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Familial Risk of Lung Carcinoma in the Icelandic Population
Steinn Jonsson, MD;
Unnur Thorsteinsdottir, PhD;
Daniel F. Gudbjartsson, PhD;
Hjortur H. Jonsson, MSc;
Kristleifur Kristjansson, MD;
Sigurdur Arnason, MD;
Vilmundur Gudnason, MD, PhD;
Helgi J. Isaksson, MD;
Jonas Hallgrimsson, MD;
Jeffrey R. Gulcher, MD, PhD;
Laufey T. Amundadottir, PhD;
Augustine Kong, PhD;
Kari Stefansson, MD, PhD
JAMA. 2004;292:2977-2983.
Context The dominant role of tobacco smoke as a causative factor in lung carcinoma is well established; however, an inherited predisposition may also be an important factor in the susceptibility to lung carcinoma.
Objective To investigate the contribution of genetic factors to the risk of developing lung carcinoma in the Icelandic population.
Design, Setting, and Participants Risk ratios (RRs) of lung carcinoma for first-, second-, and third-degree relatives of patients with lung carcinoma were estimated by linking records from the Icelandic Cancer Registry (ICR) of all 2756 patients diagnosed with lung carcinoma within the Icelandic population from January 1, 1955, to February 28, 2002, with an extensive genealogical database containing all living Icelanders and most of their ancestors since the settlement of Iceland. The RR for smoking was similarly estimated using a random population-based cohort of 10 541 smokers from the Reykjavik Heart Study who had smoked for more than 10 years. Of these smokers, 562 developed lung cancer based on the patients with lung cancer list from the ICR.
Main Outcome Measures Estimation of RRs of close and distant relatives of patients with lung carcinoma and comparison with RRs for close and distant relatives of smokers.
Results A familial factor for lung carcinoma was shown to extend beyond the nuclear family, as evidenced by significantly increased RR for first-degree relatives (for parents: RR, 2.69; 95% confidence interval [CI], 2.20-3.23; for siblings: RR, 2.02; 95% CI, 1.77-2.23; and for children: RR, 1.96; 95% CI, 1.53-2.39), second-degree relatives (for uncles/aunts: RR, 1.34; 95% CI, 1.15-1.49; and for nephews/nieces: RR, 1.28; 95% CI, 1.10-1.43), and third-degree relatives (for cousins: RR, 1.14; 95% CI, 1.05-1.22) of patients with lung carcinoma. This effect was stronger for relatives of patients with early-onset disease (age at onset  60 years) (for parents: RR, 3.48; 95% CI, 1.83-8.21; for siblings: RR, 3.30; 95% CI, 2.19-4.58; and for children: RR, 2.84; 95% CI, 1.34-7.21). The hypothesis that this increased risk is solely due to the effects of smoking was rejected for all relationships, except cousins and spouses, with a single-sided test of the RRs for lung carcinoma vs RRs for smoking.
Conclusions These results underscore the importance of genetic predisposition in the development of lung carcinoma, with its strongest effect in patients with early-onset disease. However, tobacco smoke plays a dominant role in the pathogenesis of this disease, even among those individuals who are genetically predisposed to lung carcinoma.
Author Affiliations: Departments of Medicine and Pathology, Landspitali-University Hospital (Drs S. Jonsson, Isaksson, and Hallgrimsson), deCODE Genetics (Drs Thorsteinsdottir, Gudbjartsson, Kristjansson, Arnason, Gulcher, Amundadottir, Kong, and Stefansson, and Mr H. Jonsson), and Icelandic Heart Association (Dr Gudnason), Reykjavík, Iceland.
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