Birth order, allergies and lymphoma risk: Results of the European collaborative research project Epilymph
Introduction
Lymphomas are a heterogeneous group of malignant diseases of cells of the immune system. The best established risk factors are those related to down-regulation of immune function, e.g. genetically determined or acquired immune deficiencies including HIV infection or iatrogenically induced immune suppression after transplantation. Recent studies suggest that risk might additionally be affected by immunological conditions, themselves modulated by life-style or culturally determined (e.g., family size, hygienic circumstances, outlined in the so called “hygiene hypothesis, for summary see [1]). Epidemiologically testable indicators of this hypothesis include birth order, assumed to be an indicator for variation in early-life exposure to infection, and a history of allergies as an indicator for lifestyle-related altered immune responsiveness.
Although this hypothesis is conceptually striking, current evidence supporting it appears inconclusive. While several studies have found increasing adulthood lymphoma risk with increasing sibship size or birth order [1], [2], [3], [4], others have found no association [5], [6], [7] or opposite results [8], [9].
The association to allergic disorders appears more conclusive: several studies have shown a statistically significantly reduced risk, some an insignificantly decreased risk or null result, but none have reported an elevated lymphoma risk associated with allergies (for details see [1]).
A limitation of many studies was the comparatively small study size largely preventing detailed analyses of different lymphoma entities, which would be appropriate given the heterogeneity of the disease. Here, we present results on the relationship between birth order and allergies and lymphoma risk in Epilymph. This large European collaborative research effort with about 2500 lymphoma cases and 2500 hospital or population controls allows for the analysis of entity-specific associations.
Section snippets
Materials and methods
Epilymph comprises case–control data from seven European countries (Czech Republic, Finland, France, Germany, Ireland, Italy, and Spain) based on a common core protocol and conducted between 1998 and 2004. In two of the studies, recruitment was population-based (Germany and Italy) and cases were identified and approached in hospitals and with office-based haematologists (Germany) from the respective study areas. In the other countries recruitment was hospital-based, and all consecutive lymphoma
Results for all lymphomas combined
Overall, the risk for all lymphoma was slightly increased for first-born children (OR = 1.17, p = 0.056) but not for only children (OR = 1.10, p = 0.47), compared to the reference group of fourth or later-birth order children (Table 2). The relationship was rather heterogeneous on the level of the individual countries (pHeterogeneity = 0.051) ranging from a significant (Ireland) or almost significant (Italy) risk elevation over a null result (Czech Republic) to indications of a decreased risk (Germany).
Discussion
The main results of this analysis were an inverse relationship between lymphoma risk and allergies, mainly respiratory and food allergies, and a slightly elevated lymphoma risk for first-born children, and, correspondingly, a decreased risk for having older siblings. The results were rather consistent across countries and, with few exceptions, the different lymphoma entities.
Conclusions
The observed inverse relationship between atopic disorders and risk of lymphomas is consistent with earlier observations. The findings on birth order and lymphoma risk increases the overall inconsistency of previous reports. A critical reappraisal of potential underlying mechanisms appears to be necessary. Further studies of birth order and lymphoma risk should also consider the effect of birth order on allergies when assessing the value of this variable as an indicator for potential underlying
Conflict of interests statement
None declared.
Acknowledgements
We are indebted to Aurélie Meunier (IARC, Lyon) and Evelin Deeg (German Cancer Research Center, Heidelberg) who performed data management (AM and ED) and assisted with the data analysis (ED).
This work was supported by:
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the EC 5th Framework Program Quality of Life grant No. QLK4-CT-2000-00422;
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Fondation de France no. 1999 0084 71;
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the Federal Office for Radiation Protection grants no. StSch4261 and StSch4420 (Germany);
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the Health Research Board (Ireland);
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the Spanish Ministry of Health grants FIS:
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