious conditions were particularly likely to increase risk. Among the conditions in the other category, herpes simplex, herpes zoster, infectious mononucleosis, and toxoplasmosis were associated with two- to eight-fold increased risk. Both blacks and whites had an increased risk of NHL associated with infections, but the risk was slightly higher for blacks than whites (Fig 1). This pattern was similar for systemic, reproductive, and lower airway infections (RR, 4.0; 95% CI, 3.3 to 4.9; RR, 1.7; 95% CI, 1.2 to 2.3; and RR, 1.3; 95% CI, 1.2 to 1.6, respectively, in blacks and RR, 2.7; 95% CI, 2.4 to 3.0; RR, 1.1; 95% CI, 0.89 to 1.3; and RR, 1.1; 95% CI, 1.0 to 1.2, respectively, in whites; LRT, P ≤ .001, .01, and .03, respectively). In contrast to other systemic infections, the RR for HIV was higher in whites (RR, 46.2; 95% CI, 38.8 to 55.0) than blacks (RR, 22.3; 95% CI, 17.1 to 29.0). Additional RRs for individual infection-related conditions with ≥ five exposed black and white patients are listed in Appendix Table A1 (online only). To ensure that the observed differences by race were not a result of HIV infection, we conducted analyses adjusting broad categories of infections for HIV; differences by race remained for all categories (LRT, P = .02 for total, bacterial, and parasitic infections) except viral infections (LRT, P = .2).

Table 2.

Infection-Related Conditions and Risk of NHL in US Male Veterans

Category No. of Veterans Exposed
 RR 95% CI
No NHL NHL
Total infection-related conditions 1,536,589 3,832 1.2* 1.1 to 1.2
Upper airway 223,750 573 1.1* 1.0 to 1.2
    Acute bronchitis/bronchiolitis 89,435 191 0.94 0.81 to 1.1
    Chronic sinusitis 74,701 243 1.3* 1.2 to 1.5
    Laryngitis 9,890 27 1.1 0.77 to 1.6
    Nasopharyngitis/pharyngitis 54,430 125 1.0 0.86 to 1.2
    Otitis media/mastoiditis 12,190 39 1.1 0.78 to 1.5
Lower airway 442,063 1,088 1.2* 1.1 to 1.2
    Influenza 22,172 69 1.2 0.94 to 1.6
    Pneumonia 361,834 867 1.2* 1.1 to 1.3
    Tuberculosis 82,151 225 1.1 0.92 to 1.2
Gastrohepatic 145,366 415 1.4* 1.2 to 1.5
    Cholangitis/cholecystitis 32,844 86 0.98 0.78 to 1.2
    Hepatitis virus 45,826 115 1.9* 1.5 to 2.3
        Hepatitis A virus 2,911 9 1.9 0.89 to 3.9
        Hepatitis B virus 14,678 52 2.6* 1.9 to 3.5
        Hepatitis C virus 16,610 21 1.2 0.68 to 2.2
    Intestinal 70,392 228 1.4* 1.2 to 1.6
Genital 76,399 250 1.6* 1.4 to 1.8
    Condyloma acuminatum 11,436 30 1.5* 1.0 to 2.1
    Genital herpes 3,234 34 6.9* 4.7 to 10.1
    Gonorrhea 9,387 33 1.7* 1.2 to 2.4
    Syphilis 49,161 156 1.5* 1.2 to 1.7
    Trichomoniasis 4,851 9 0.95 0.49 to 1.8
Reproductive 66,319 204 1.2* 1.0 to 1.4
    Orchitis and epididymitis 48,829 155 1.2* 1.0 to 1.4
    Chronic prostatitis 18,620 51 0.98 0.73 to 1.3
Urinary 27,583 72 1.2 0.91 to 1.5
    Chronic cystitis 4,049 8 0.98 0.49 to 2.0
    Chronic pyelonephritis 10,317 30 1.3 0.88 to 1.9
    Urethritis 13,726 34 1.1 0.76 to 1.5
Cardiovascular† 111,164 233 1.0 0.89 to 1.2
    Acute pericarditis 6,714 15 1.1 0.68 to 1.9
    Endocarditis 104,554 216 1.0 0.87 to 1.2
Systemic 96,770 508 2.9* 2.7 to 3.3
    HIV 14,410 329 35.8* 30.9 to 41.5
    Meningitis 13,827 74 2.4* 1.9 to 3.1
    Septicemia 72,643 193 1.3* 1.1 to 1.6
Arthropod-borne diseases‡ 20,720 55 1.5* 1.1 to 1.9
    Acariasis 7,522 17 1.2 0.73 to 1.9
    Malaria 4,656 7 1.2 0.54 to 2.7
    Pediculosis and Phthirus infestation 6,157 14 1.2 0.72 to 2.1
    Rickettsia 815 7 3.7* 1.7 to 8.2
    Viral arthropod-borne diseases 1,147 6 2.2* 1.0 to 5.0
Other
    Conjunctivitis 16,790 42 0.96 0.70 to 1.3
    Gingivitis and periodontitis 478,113 1,142 0.93* 0.87 to 0.99
    Helminthiases 4,251 17 1.6 0.98 to 2.7
    Herpes simplex 13,441 110 3.8* 3.0 to 4.7
    Herpes zoster 18,913 106 2.2* 1.8 to 2.7
    Infectious mononucleosis 2,330 11 2.7* 1.4 to 5.5
    Infective arthritis 8,079 28 1.8* 1.2 to 2.7
    Mycoses 174,953 599 1.7* 1.5 to 1.8
    Osteomyelitis 57,655 112 0.86 0.71 to 1.1
    Skin and soft tissue infections 296,539 757 1.2* 1.1 to 1.3
    Toxoplasmosis 1,509 40 7.8* 4.8 to 12.7
    Zoonoses 1,630 5 1.5 0.61 to 3.5
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NOTE. All analyses were adjusted for age, calendar time, race, latency, and number of hospital visits.

Abbreviations: NHL, non-Hodgkin's lymphoma; RR, rate ratio.

*

Significant result.

†

Includes acute myocarditis, for which only two veterans had NHL.

‡

Includes Lyme disease and babesiosis, for which no veterans had NHL, and other bacterial and protozoan arthropod-borne disease, for which only four veterans had NHL.

Fig 1.

Fig 1.

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Forest plots of the rate ratios (RRs) and 95% CIs for infectious, autoimmune, and allergic conditions (left) and subsequent non-Hodgkin's lymphoma among blacks and whites. The likelihood ratio test (LRT) provides a formal evaluation of the difference in RRs by race. All analyses were adjusted for age, calendar time, latency, and number of hospital visits.

Autoimmune Disease and Risk of NHL

Patients with autoimmune disease had a 1.4-fold increased risk of NHL (95% CI, 1.3- to 1.5-fold), although there was considerable variability across individual conditions (Table 3). The strongest associations tended to be for autoimmune diseases in which autoantibodies are detectable (RR, 1.5; 95% CI, 1.3 to 1.6), especially for those with systemic involvement (RR, 2.0; 95% CI, 1.8 to 2.2). Autoimmune diseases with organ involvement had a much lower increased risk (RR, 1.2; 95% CI, 1.1 to 1.4), although some conditions, such as autoimmune hemolytic anemia (RR, 5.0; 95% CI, 3.4 to 7.3), immune thrombocytopenic purpura (RR, 3.7; 95% CI, 2.2 to 6.4), discoid lupus erythematosus (RR, 2.2; 95% CI, 1.5 to 3.4), and celiac disease (RR, 2.6; 95% CI, 1.5 to 4.5), showed notable elevations. Interestingly, risk of NHL was decreased in patients with multiple sclerosis (RR, 0.66; 95% CI, 0.45 to 0.96). Patients with autoimmune conditions that generally do not have detectable autoantibodies had a slightly increased risk of NHL (RR, 1.2; 95% CI, 1.1 to 1.4), especially for sarcoidosis (RR, 1.6; 95% CI, 1.0 to 2.4), Crohn's disease (RR, 1.5; 95% CI, 1.0 to 2.1), psoriasis (RR, 1.3; 95% CI, 1.1 to 1.6), and Wegener's granulomatosis (RR, 3.8; 95% CI, 1.4 to 10.3). Risks associated with autoimmune conditions were similar for black and white patients (Fig 1). Appendix Table A2 (online only) provides the distribution of individual autoimmune conditions by race.

Table 3.

Autoimmune Conditions and Risk of NHL in US Male Veterans

Category No. of Veterans Exposed
 RR 95% CI
No NHL NHL
Total autoimmune conditions 288,874 918 1.4* 1.3 to 1.5
Autoantibodies detectable 199,426 667 1.5* 1.3 to 1.6
    Systemic involvement 66,005 317 2.0* 1.8 to 2.2
        Rheumatoid arthritis 59,208 280 1.9* 1.7 to 2.2
        Sjögren's syndrome 1,875 18 3.3* 2.0 to 5.5
        Systemic sclerosis 2,667 7 1.5 0.70 to 3.1
        Systemic lupus 3,798 24 3.0* 1.9 to 4.6
    Organ involvement† 139,475 382 1.2* 1.1 to 1.4
        Addison's disease 4,192 9 0.84 0.38 to 1.9
        Amyotrophic lateral sclerosis 7,269 11 0.80 0.41 to 1.5
        Autoimmune hemolytic anemia 3,046 32 5.0* 3.4 to 7.3
        Celiac disease 2,019 13 2.6* 1.5 to 4.5
        Chronic rheumatic heart disease 64,839 151 1.1 0.90 to 1.3
        Discoid lupus erythematosus 5,076 27 2.2* 1.5 to 3.4
        Graves' disease 6,391 9 0.55 0.27 to 1.1
        Hashimoto's thyroiditis 1,185 5 1.4 0.54 to 3.8
        Immune thrombocytopenic purpura 9,160 47 2.8* 2.1 to 3.8
        Multiple sclerosis 19,341 27 0.66* 0.45 to 0.96
        Myasthenia gravis 2,429 8 1.2 0.59 to 2.6
        Pernicious anemia 9,220 30 1.1 0.71 to 1.6
        Primary biliary cirrhosis 7,807 15 0.98 0.59 to 1.6
Autoantibodies not detectable‡ 106,340 317 1.2* 1.1 to 1.4
    Ankylosing spondylitis 10,468 30 1.2 0.81 to 1.7
    Crohn's disease 9,313 31 1.5* 1.0 to 2.1
    Hemorrhagic proctitis 19,896 40 0.84 0.59 to 1.2
    Polymyalgia rheumatica 9,488 8 1.2 0.44 to 3.1
    Psoriasis 40,540 133 1.3* 1.1 to 1.6
    Reiter's disease 3,628 12 1.5 0.80 to 2.8
    Rheumatic fever 4,677 14 1.3 0.70 to 2.3
    Sarcoidosis 8,264 26 1.6* 1.0 to 2.4
    Ulcerative colitis 11,464 24 0.82 0.54 to 1.3
    Wegener's granulomatosis 9,488 8 3.8* 1.4 to 10.3
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NOTE. All analyses were adjusted for age, calendar time, race, latency, and number of hospital visits.

Abbreviations: NHL, non-Hodgkin's lymphoma; RR, rate ratio.

*

Significant result.

†

Includes polyarteritis and localized scleroderma, for which only two and four veterans had NHL, respectively.

‡

Includes Behçet's syndrome, for which no veterans had NHL, and rheumatic chorea, for which only one veteran had NHL.

Allergies and Risk of NHL

Overall, risk of NHL was increased with previous diagnosis of an allergic condition (RR, 1.4; 95% CI, 1.3 to 1.5), but the association was not consistent across individual conditions (Table 4). Allergic alveolitis, dermatitis, and erythema were associated with approximately two- to four-fold increased risk (although the RR for allergic alveolitis was based on only five exposed patients with NHL), whereas prior asthma, rhinitis, and urticaria were not associated with NHL. The risk of NHL associated with allergies seemed slightly higher for blacks than whites (LRT, P = .05; Fig 1). Appendix Table A3 (online only) provides the distribution of individual allergic conditions by race.

Table 4.

Allergic Conditions and Risk of NHL in US Male Veterans

Category No. of Veterans Exposed
 RR 95% CI
Non-NHL NHL
Total allergic conditions 223,529 718 1.4* 1.3 to 1.5
Asthma 86,099 175 0.90 0.77 to 1.1
Allergic alveolitis 633 5 4.2* 1.8 to 10.1
Dermatitis 92,651 367 1.6* 1.5 to 1.8
Erythema 29,202 189 2.7* 2.3 to 3.2
Rhinitis 16,800 29 0.81 0.56 to 1.2
Urticaria 10,895 33 1.2 0.85 to 1.7
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NOTE. All analyses were adjusted for age, calendar time, race, latency, and number of hospital visits.

Abbreviations: NHL, non-Hodgkin's lymphoma; RR, rate ratio.

*

Significant result.

Sensitivity Analyses

For all but infections of the reproductive system, the risk of NHL was more strongly elevated for infections that occurred 2 to 4 years before NHL than ≥ 5 years before NHL (Table 5). Infections also tended to be more strongly associated with NHL when they occurred after 1980. Nearly all of the increased risk associated with infections occurred among patients who were younger than 50 years old at their first visit. In contrast, we saw few differences for autoimmune conditions across latency, calendar year, or age (Table 5). Although the association between autoimmune conditions and NHL seemed somewhat stronger for diagnoses before 1980 versus 1980 or later, the RRs were fairly similar across calendar year for subgroups of autoimmune conditions. Autoimmune conditions with organ involvement had slightly stronger associations with NHL diagnosed before age 50 years (RR, 1.4; 95% CI, 1.2 to 1.7) than NHL diagnosed at or after age 50 years (RR, 1.2; 95% CI, 1.0 to 1.3; LRT, P = .03), but the RRs for total autoimmune diseases were the same across age groups. Allergies were more strongly associated when diagnosed 2 to 4 years before NHL than ≥ 5 years before NHL (LRT, P = .02), but the association did not vary by calendar year or age (Table 5).

Table 5.

Risk of NHL for Selected Conditions by Years of Follow-Up (latency), Year of First Visit, and Age at First Visit in US Male Veterans

Condition Follow-Up (Latency)
 Year of First Visit
 Age at First Visit
2-4 Years
 ≥ 5 Years
 LRT P < 1980
 ≥ 1980
 LRT P < 50 Years
 ≥ 50 Years
 LRT P
RR 95% CI RR 95% CI RR 95% CI RR 95% CI RR 95% CI RR 95% CI
Total infectious diseases 1.4 1.3 to 1.5 1.1 1.0 to 1.1 < .001* 1.1 1.1 to 1.2 1.2 1.1 to 1.3 .2 1.5 1.4 to 1.6 1.0 0.98 to 1.1 < .001*
    Upper airway 1.3 1.1 to 1.5 1.1 0.95 to 1.2 .1 1.1 0.99 to 1.2 1.1 0.93 to 1.3 > .5 1.1 0.98 to 1.3 1.1 0.96 to 1.2 > .5
    Lower airway 1.4 1.2 to 1.6 1.1 1.0 to 1.2 .003* 1.1 1.0 to 1.2 1.3 1.2 to 1.5 .02* 1.6 1.4 to 1.8 1.0 0.91 to 1.1 < .001*
    Gastrohepatic 1.7 1.4 to 2.1 1.3 1.1 to 1.5 .3 1.3 1.1 to 1.5 1.6 1.4 to 2.0 .03* 1.9 1.7 to 2.2 1.0 0.88 to 1.2 < .001*
    Genital 1.8 1.4 to 2.4 1.5 1.3 to 1.8 .07 1.4 1.2 to 1.7 2.1 1.7 to 2.7 .004* 2.2 1.8 to 2.6 1.1 0.87 to 1.4 < .001*
    Reproductive 0.9 0.58 to 1.3 1.2 1.1 to 1.5 .04* 1.3 1.1 to 1.5 1.0 0.72 to 1.3 .07 1.3 1.0 to 1.7 1.1 0.91 to 1.3 .2
    Urinary 1.8 1.2 to 2.8 1.0 0.76 to 1.3 .04* 1.2 0.88 to 1.5 1.2 0.69 to 1.9 > .5 0.9 0.6 to 1.4 1.3 0.99 to 1.8 .2
    Cardiovascular 1.1 0.88 to 1.5 1.0 0.76 to 1.3 .3 0.9 0.76 to 1.2 1.1 0.90 to 1.3 .4 1.1 0.8 to 1.4 1.0 0.85 to 1.2 > .5
    Systemic 5.6 4.8 to 6.5 2.1 1.9 to 2.4 < .001* 1.7 1.5 to 2.1 4.3 3.8 to 4.9 < .001* 6.5 5.7 to 7.4 1.3 1.1 to 1.5 < .001*
    Arthropod-borne diseases 1.8 0.98 to 3.2 1.4 1.0 to 1.9 .5 1.2 0.84 to 1.8 2.0 1.3 to 3.1 .08 1.5 1.0 to 2.1 1.4 0.93 to 2.3 > .5
Total autoimmune diseases 1.5 1.3 to 1.7 1.4 1.3 to 1.5 .4 1.5 1.4 to 1.6 1.2 1.1 to 1.4 .01* 1.4 1.2 to 1.5 1.4 1.3 to 1.5 > .5
    Autoantibodies detectable 1.5 1.3 to 1.8 1.4 1.3 to 1.6 > .5 1.5 1.4 to 1.7 1.3 1.1 to 1.5 .08 1.5 1.3 to 1.8 1.5 1.3 to 1.6 > .5
    Systemic involvement 1.8 1.4 to 2.3 2.0 1.7 to 2.3 .1 2.1 1.8 to 2.4 1.7 1.4 to 2.1 .1 2.1 1.7 to 2.7 2.0 1.7 to 2.2 .3
    Organ involvement 1.5 1.2 to 1.8 1.1 0.99 to 1.3 .3 1.3 1.1 to 1.4 1.1 0.93 to 1.4 > .5 1.4 1.2 to 1.7 1.2 1.0 to 1.3 .03*
    Autoantibodies not detectable 1.3 1.0 to 1.6 1.2 1.1 to 1.4 > .5 1.3 1.2 to 1.5 1.1 0.88 to 1.3 .2 1.2 0.99 to 1.5 1.2 1.1 to 1.4 > .5
Total allergies 1.7 1.5 to 2.0 1.3 1.2 to 1.4 .02* 1.5 1.3 to 1.6 1.4 1.2 to 1.6 > .5 1.4 1.2 to 1.6 1.5 1.3 to 1.6 .4
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Abbreviations: NHL, non-Hodgkin's lymphoma; RR, rate ratio; LRT, likelihood ratio test.

*

Significant result.

DISCUSSION

In this large study of more than 4 million US veterans, infectious, autoimmune, and allergic conditions were all associated with increased risk of NHL, but the risk of NHL associated with infections was slightly higher in blacks compared with whites. A notable exception was the risk associated with HIV, which was two-fold higher in whites. Allergies also tended to be more strongly associated with risk of NHL in blacks than in whites, whereas the risks associated with autoimmune conditions were generally similar by race.

Similar to previous studies,2,21 we found an increased risk of NHL in patients with autoimmune conditions such as rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, autoimmune hemolytic anemia, and celiac disease. We found that patients with multiple sclerosis had a reduced risk of NHL, in accord with previous studies,22,23 although the literature is mixed.21,24,25 Patients with multiple sclerosis have an innate immune profile skewed toward T helper 1–type immune activation, which may inhibit carcinogenesis.26–31 Previous studies have largely included white participants, preventing stratification by race.21 With more than 800,000 black patients, our study demonstrates that autoimmune conditions are associated with increased risk of NHL in both blacks and whites.

Results from previous studies of allergies and NHL are inconsistent. Many previous studies have found an inverse association with NHL,2,32 but prospective cohort studies tend to suggest that allergies are associated with an increased risk of NHL.33 Part of this inconsistency may be a result of the reliance on self-report of allergies,2 which is less objective than assessment based on discharge diagnoses. In addition, because NHL may reduce immunoglobulin reactivity, an apparent inverse association between allergies and NHL may be a result of reverse causality (ie, patients with undetected NHL may have an impaired immune response and thus reduced allergic responses).9,34 To our knowledge, only one previous study has evaluated allergies and risk of NHL by race and found some variation by race/ethnicity.35

Previous studies have fairly consistently reported an increased risk of NHL for a number of individual infectious agents, such as HIV, Epstein-Barr virus, human herpesvirus 8, and human T-cell lymphotropic virus.2 Similarly, we found that patients with infection-related conditions had an increased risk of NHL, most notably for systemic, genital, or arthropod-borne diseases. Although one recent study found no associations between genital infectious or sexual behavior and NHL,36 it had few exposed patients and controls and thus limited power.

Few studies have examined the association between infections and NHL by race. One case-only study found that Chinese patients with NHL were three times more likely to have Epstein-Barr virus–associated B-cell lymphoma than Malay patients with NHL.37 In a black South African population, HIV was associated with a six-fold increased risk of NHL, which is an order of magnitude lower than that observed in developed countries38 and implicates a racial disparity. In our study, the RR of NHL associated with HIV in blacks was approximately half as high as the RR in whites. Such racial differences in the incidence of HIV-associated NHL might be a result of racial/ethnic variation in stromal cell–derived factor 1-3′A chemokine allele frequency.39

The patterns of NHL and immune response in different ethnic groups also implicate genetic dissimilarities. For instance, the risk of NHL varies by ethnicity among second-generation immigrants to Sweden, and γ-globulin levels remain high in indigenous people who have migrated from tropical to temperate regions even several centuries after their migration.40–42 In addition, some evidence suggests that immune response to infections, such as Epstein-Barr virus, is depressed in African children compared with Chinese, Indian, and white children.43

A recent pooled analysis from the International Lymphoma Epidemiology Consortium found evidence for ethnic variability in the risk of NHL associated with polymorphisms in two immune system–related genes, tumor necrosis factor (TNF) and interleukin-10 (IL10).12 For example, the TNF-308A allele increased the risk of diffuse large B-cell lymphoma by 2.7-fold (95% CI, 1.3- to 5.6-fold) in blacks but only 1.3-fold (95% CI, 1.2- to 1.4-fold) in whites. Similarly, the IL10-1082G allele was associated with a 1.7-fold (95% CI, 1.1- to 2.6-fold) increased risk of NHL in Hispanic whites but no increased risk (odds ratio, 1.1; 95% CI, 0.98 to 1.2) in non-Hispanic whites. Thus, the differential distribution of immune gene polymorphisms by race might explain why infections, and possibly allergies, are more strongly associated with NHL in blacks than whites. At this time, we have no clear explanation for the observed similar associations for blacks and whites regarding autoimmune diseases and subsequent NHL risk.

Given that the development of NHL can alter immunity in and of itself,8 the potential for reverse causality (ie, that the observed associations are a result of developing disease, rather than a cause of the disease) is of concern. However, our cohort design allowed us to evaluate associations with NHL over time. The stability of RRs for autoimmune diseases across latency categories suggests that they are not explained by reverse causality. Although associations with infection-related conditions were generally stronger when they occurred closer to the diagnosis of NHL, many of the site-specific categories remained elevated with a latency of ≥ 5 years, suggesting that the observed associations are not entirely a result of undetected NHL. In addition, nearly all the increased risk of NHL occurred in patients younger than 50 years old, which is consistent with infection-related lymphomagenesis because infection-related cancer tends to occur at younger ages.44,45 Alternatively, this pattern could reflect minor immunologic defects, as suggested by the observation that children hospitalized for infection in the first year of life are at increased risk of developing NHL later in life.46 Allergies also were associated more strongly with NHL when diagnosed within 2 to 4 years of disease. Because the development of NHL is inversely associated with immunoglobulin reactivity,9,34 reverse causality would be expected to produce an inverse association. Instead, we observed a positive association, similar to other prospective studies.33,35

NHL was more strongly associated with several categories of infection-related conditions at or after 1980, possibly as a result of the discovery, and therefore increased diagnosis, of cancer-related infections. For example, the relation between human papillomavirus (HPV) and cervical cancer was not clearly elucidated until the development of sensitive polymerase chain reaction assays in the late 1980s to early 1990s.47 This improved understanding of cervical carcinogenesis may also have led to increased reporting of the HPV-associated condition condyloma acuminatum, even though genital warts are caused by noncarcinogenic HPV. Similarly, the discovery of hepatitis C virus in 1989 and HIV in 1983 might have influenced associations with gastrohepatic and systemic infections over time.

Our study included only hospitalized male US veterans, limiting generalizability. Also, less severe immune-related conditions, typically diagnosed in outpatient settings, may be under-represented. Clinical data, laboratory data, and medical records were not available to verify diagnoses. However, we expect any potential exposure misclassification to be nondifferential because immune-related conditions were identified similarly for patient cases and non–patient cases. Another limitation is the large number of tested immune-related conditions, which implies that one has to interpret detected associations with caution as a result of multiple comparisons. Some diagnoses may have been missed because veterans may choose either VA or civilian health care, although this potential bias may be limited because many patients who choose VA care lack other health insurance.48 In addition, we do not have data on potential confounders such as organ transplantation; chemotherapy/radiation; chemical exposure to benzene, solvents, herbicides, or pesticides; family history; or socioeconomic status. Within this study population, the potential for confounding by socioeconomic status may be limited because patients within the VA system typically have low socioeconomic status,48 and previous VA studies found similar health care utilization and outcomes for blacks and whites.49,50

This study has several strengths. First, the large sample size of more than 4 million veterans permitted us to evaluate risk of NHL separately in blacks and whites for infectious, autoimmune, and allergic conditions. These patients had access to standardized medical care without regard to socioeconomic status. The follow-up time was extensive. In addition, immune-related conditions were identified before the development of NHL using discharge diagnoses, thus eliminating recall bias.

In summary, we found that risk of NHL is associated with infectious, autoimmune, and allergic conditions. The increased risk of NHL associated with infection-related conditions, and possibly allergies, seemed to be stronger in blacks than in whites, whereas the risk related to autoimmune conditions was similar for both. These patterns could reflect underlying race-related genetic differences in immune response. Additional studies are needed to explore the pathologic mechanisms underlying these associations.

Acknowledgment

We thank the Medical Administration Service of the Veterans Health Services and Research Administration for providing the data on which this study is based and David Campbell and Eric Boyd, Information Management Services, Silver Spring, MD, for assistance with data preparation. This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute.

Appendix

Table A1.

RRs for Each of the Specific Infectious Conditions and Subsequent NHL Among Blacks and Whites

Category Whites
 Blacks
 LRT P
No. of Veterans Exposed
 RR 95% CI No. of Veterans Exposed
 RR 95% CI
No NHL NHL No NHL NHL
Total infection-related conditions 1,213,610 3,086 1.1 1.1 to 1.2 322,979 746 1.4 1.2 to 1.5 .002*
Upper airway 186,795 489 1.1 0.99 to 1.2 36,955 84 1.1 0.87 to 1.4 > .5
    Acute bronchitis/bronchiolitis 77,337 169 0.94 0.80 to 1.1 12,098 22 0.97 0.62 to 1.5 > .5
    Chronic sinusitis 62,433 202 1.3 1.1 to 1.5 12,268 41 1.5 1.1 to 2.2 .4
    Nasopharyngitis/pharyngitis 41,906 103 1.1 0.88 to 1.3 12,524 22 0.88 0.56 to 1.4 .4
Lower airway 346,387 845 1.1 1.0 to 1.2 95,676 243 1.3 1.2 to 1.6 .02*
    Influenza 18,788 62 1.3 0.96 to 1.6 3,384 7 0.44 0.06 to 3.1 .3
    Pneumonia 289,391 676 1.1 1.0 to 1.2 72,443 191 1.4 1.2 to 1.7 .008*
    Tuberculosis 55,462 149 1.0 1.0 to 1.2 26,689 76 1.2 0.90 to 1.5 .4
Gastrohepatic 116,070 335 1.3 1.2 to 1.5 29,296 80 1.5 1.2 to 2.0 .3
    Cholangitis/cholecystitis 28,563 76 0.97 0.76 to 1.2 4,281 10 1.1 0.53 to 2.1 > .5
    Hepatitis virus 32,035 83 2.0 1.6 to 2.5 13,827 32 1.6 1.1 to 2.4 .4
        Hepatitis B virus 9,414 34 2.7 1.9 to 3.9 5,264 18 2.4 1.4 to 4.0 > .5
        Hepatitis C virus 10,835 15 1.4 0.70 to 2.8 5,775 6 0.95 0.30 to 3.0 > .5
    Intestinal 58,394 188 1.4 1.2 to 1.6 11,998 40 1.4 1.2 to 1.6 > .5
Genital 37,432 127 1.5 1.3 to 1.8 38,967 123 1.6 1.4 to 2.0 > .5
    Condyloma acuminatum 8,007 23 1.6 1.0 to 2.4 3,429 7 1.2 0.58 to 2.6 > .5
    Genital herpes 2,078 14 4.2 2.3 to 7.6 1,156 20 12.4 7.5 to 20.5 .006*
    Gonorrhea 4,155 18 2.1 1.3 to 3.3 5,232 15 1.3 0.8 to 2.3 .2
    Syphilis 22,198 73 1.3 1.1 to 1.7 26,963 83 1.6 1.3 to 2.0 .4
Reproductive 52,638 155 1.1 0.89 to 1.3 13,681 49 1.7 1.2 to 2.2 .01*
    Orchitis and epididymitis 37,794 111 1.1 0.88 to 1.3 11,035 44 1.8 1.3 to 2.5 .006*
    Chronic prostatitis 15,790 46 1.0 0.74 to 1.4 2,830 5 0.79 0.30 to 2.1 > .5
Urinary 20,323 60 1.2 0.96 to 1.6 7,260 12 0.86 0.48 to 1.5 .2
    Urethritis 9,255 26 1.1 0.77 to 1.7 4,471 8 0.89 0.44 to 1.8 > .5
Cardiovascular 90,210 196 1.0 0.88 to 1.2 20,954 37 0.97 0.68 to 1.4 > .5
    Endocarditis 85,232 183 1.0 0.87 to 1.2 19,322 33 0.99 0.68 to 1.4 > .5
Systemic 71,346 367 2.7 2.4 to 3.0 25,424 141 4.0 3.3 to 4.9 < .001*
    HIV 7,589 225 46.2 38.8 to 55.0 6,821 104 22.3 17.1 to 29.0 < .001*
    Meningitis 10,142 48 2.1 1.5 to 2.8 3,685 26 3.6 2.3 to 2.8 .06
    Septicemia 55,828 145 1.3 1.0 to 1.5 16,815 48 1.6 1.1 to 2.3 .2
Arthropod-borne diseases 17,563 43 1.3 0.96 to 1.8 3,158 12 2.2 1.3 to 4.0 .1
    Pediculosis and Phthirus infestation 4,486 8 0.95 0.48 to 1.9 1,671 6 1.9 0.86 to 4.3 .2
Other
    Conjunctivitis 13,763 31 0.86 0.60 to 1.2 3,027 11 1.5 0.80 to 2.8 .1
    Gingivitis and periodontitis 374,567 936 0.95 0.88 to 1.0 103,546 206 0.85 0.73 to 1.0 .2
    Herpes simplex 10,195 70 3.0 2.3 to 3.9 3,246 40 7.0 4.8 to 10.1 < .001*
    Herpes zoster 16,226 86 2.0 1.6 to 2.5 2,687 20 4.0 2.4 to 6.7 .02*
    Infective arthritis 5,990 23 1.9 1.2 to 2.9 7,976 5 1.7 0.70 to 4.0 > .5
    Mycoses 128,474 431 1.6 1.4 to 1.7 7,568 168 2.1 1.8 to 2.5 .006*
    Osteomyelitis 45,899 93 0.85 0.68 to 1.1 11,756 19 0.90 0.57 to 1.4 > .5
    Skin and soft tissue infections 241,710 612 1.1 1.0 to 1.2 54,829 145 1.5 1.2 to 1.7 .02*
    Toxoplasmosis 1,044 32 9.3 5.5 to 15.7 465 8 3.7 0.92 to 14.7 .2
Open in a new tab

NOTE. Only conditions with five or more exposed black and white veterans are included. The LRT provides a formal evaluation of the difference in RRs by race. All analyses were adjusted for age, calendar time, latency, and number of hospital visits.

Abbreviations: RR, rate ratio; NHL, non-Hodgkin's lymphoma; LRT, likelihood ratio test.

*

Significant result.

Table A2.

RRs for Each of the Specific Autoimmune Conditions and Subsequent NHL Among Blacks and Whites

Category Whites
 Blacks
 LRT P
No. of Veterans Exposed
 RR 95% CI No. of Veterans Exposed
 RR 95% CI
No NHL NHL No NHL NHL
Total autoimmune conditions 244,024 791 1.4 1.3 to 1.5 44,850 127 1.5 1.2 to 1.8 .5
Autoantibodies detectable 168,711 584 1.5 1.4 to 1.6 30,715 83 1.4 1.1 to 1.8 > .5
    Systemic involvement 57,044 283 2.0 1.7 to 2.2 8,961 34 2.1 1.4 to 2.8 > .5
        Rheumatoid arthritis 51,736 253 1.9 1.7 to 2.2 7,472 27 1.8 1.2 to 2.6 > .5
        Sjögren's syndrome 1,583 13 2.5 1.4 to 4.7 292 5 8.7 3.6 to 21.0 .04*
    Organ involvement 116,665 329 1.2 1.1 to 1.4 22,810 53 1.2 0.88 to 1.6 .5
        Amyotrophic lateral sclerosis 6,157 6 0.51 0.21 to 1.2 1,112 5 2.8 1.0 to 7.4 .02*
        Chronic rheumatic heart disease 53,875 138 1.1 0.95 to 2.6 10,964 13 0.58 0.31 to 1.1 .03*
        Immune thrombocytopenic purpura 7,660 39 2.7 2.0 to 3.8 1,500 8 3.1 2.1 to 3.8 > .5
        Multiple sclerosis 17,352 22 0.59 0.39 to 0.90 1,989 5 1.3 0.56 to 3.2 .1
Autoantibodies not detectable 90,348 268 1.2 1.0 to 1.3 15,992 49 1.5 1.1 to 2.1 .1
    Sarcoidosis 2,923 14 1.9 1.0 to 3.6 5,341 12 1.3 0.74 to 2.4 .4
    Reiter's disease 2,906 7 1.1 0.50 to 2.5 722 5 2.9 1.1 to 7.8 .2
    Psoriasis 37,532 118 1.2 1.0 to 1.5 3,008 15 2.7 1.6 to 4.5 .02*
    Hemorrhagic proctitis 16,371 33 0.83 0.57 to 1.2 3,525 7 0.86 0.36 to 2.1 > .5
Open in a new tab

NOTE. Only conditions with five or more exposed black and white veterans are included. The LRT provides a formal evaluation of the difference in RRs by race. All analyses were adjusted for age, calendar time, latency, and number of hospital visits.

Abbreviations: RR, rate ratio; NHL, non-Hodgkin's lymphoma; LRT, likelihood ratio test.

*

Significant result.

Table A3.

RRs for Each of the Specific Allergic Conditions and Subsequent NHL Among Blacks and Whites

Category No. of Veterans Exposed
 RR 95% CI No. of Veterans Exposed
 RR 95% CI LRT P
No NHL NHL No NHL NHL
Total allergic conditions 182,246 584 1.4 1.2 to 1.5 41,283 134 1.7 1.4 to 2.0 .05
Asthma 68,133 140 0.89 0.75 to 1.1 17,966 35 0.95 0.66 to 1.3 > .5
Dermatitis 76,486 294 1.5 1.4 to 1.8 16,165 73 2.2 1.7 to 2.8 .02*
Erythema 24,575 154 2.6 2.2 to 3.0 4,627 35 3.7 2.6 to 5.4 .08
Rhinitis 13,876 24 0.79 0.53 to 1.2 2,924 5 0.97 0.40 to 2.3 > .5
Open in a new tab

NOTE. Only conditions with five or more exposed black and white veterans are included. The LRT provides a formal evaluation of the difference in RRs by race. All analyses were adjusted for age, calendar time, latency, and number of hospital visits.

Abbreviations: RR, rate ratio; NHL, non-Hodgkin's lymphoma; LRT, likelihood ratio test.

*

Significant result.

Footnotes

Supported by general funds from the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics; and the Cancer Prevention Fellowship Program, Office of Preventive Oncology, National Cancer Institute, Bethesda, MD.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

AUTHOR CONTRIBUTIONS

Conception and design: Jill Koshiol, Gloria Gridley, David Check,Ola Landgren

Administrative support: Gloria Gridley, David Check

Collection and assembly of data: Jill Koshiol, Gloria Gridley,David Check

Data analysis and interpretation: Jill Koshiol, Tram Kim Lam, Gloria Gridley, David Check, Linda Morris Brown, Ola Landgren

Manuscript writing: Jill Koshiol, Tram Kim Lam, Gloria Gridley, David Check, Linda Morris Brown, Ola Landgren

Final approval of manuscript: Jill Koshiol, Tram Kim Lam, Gloria Gridley, David Check, Linda Morris Brown, Ola Landgren

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