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Diabetes & Metabolism
Vol 25, N° 6  - novembre 1999
p. 516
Doi : DM-11-1999-25-6-1262-3636-101019-EVT52
Short communication

Absence of replication in the french population of the association betweenbeta2/neurod-a45t polymorphism and type 1 diabetes
 
S. Dupont [1], C. Dina [1], E.H. Hani [1], P. Froguel [1]
[1] CNRS UPRES A 8090, Institut Pasteur de Lille, 1 rue du ProfesseurCalmette, 59019 Lille Cedex, France.

Keywords: BETA2/NEUROD1. , transcription factor. , type 1 diabetes. , association study.


Mots clés : BETA2/NEUROD1. , facteur de transcription. , diabète de type 1. , étuded'association.

ETA2/NEUROD1, a basic helix-loop-helix (bHLH) transcription factor which transactivatesthe insulin gene, plays a pivotal role in the endocrine pancreas tissue-specificdifferentiation, as revealed by the phenotype of mice with targeted deletion of theNEUROD1 gene. These mice exhibit a marked reduction in the number of pancreatic B-cells,and die perinatally from severe hyperglycemia [ [1]]. Three recent studies examinedthe coding sequences of NEUROD1 for mutations in patients with Type 2 diabetes from theJapanese, the Danish and the French populations, respectively [ [2], [3], [4]]. These studies reported an A45Tcommon polymorphism in NEUROD1, but failed to detect any evidence for linkagedisequilibrium between this variant and Type 2 diabetes. However, Copeman

et al.

showed significant evidence for linkage of the NEUROD1 locus (D2S152 at chromosome 2q32)with Type 1 diabetes in Caucasian populations (IDDM7, Ref. 5). Iwata

et al.

, in arecent study, reported an association of the polymorphism A45T with Type 1 diabetes in aJapanese cohort [ [6]]. Their studywas performed on 60 subjects with type 1 diabetes and 174 controls, and the odd ratio oftype 1 diabetes for the variant versus wild homozygote was estimated to be 3.1 based oncomparison with the control subjects.

In order to try to replicate this finding in the French population, we conducted acase/control study in 87 unrelated subjects with Type 1 diabetes, who were diagnosedaccording to the WHO criteria [ [7]],and in 114 normoglycemic control subjects. We selected those 87 subjects on the basis oftheir familial history of Type 1 diabetes allowing eventual transmission disequilibriumanalyses that we would perform in case of positive association. It is noteworthy that thesize of our sample allows us to detect an effect of the variant for an odd ratio of atleast 3.1 and a decision criterion of p<0.05 conferring a power of more than 80% to ourstudy. This corresponds to the statistical thresholds raised in the association study byIwata

et al.

[ [6]]. TheNEUROD1 A45T variation results in a loss of a MwoI endonuclease restriction site and,therefore, subjects were screened for this mutation using a PCR-RFLP test as previouslydescribed [ [4]].

The genotype frequencies for the NEUROD1 A45T variant in our samples (affected andnon-affected) were very dissimilar to those reported in the Japanese cohort by Iwata

etal.

[ [6]]. There were nohomozygote carriers among the Japanese subjects, while we found 20.7% and 16% homozygotecarriers in our affected and non-affected groups, respectively Table I

. In our population,the genotype frequencies were compared, using chi-square tests under dominant, codominantand recessive models, between Type 1 diabetic and control groups. Student's

t

testwas used to assess the association between the A45T polymorphism and clinicalsub-phenotypes (BMI and age at onset of diabetes) under the dominant and recessive models.The genotype frequencies for the A45T variant were not different when comparing Type 1diabetics to control subjects Table I

. We also failed to reveal any association between the BMI or the age at onset and thepresence of A45T variation (data not shown).

Together with the findings by Owerbach

et al.

, which reported no associationbetween the polymorphism A45T and Type 1 diabetes in white Americans (8), our studystrongly suggests that BETA2/NEUROD1 is unlikely to have a major role in susceptibility toType 1 diabetes among the Caucasian population.

E-mail : froguel@xenope.pasteur-lille.fr

Tableau I.

Type 1 diabetic subjectsControl subjectsnumber of individuals 87 114 sex (M/F) 51/36 51/63 present age (years) 33.5 ± 13.5 57 ± 11.7 age at onset (years) 12.9 ± 7 - BMI (kg/m2) 22.6 ± 3.2 23 ± 2.7 A45T genotype frequencies (%) Homozygotes A/A 41.4 38Heterozygotes A/T 37.9 46Homozygotes T/T 20.7 16

(Les tableaux sont exclusivement disponibles en format PDF).

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Références

[1]
Naya FJ, Huang HP, Qiu Y, Mutoh H, DeMayo FJ, Leiter AB, Tsai MJ. Diabetes, defective pancreatic morphogenesis, and abnormal enteroendocrine differentiation in BETA2/neuroD-deficient mice. Genes Dev, 1997, 11, 2323-2334.
[2]
Furuta H, Horikawa Y, Iwasaki N et al. Beta-cell transcription factors and diabetes: mutations in the coding region of the BETA2/NeuroD1 (NEUROD1) and Nkx2.2 (NKX2B) genes are not associated with maturity-onset diabetes of the young in Japanese. Diabetes, 1998, 47, 1356-1358.
[3]
Hansen T, Hansen L, Urhammer S, Eiberg H, Pedersen O. Studies of the variability in the genes encoding the insulin promoter factor-1 and its upstream activator NEUROD/BETA2 in Danish caucasian NIDDM families. Diabetologia, 1998, suppl 1, A110, PS428.
[4]
Dupont S, Vionnet N, Chèvre JC. et al. No evidence of linkage or diabetes-associated mutations in the transcription factors BETA2/NEUROD1 and PAX4 in type 2 diabetes in France. Diabetologia, (in press).
[5]
Copeman JB, Cucca F, Hearne CM et al. Linkage disequilibrium mapping of a type 1 diabetes susceptibility gene (IDDM7) to chromosome 2q31-q33. Nat Genet, 1999, 1, 80-85.
[6]
Iwata I, Nagafuchi S, Nakashima H et al. Association of polymorphism in the NeuroD/BETA2 gene with type 1 diabetes in the Japanese. Diabetes, 1999, 48, 416-419.
[7]
Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care, 1997, 20, 1183-1197.
[8]
Owerbach D, Naya FJ, Tsai MJ, Allander SV, Powell DR, Gabbay KH. Analysis of candidate genes for susceptibility to type I diabetes: a case-control and family-association study of genes on chromosome 2q31-35. Diabetes, 1997, 46, 1069-1074.

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