Rheumatology Advance Access originally published online on February 27, 2008
Rheumatology 2008 47(4):549-551; doi:10.1093/rheumatology/ken051
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LETTERS TO THE EDITOR |
Shared familial risk factors between cancer and RA patients
1Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany and 2Department of Family and Community Medicine Stockholm, Karolinska Institute, Huddinge, Sweden
Correspondence to: K. Hemminki, DKFZ, Im Neuenheimer Feld 580, D-69120 Heidelberg, Germany. E-mail: k.hemminki{at}dkfz.de
SIR, Twin and family studies show that susceptibility to RA has a heritable basis, transmitted in part with some identified candidate genes [1, 2]. As RA patients are at a risk of many cancers [3], a question arises whether RA and cancer share heritable risk factors, which has not been settled. Most studies have analysed the links between RA and lymphohaemato-proliferative diseases, providing some evidence on familial aggregation [4, 5]. Family members of RA patients have not shown an overall risk of lymphoma or cancer, but childhood Hodgkin disease has been in excess and even other autoimmune conditions have been associated with Hodgkin disease [4, 5]. No data have been available on the risk of individual site-specific tumours in family members of RA patients. In the present study, we used the Swedish data resources on registered families and medically diagnosed RA and cancer, all with a national coverage, to analyse risks of cancer in family members of RA patients, with a specific aim to settle the issue on possible shared genetic risk factors for cancer and RA.
The RA research database was constructed by linking the Multigeneration Register (persons born in Sweden in 1932 and later are linked to their parents) to the Swedish Hospital Discharge Register (all hospital discharges with dates of hospitalization and diagnoses since the 1960s with a complete nation-wide coverage since 1986) and to the nation-wide Swedish Cancer Registry (cancers from 1958 to 2004). The database contains 11.5 million individuals among whom a total of 50 354 RA patients were identified. Details of the data sources and methods can be found in our previous publications [5, 6]. In the analysis of familial risks, parents were considered probands and standardized incidence ratios (SIRs) were calculated for offspring, who were followed until 31 December 2004. SIRs were calculated as the ratio of observed (O) to expected (E) number of cases. The expected number of cases was calculated for age (5-yr groups), sex, period (5-yr groups), region and socioeconomic status-specific SIRs.
Familial risks between RA and cancer were examined in two ways (Table 1): risk of a specific cancer in offspring whose parents were diagnosed with RA (excluding parent–offspring pairs with the concordant cancers), and risk of RA in offspring whose parents were diagnosed with a specific cancer (excluding parent–offspring pairs with RA). We wanted to make sure that we examined familial risks between discordant diseases, RA and a specific cancer, by excluding families with concordant disease. However, familial diseases were so rare that the exclusions did not change the results. The SIR for no offspring cancer was changed when a parent was diagnosed with RA. SIRs for RA were decreased in offspring whose parents were diagnosed with tumours of the oesophagus (0.53), colon (0.85), breast (0.84) and ovary (0.61). The analysis was repeated for siblings, which presented about 60% of the cases noted in Table 1. No SIR was significantly different from unity.
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The aim of the present work was to provide an answer to the question of shared familial risk factors between cancer and RA, which has earlier been addressed only for lymphomas [4, 5]. To settle this question, data linkages between the Swedish Multigeneration Register, the Cancer Registry and the Hospital Discharge Register offer an excellent and, in principle, unbiased opportunity, used by us and others for a number of diseases, with the main emphasis on cancer [4, 7, 8]. The study was approved by the local ethical board. Familial risks of RA and cancer were examined through three independent analyses by calculating SIRs for (i) cancer in offspring of RA patients, (ii) RA in offspring of cancer patients and (iii) cancer and RA in siblings; in the sibling analysis, SIRs were calculated for both RA and cancer but the affected sibling pairs were not independent. The results of two of these analyses (i and iii) showed no familial aggregation between any type of cancer or RA. For one analysis, SIRs for offspring RA were decreased when parents were diagnosed with oesophageal, colon, breast or ovarian cancers. The SIRs were of borderline significance (the upper CI was close to 1.00) for all except ovarian cancer; however, it is unlikely that the associations with four cancer sites arose by chance. These cancers are not known to share genetic susceptibility [9], whereby environmental factors are the likely cause. For example, low parity is a risk factor of ovarian and breast cancers but small sibships could be protective of RA [10].
The present study provides evidence against any strong genetic risk factors shared between RA and common cancers. Thus, cancer risks observed in RA patients [3] are likely to be a manifestation of the dysregulated immune function or medication rather than a heritable susceptibility.
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Acknowledgements |
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Supported by Deutsche Krebshilfe, the Swedish Cancer Society, the EU, LSHC-CT-2004-503465 and the Swedish Council for Working Life and Social Research. The Family-Cancer Database was created by linking registers maintained at Statistics Sweden and the Swedish Cancer Registry.
Disclosure statement: The authors have declared no conflicts of interest.
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TopAcknowledgementsReferences |
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