European Human Genetics Conference 2007 June 16 – 19, 2007 ...

Genetic analysis, linkage, and association
gene (MTHFR) is considered to be an important candidate gene of
MDD. A single base mutation C677T (rs1801133) results in the production
of a mildly dysfunctional thermolabile enzyme. The MTHFR
677T/T genotype and, to a lesser extent the 677C/T genotype, is associated
with a significant elevation in the circulating concentrations of
the homocystein and a decrease in serum folate concentrations, which
may parallel a similar reduction in 5-methyltetrahydrofolate in CNS
and may lead to a reduction in monoamine neurotransmitter function
and elevated risk of MDD. To test the hypothesis that MTHFR C677T
polymorphism can be involved in predisposition to MDD we conducted
the association study in sample of 1222 patients with recurrent MDD
and 833 control subjects. The statistical power of our sample to detect
an odds ratio of 1.5 for 677T/T genotype was 88%. There are not
significant differences in genotype/allele frequencies between depressive
patients and controls, neither in total samples, nor in females and
males separately. We also failed to confirm the association of this gene
with MDD using meta-analysis of 4 case-control studies. Our results
exclude a major role for the MTHFR C677T polymorphism in conferring
susceptibility to recurrent unipolar depression in British population.
However, there are many rare mutations in the MTHFR gene,
also associated with minor changes in the enzyme activity of MTHFR,
which could play a role in susceptibility to depression.
P0957. Association of INSR and IRS-1 gene polymorphisms with
type 2 diabetes in the Northern Greek population
A. Leondiadou, A. Kouvatsi;
Aristotle University, Thessaloniki, Greece.
Type 2 diabetes is a heterogeneous disorder. Several genes have
been proposed to contribute to its pathogenesis. Associations found
in a particular population were often not confirmed in others, suggesting
regional differences. In the present study we tested the possible
association of variants in the genes for insulin receptor (INSR) and
insulin receptor substrate-1 (IRS-1) with type 2 diabetes in the Northern
Greek population. The distribution of three polymorphisms of the
INSR gene (3559C>T or Y984Y, 3560G>A or V985M and 3781C>T
or H1058H) and one polymorphism of the IRS-1 gene (3932G>A or
G972R) were determined in 100 unrelated diabetic patients and 100
age-matched unrelated control subjects. Genotyping was performed
by PCR amplification followed by restriction digestion with appropriate
enzymes. Samples with certain patterns were further sequenced
in order not to conceal the coupling between the Y984Y and V985M
polymorphisms.
Genotypic and allelic frequencies were compared between the two
groups. No association was found for the four polymorphisms with diabetes.
The analysis of composite genotypes revealed that individuals
heterozygous for the Y984Y polymorphism and homozygous normal
for the other three, were found more frequently among the controls
(p=0.033). This genotype might be protective against type 2 diabetes
in Greek individuals.
P0958. Using high-density SNP genotyping to fine-map the
diabetic nephropathy locus on 3q in patients from Finland
B. He 1 , A. Österholm 1 , M. Wessman 2 , C. Forsblom 2 , J. Tuomilehto 3 , P. Groop 2 ,
K. Tryggvason 1 ;
1 Matrix Biology, MBB, Karolinska Institutet, Stockholm, Sweden, 2 Folkhälsan
Research Center, Biomedicum Helsinki, Helsinki, Finland, 3 National Public
Health Institute, Helsinki, Finland.
Diabetic nephropathy (DN) is the leading cause of end-stage renal
disease and affects about 30 % of all diabetic patients. Our previous
genome scan using discordant sib pairs from Finland identified the
3q locus with a suggestive linkage (LOD 2.6, P=0.0004) to DN (Kidney
International 2007;71:140). To capture genetic variants in LD with
the causal SNP, we carried out a high-density SNP genotyping strategy
for fine-mapping the 3q locus. Based on the HapMap database,
3072 tagged SNPs (r2>0.7, MAF>2%) covering 28 Mb, from 124 to
152 Mb on chromosome 3 (build 35), were selected by the LD-based
tagging method and were genotyped in 643 samples (456 Finnish and
187 Icelandic) using the Illumina SNP genotyping platform. In results,
635 samples (98.7%) and 2820 SNPs (92%) reached the threshold of
data quality controls. In association analysis, 154 SNPs in the Finnish
samples and 149 SNPs in the Icelandic samples showed allelic associations
(P