Role of CTLA-4 polymorphism in susceptibility to type 1 diabetes:

Results of a family and a case-control study in Southern Tunisia

Immunology Department, Habib Bourguiba University

Hospital, Sfax ,Tunisia

Ferjeni ZOUIDI

Pr Hatem MASMOUDI

Type 1 diabetes (T1D) is characterized by autoimmune

destruction of insulin-producing β-cells in the pancreas resulting

from the action of environmental factors on genetically

predisposed individuals

β cells Destruction is caused by the infiltration of islets of

Langerhans by CD8+ and CD4+ T lymphocytes

The HLA region account for approximately 50% of the genetic

determination of the T1D. The other half is made up of multiple

genes, each having a limited individual impact on genetic

susceptibility

INTRODUCTION

OBJECTIVE

Studying the role of two SNPs (CT/60 and AG/49) CTLA-4 gene in

susceptibility to T1D.

SUBJECTS AND METHODSSubjects

Family study: 56 families (25 multiplex each comprising at least 2

diabetics and 31 simplex) including 87 with type 1 diabetes and 178

of their first-degree relatives were analysed Case-control study

The case-control study has been performed on the 56 index cases

(35 men, 21 women ;median onset age 13,10 ± 4,5 years; range, 2 to

45 ) and 120 healthy control subjects (12 men and 108 women;

median onset age 42 years; range, 25 to 65) with no family history of

diabetes Methods

PCR-RFLP

Statistical study

FBAT( family based association test) was applied to identify alleles

and haplotypes preferentially transmitted from heterozygous parents

to affected offspring

RESULTS

X ² test was used to compare categorical data between patients with type 1 diabetes and controls

Allèles/haplotypes Frequencies (%) Z p A 72% -1.23 2.21G 28% 1.23 2.21C 54% 1.51 0.13T 46% -1.51 0.13

AT 41% -1.49 0.13 GC 29.2% 1.54 0.12AC 28.5% 0.15 0.87 GT 01.4% - -

Z is significant if its value is ≥ 1.96 or ≤ -1.96 with a p less than 0.05

Table 1: Distribution of alleles frequencies (%), haplotype and FBAT results

FBAT analysis showed no preferential transmission of both alleles

and haplotypes from parents to affected children for the AG/49 and CT60

polymorphisms (p=2.21,p=0.13 respectively)

CT60

Alleles/Genotypes controls(%) DT1(%)

C 55.83 55.35T 44.16 44.64CC 37.5 30.35CT 36.66 50.00TT 25.83 19.64

p 0.93 0.930.350.930.36

AG/49

A 68.33 69.64G 31.66 30.35AG 10.00 07.81GG 43.33 39.28AA 46.66 50

0.800.800.61 0.880.68

Table 2: Genotype and allele distribution of the CTLA-4 CT60 and AG/49 SNP in DT1 patients and controls.

This result is consistent with that reported by others family studies [Marron MP et

al;1997- Angel B et al;2009]. Furthermore other case-control studies in Great

Britain, Northern Ireland, China, and Slovakia found no association between

polymorphism AG/49, CT60 and T1D[Nisticò L et al;1996-Dallos T et al;2008].

However, the results of many case-control studies showed a great association

between the two markers and DT1[Benmansour J et al;2010-Mayans S et

al;2007]

Our study indicate that the 49A/G and CT60 polymorphisms of the CTLA-4 gene are not associated with increased susceptibility to DT1 in southern Tunisia.Discussion

For the case-control study no

significant differences (p=0.80,

p=0.93 respectively) was

detected for the markers CTLA-4

CT60 and AG/49 respectively.

Thank you