Number of Siblings and Risk of Hodgkin’s Lymphoma Ellen T. Chang, 1 Scott M. Montgomery, 2 Lorenzo Richiardi, 1 Anna Ehlin, 2 Anders Ekbom, 2 and Mats Lambe 1 1 Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden and 2 Clinical Epidemiology Unit, Department of Medicine, Karolinska Hospital, Karolinska Institute, Stockholm, Sweden Abstract Background: Epidemiologic evidence indicates that risk of Hodgkin’s lymphoma (HL) in young adults is as- sociated with correlates of delayed exposure to infection during childhood. In contrast, HL among children and older adults may be associated with earlier childhood infection. This study examines the associations of HL risk with having older or younger siblings. Methods: We conducted a case-control study in Sweden compar- ing 2,140 HL patients identified from the Swedish Cancer Register with 10,024 controls identified from national population registers. The Swedish Multi- Generation Register was used to link individuals to their parents and siblings. Results: Among young adults ages 15 to 39 years, the odds ratios (OR) asso- ciated with having one, two, and three or more older siblings, compared with none, were 0.96 [95% con- fidence interval (CI), 0.82-1.13], 0.88 (95% CI, 0.72-1.09), and 0.72 (95% CI, 0.55-0.93), respectively (P value for trend = 0.01). In contrast, number of older siblings was not associated with HL risk among children or older adults. Number of younger or total siblings, mother’s age at birth, and father’s occupation were not associated with HL at any age. The decreased risk of young-adult HL did not vary appreciably by age difference or sex of older siblings. Conclusions: Risk of HL was lower among young adults with multiple older but not younger siblings. Having older siblings is associated with earlier exposure to common childhood pathogens. Pediatric and older-adult HL were not associated with number of siblings, suggesting a different pathogene- sis of disease in these age groups. (Cancer Epidemiol Biomarkers Prev 2004;13(7):1236 – 43) Introduction In most developed nations, the age-specific incidence of Hodgkin’s lymphoma (HL) has a bimodal pattern, with an initial peak occurring among young adults ages 15 to 39 years, followed by a second peak among older adults. In developing nations, the first peak occurs ear- lier, among children under age 15 years (1, 2). HL has long been thought to have an infectious origin (2, 3), with the Epstein-Barr virus (EBV) being the most likely candidate etiologic agent (4). EBV is a typically benign lymphotropic herpesvirus that infects more than 90% of the world’s population, usually during childhood (5). A causal role of EBV in HL is supported by findings of elevated levels of EBV antibodies in individuals before HL onset (6-8), as well as by the molecular detection of monoclonal EBV genome and viral products in the malignant cells of one quarter to one half of HL tumors (4, 9, 10). When EBV infection is delayed from childhood to adolescence, it can cause infectious mononucleosis in about half of infected individuals (11, 12); a history of infectious mononucleosis increases the risk of young- adult HL by about 3-fold (13-23). Correspondingly, factors that influence age at infection with EBV and other common pathogens also seem to affect HL risk in young adults. For example, late birth order and large family size favor earlier childhood exposure to infectious agents, because younger siblings are often exposed to infections at an early age by older siblings who attend school (24-26). It follows, then, that later-born children and those with many siblings should have a lower risk of young-adult HL (19, 27-30). However, some studies have reported no association between birth order or sibship size and HL risk (31-33). Furthermore, early infection seems to be unrelated to risk of HL in childhood or older adulthood, or may even increase both pediatric and elderly HL risk (28, 34-36), suggesting that the etiology of disease differs by age group (3). Although previous studies have investigated the association between number of siblings and risk of HL, none have examined older and younger siblings sepa- rately, most likely due to limitations in sample size. Differentiating older from younger siblings enables us to distinguish between associations with birth order—that is, number of older siblings—and sibship size. We conducted a register-based case-control study in Sweden to investigate the effect of having older and younger siblings on HL risk by age of diagnosis, as well as re- examine the associations of total sibship size and parental characteristics with HL risk. Materials and Methods Study Population. HL cases were identified through the population-based Swedish Cancer Register, which Received 12/17/03; revised 1/29/04; accepted 2/9/04. Grant support: Karolinska Research Fund and the Special Project ‘‘Oncology,’’ Compagnia di San Paolo/FIRMS (to L. Richiardi). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Requests for reprints: Ellen T. Chang, Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Box 281, SE-171 77 Stockholm, Sweden. Phone: 46-8-524-86154; Fax: +46-8-31-49-57. E-mail: ellen.chang@meb.ki.se Copyright D 2004 American Association for Cancer Research. Cancer Epidemiology, Biomarkers & Prevention 1236 Cancer Epidemiol Biomarkers Prev 2004;13(7). July 2004 Downloaded from http://aacrjournals.org/cebp/article-pdf/13/7/1236/1939185/1236-1243.pdf by guest on 13 June 2022