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CLINICAL STUDY |
Department of Clinical Genetics, Oulu University Hospital, PB 24, FIN-90029 Oys, Oulu, Finland, 1 Department of Internal Medicine, Oulu University Hospital, FIN-90029 Oys, Oulu, Finland, 2 Medix Laboratories Ltd, FIN-02630 Espoo, Finland, 3 Department of Medical Informatics, Faculty of Medicine, FIN-90014 Oulu University, Oulu, Finland, 4 Department of Internal Medicine, Tampere University Hospital, FIN-33014 Tampere, Finland, 5 Department of Internal Medicine, Seinäjoki Central Hospital, FIN-60220 Seinäjoki, Finland, 6 Department of Medicine, Kuopio University Hospital, FIN-70211 Kuopio, Finland, 7 Department of Medicine, Central Hospital of Kanta-Häme, FIN-13530 Hämeenlinna, Finland, 8 Department of Medicine, Central Hospital of Pohjois-Karjala, FIN-80210 Joensuu, Finland, 9 Department of Medicine, Central Hospital of Mikkeli, FIN-50100 Mikkeli, Finland and 10 Division of Endocrinology, Department of Medicine, Helsinki University Central Hospital, FIN-00029 Helsinki, Finland
(Correspondence should be addressed to O Vierimaa; Email: outi.vierimaa{at}oulu.fi)
Objective: The existence of genotype–phenotype correlation in multiple endocrine neoplasia type 1 (MEN1) is controversial. Two founder mutations of the MEN1 gene in Northern Finland gave us an opportunity to compare clinical features among heterozygotes of different mutations.
Design and methods: Study cohort included 82 MEN1 heterozygotes who were tested for MEN1 during the years 1982–2001. Medical records were reviewed for manifestations of MEN1, other tumours and cause of death by the end of August 2003. Logistic regression analysis was used in evaluating the impact of age, gender and mutational status of affected heterozygotes on the likelihood of developing manifestations of MEN1.
Results: Founder mutations 1466del12 and 1657insC were found in 39 and 29 individuals, and D418N, G156R and R527X mutations in 9, 3 and 2 individuals respectively. Except for pituitary adenoma and nonfunctional pancreatic tumour (NFPT), age was a risk factor for all the disease manifestations. For NFPT, frameshift/nonsense mutations (1657insC, R527X) gave an odds ratio (OR) of 3.26 (95% confidence intervals (CI), 1.27–8.33; P = 0.014) compared with in-frame/missense mutations (1466del12, D418N, G156R); including the founder mutation carriers (n = 68) only, the 1657insC mutation gave an OR of 3.56 (CI, 1.29–9.83; P = 0.015). For gastrinoma, in-frame/missense mutations predicted the risk with an OR of 6.77 (CI, 1.31–35.0; P = 0.022), and in the founder mutations group the 1466del12 mutation gave an OR of 15.09 (CI, 1.73–131.9, P = 0.014).
Conclusions: In this study population, NFPT was more common in the frameshift/nonsense or 1657insC mutation carriers, whereas gastrinoma was more common in the in-frame/missense or 1466del12 mutation carriers.
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