2008 Barcelona - European Society of Human Genetics

Molecular and biochemical basis of disease
from other less T1D-predisposing DR3 chromosomes (like B8-DR3
CEH) .
To test this hypothesis, we genotyped a panel of 2,360 SNPs in the
MHC region, spanning 4 .9 Mb (MHC Panel Set - Illumina Inc, San Diego,
CA) in 21 T1D patients and 39 non-diabetic individuals who were
homozygous for HLA-DR3 and carried only one copy of the complete
B18-DR3 CEH (HLA-A*30-B*18-DR3-DQ2) . Genotype and allele frequency
calculations and association analyses were performed using
PLINK v.1.0 (http://pngu.mgh.harvard.edu/purcell/plink/).
After stringent correction for multiple testing (Bonferroni) six independent
SNPs remained associated (uncorrected p-value: 1 .03·10 -5 and
2 .73·10 -7 ) .
Our results add further evidence for the presence of additional susceptibility
determinants in the MHC . Since the associated markers might
just be proxies of the etiological variants in B18-DR3 haplotypes, we
are genotyping these SNPs in HLA-unmatched cases and controls .
Further in-depth analysis of these associated regions might be necessary
to identify the etiological variants .
P06.295
Family-based analysis of tumour necrosis factor and
lymphotoxin alpha tag polymorphisms and type 1 diabetes in the
population of south croatia
V. Boraska 1 , E. Zeggini 2 , C. J. Groves 3 , N. W. Rayner 2 , V. Škrabić 4 , M. Diakite 2 ,
K. A. Rockett 2 , D. Kwiatkowski 2 , M. McCarthy 3 , T. Zemunik 1 ;
1 School of Medicine, Split, Croatia, 2 Wellcome Trust Centre for Human Genetics,
University of Oxford, Oxford, United Kingdom, 3 Oxford Centre for Diabetes,
Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom,
4 Clinical Hospital Split, Split, Croatia.
Type 1 diabetes is an autoimmune disease characterized by destruction
of pancreatic β cells. It is influenced by environmental and genetic
factors . TNF and LTA are cytokines with a wide range of inflammatory
and immunomodulatory activities possibly related with type 1 diabetes
. The aim of the present study was to evaluate the association of
11 TNF/LTA tag polymorphisms in 160 type 1 diabetes trio families
from South Croatia . Investigated tag polymorphisms were designed
to capture the majority (62%) of common variation in TNF/LTA gene
region, based on the HapMap database . We observed overtransmission
of alleles from parents to affected child at four variants: rs909253,
allele C, p=1 .2x10 -4 ; rs1041981, allele A, p=1 .1x10 -4 , rs1800629 (G-
308A), allele A, p=1 .2x10 -4 and rs361525 (G-238A), allele G, p=8 .2x10 -
3 . We also identified overtransmission of the rs1800629(G-308A)rs361525(G-238A)
G-A haplotype, p=2 .384x10 -5 . The present study
found an association of TNF/LTA gene region with type 1 diabetes . A
careful assessment of TNF/LTA variants adjusted for linkage disequilibrium
with HLA loci is needed to further clarify the role of these genes
in type 1 diabetes susceptibility .
P06.296
Polymorphisms of the NOs2, tNFB and tNFR1 genes are
associated with type 1 Diabetes mellitus in tatars and Russians
from Bashkortostan
Z. R. Balkhiyarova 1 , D. S. Avzaletdinova 2 , T. V. Morugova 2 , O. E. Mustafina 1 ;
1 Institute of Biochemistry and Genetics, Ufa Research Center, Russian Academy
of Sciences, Ufa, Russian Federation, 2 Bashkir State Medical University,
Ufa, Russian Federation.
Apoptosis may play a role in two different aspects of autoimmune disease
- generation of autoreactive cells and tissue destruction . Type one
diabetes mellitus (T1DM) is a typical autoimmune disease . The aim of
the present study was to investigate the association between apoptosis
genes (NOS2, TNFB and TNFR1) polymorphisms with T1DM in
Tatar and Russian ethnic groups (Bashkortostan, Russia) .
We studied 254 T1DM patients and 544 controls . DNA was isolated
by phenol-chloroform extraction from 8 ml venous blood and used as
template in PCR-RFLP . Two-tailed test of Fisher was used for statistical
analysis .
We have found that NOS2*G/*G genotype was associated with decreased
risk and *G/*A genotype was associated with increased risk of
T1DM in Tatar males (OR=0 .50, P=0 .02, CI: 0 .28-0 .88 and OR=2 .18,
P=0 .011, CI: 1 .22-3 .87, respectively) .
Carriers of TNFB *A/*A genotype had lower risk of T1DM in Tatars
(OR=0 .56, CI=0 .36-0 .87) . At the same time, TNFB *G/*G is associated
with higher risk of T1DM (OR=2 .52, CI=1 .33-4 .79) in Russian ethnic
group .
We have shown that TNFR1*G/*G genotype was less frequent among
patients with T1DM (15 .5±2 .2% vs . 26 .1±2 .8%, P=0 .020) . We may
conclude that TNFR1*G/*G genotype is associated with decreased
risk of T1DM in Tatars (OR=0 .52, CI: 0 .30-0 .90 and OR=0 .73, CI: 0 .54-
0 .99) .
P06.297
Region wide association study on chromosome 10q25.1-26.3
and its contribution to type 2 diabetes susceptibility in Japanese
P. Keshavarz 1 , H. Inoue 2 , M. Itakura 3 ;
1 Guilan University of Medical Science, Rasht, Islamic Republic of Iran, 2 The
University of Tokushima, Tokushima, Japan, 3 The university of Tokushima,
Tokushima, Japan.
Several linkage studies indicated that human chromosome 10q is one
of a candidate susceptibility locus for type 2 diabetes (T2D) . But there
is no information about certain variant(s) or gene(s) have strong effects
on the disease within the region . In order to identify T2D disease susceptibility
genes in Japanese, verified SNPs from the databases with
a minor allele frequency larger than 0 .15 were applied to 10 intervals
across a 25 Mb region on chromosome 10q25 .1-26 .3 . Using the 993
SNPs for genotyping a two-stage case-control analysis was applied to
Japanese subjects consisted of 888 T2D patients and 898 control subjects
. Haplotype and linkage disequilibrium (LD) were assessed based
on SNP genotypes of all study subjects . To search for new SNPs in
the detected significant gene, screening of exons and 3’UTR are performed
in 32 randomly selected T2D patients . We detected 10 SNPs
(six intronic and four 3’UTR) in DOCK1 (detictor of cytokinesis 1) gene
were showed replicated association in the two set of independent DNA
samples. These nominal significant SNPs were located in two different
Linkage disequilibrium (LD) block containing exons 7-23 and exons
51-52 respectively . When the two data were combined, the most significant
association was observed with SNP 827 in 3’ UTR of DOCK1
gene (p=0 .0005) . Real time quantitative revealed that the expression
of DOCK1 was rather ubiquitous with relatively abundant expression
in the pancreas, kidney and brain in T2D patients . Our region-wide
association analysis suggests the strong impact of DOCK1 gene with
risk of T2D in Japanese .
P06.298
study of mtDNA polymorphism in type 2 diabetes patients
S. V. Buikin 1 , M. V. Golubenko 1 , K. V. Puzyrev 2 , O. A. Makeeva 1 , I. V. Tsimbaluk
3 , O. A. Koshelskaja 2 , V. P. Puzyrev 1 ;
1 Research Institute of Medical Genetics, Tomsk, Russian Federation, 2 Research
Institute of Cardiology, Tomsk, Russian Federation, 3 Siberian State
Medical University, Tomsk, Russian Federation.
Diabetes is among frequent endocrine diseases . Endocrine system is
one of energy-dependent systems in human organism . Phylogenetic
mtDNA haplogroups possess different common polymorphisms and
can mark effects of these variants on predisposition to common diseases
. Samples of 119 type 2 diabetes patients (78 women, 41 men)
and 134 healthy people were studied (all living in Tomsk region) . Mean
age in the groups was 52+5 .5 and 47 .6+10 .2 years, respectively . Ultrasound
examination, 24-hours monitoring of blood pressure and
fasting glucose measure were performed . Comparison of frequencies
of some of Europeans haplogroups (H, U, T, J) has uncovered lower
frequency of haplogroup T in type 2 diabetes patients as compared
to control group (OR=0 .14; 0 .02