Abstract
Background The hereditary predisposition to diabetes
is only partially explained by genes identified so far.
Neurofibromatosis type 1 (NF1) is a rare monogenic
dominant syndrome caused by aberrations of the NF1
gene. Here, we used a cohort of 1410 patients with NF1
to study the association of the NF1 gene with type 1
(T1D) and type 2 diabetes (T2D).
Methods A total of 1410 patients were confirmed to
fulfil the National Institutes of Health diagnostic criteria
for NF1 by individually reviewing their medical records.
The patients with NF1 were compared with 14 017
controls matched for age, sex and area of residence as
well as 1881 non-­NF1 siblings of the patients with NF1.
Register-based information on purchases of antidiabetic
medication and hospital encounters related to diabetes
were retrieved. The Cox proportional hazards model was
used to calculate the relative risk for diabetes in NF1.
Results Patients with NF1 showed a lower rate of T2D
when compared with a 10-fold control cohort (HR 0.27,
95% CI 0.17 to 0.43) or with their siblings without NF1
(HR 0.28, 95% CI 0.16 to 0.47). The estimates remained
practically unchanged after adjusting the analyses for
history of obesity and dyslipidaemias. The rate of T1D
in NF1 was decreased although statistically nonsignificantly (HR 0.58, 95% CI 0.27 to 1.25).
Conclusion Haploinsufficiency of the NF1 gene may
protect against T2D and probably T1D. Since NF1
negatively regulates the Ras signalling pathway, the
results suggest that the Ras pathway may be involved in
the pathogenesis of diabetes.