Association of the WFS1 gene with disease progression in children with new onset T1D. Results from the Hvidoere study group on childhood diabetes

Objective: The wolframin gene, WFS1, encodes a glucoprotein
involved in the calcium homeostasis of the endoplasmatic
reticulum; WFS1 is critical for the function and survival of the
pancreatic beta-cells. Genetic variation within the WFS1 gene is
known to be associated with T2D and for rare variants the
Wolfram syndrome.
The aim of this study was to investigate the impact of a common
genetic variant (rs10010131) of the WFS1 gene on disease
progression in a group of children newly diagnosed with T1D.
Methods: The study is a multicenter longitudinal investigation
with 18 participating paediatric centres from 15 countries.
Clinical information and blood samples were collected from
275 children less than 16 years at diagnosis and at 1, 6, and
12 months after onset. Genotyping of the rs10010131 variant was
done by KBioscience using an in-house KASPar assay system.
Statistics: C-peptide, HbA1c, IDAA1c and proinsulin were
analysed by multiple regression using age at onset, gender,
DKA at onset, HLA class II risk groups, and genotypes as
explanatory factors in a compound symmetric repeated
measurement model.
Results: The genotype frequencies were: 17% (AA), 48% (AG),
35% (GG), where the G allele is the wildtype allele. In a dominant
model the G allele carriers of the rs10010131 variant was
significantly positively associated with stimulated C-peptide
(est.: 1.73, P < 0.0001), negatively with HbA1c (est.: )0.49,
P = 0.005), negatively with IDAA1c (est.: )0.67, P = 0.02)
and positively with proinsulin (est.: 1.55, P = 0.005) the first
12 month after disease onset compared to the AA genotype
carriers.
Conclusions: A common variant of the WFS1 gene is highly
associated with better residual beta-cell function and
corresponding better metabolic control during disease
progression in new onset T1D compared to AA genotype
carriers. Thus, genotyping WFS1 might serve as a suitable
selection tool for patients eligible for beta-cell regenerative
intervention studies.