2008 Barcelona - European Society of Human Genetics

Molecular and biochemical basis of disease
P06.100
An association between essential tremor and Etm2 locus in
Latvian population
I. Inashkina 1 , I. Radovica 1 , E. Vitols 2 , L. Smeltere 3 , E. Jankevics 1 ;
1 Latvian Biomedical Research and Study Centre, Riga, Latvia, 2 Riga Stradins
University, Department of Neurology, Riga, Latvia, 3 Paul Stradins University
Clinical Hospital, Riga, Latvia.
Essential tremor (ET) is one of the most common neurological disorders
in humans . An autosomal dominantly inherited form of ET is genetically
linked to two loci on chromosomes 3q13 (ETM1) and 2p24 .1
(ETM2) in families from different parts of the world . Numerous of candidate
genes for ET disorder - HS1-BP3, HCLS1, DRD3 - have been
suggested during last years .
Here we report study analysing a group of 104 unrelated Latvian patients
with ET for a genetic association with loci in candidate regions
ETM1 and ETM2. Out of them, 52 were classified as familial on the
bases of familial history . All patients were genotyped using sixteen informative
STR markers within two loci associated with ET (9 markers
for ETM2 and 7 for ETM1) and statistically analysed . Allele frequencies
were estimated on 97 normal controls, matched by age and gender .
The one concrete allele frequencies were significantly different between
familial ET samples in case of marker D2S220 (p=0 .0281) and
total ET samples in case of marker D2S2201 (p=0 .0385) in comparison
to control samples. Other loci did not show significant allele frequency
differences between familial cases, total ET cases or control groups .
In addition, 7 th exon of HS1-BP3 gene containing A265G substitution
and 1 st exon of DRD3 gene containing S9G substitution were analysed
in all ET patients and control samples . Analysed data did not reveal
any association between known variants of HS1-BP3 and DRD3
genes and ET phenotype .
Our data suggest an association between ETM2 locus and familial essential
tremor in Latvian population .
P06.101
Lysyl Oxidase-like 1 gene Polymorphisms in Exfoliation
syndrome, Exfoliation Glaucoma and Primary Open Angle
Glaucoma in the Finnish Population
S. Lemmelä 1 , E. Forsman 2 , H. Nurmi 1 , H. Laivuori 1 , T. Kivelä 3 , P. Puska 3 , E.
Vesti 3 , A. Eriksson 2 , H. Forsius 2 , I. Järvelä 1 ;
1 Department of Medical Genetics, University of Helsinki, Helsinki, Finland,
2 Population Genetics Unit, Folkhälsan Institute of Genetics, Helsinki, Finland,
3 Department of Ophthalmology, University of Helsinki, Helsinki, Finland.
Exfoliation syndrome (XFS) is an age-related ocular disorder and a risk
factor for the development of glaucoma . XFS is characterized by abnormal
accumulation of greyish fibril-like material in the anterior segment
of the eye . Similar material has also been found in extraocular tissues .
XFS is prevalent worldwide but the prevalence varies widely in different
populations; being even 20%-40% among individuals >80 years in
Scandinavian countries . Familiar aggregation studies suggest genetic
contribution to XFS . In a recent genome-wide association study, three
SNPs, (rs2165241, rs1048661 (R141L) and rs3825942 (G153D)) on
lysyl oxidase-like 1 (LOXL1) gene were found to be strongly associated
with XFS and XFG, in Icelandic and Swedish patients . Together
two non-synonymous SNPs accounted for 99% of XFG in this population
. These two SNPs were in complete LD and three haplotypes were
observed . Haplotypes G/G (OR=27 .05) and T/G (OR=8 .90) were risk
haplotypes relatively to G/A with lowest estimated risk . In this study
we investigate whether three LOXL1 SNPs are associated with XFS/
XFG in Finnish population . SNPs are screened by direct-sequencing in
XFS-, XFG- and POAG- patients (100/group) and as controls in ~120
individuals without any sign of XFS/XFG/POAG and ~300 Finnish
blood donors . In preliminary results 59% (30/51) of XFS patients, 69%
(40/58) of XFG patients and only 18% (10/55) of POAG patients were
homozygous for the highest risk haplotype GG . Likewise in Icelandic
and Swedish population about 25% (82/325) of general population in
Finland were homozygous for the haplotype GG . Studies are ongoing
and more XFS/XFG/POAG patients will be analyzed .
P06.102
FADs genotypes and desaturase activity estimated by
arachidonic to linoleic acid ratio are associated with
inflammation and coronary artery disease
E. Trabetti 1 , G. Malerba 1 , N. Martinelli 2 , D. Girelli 2 , P. Guarini 2 , T. Illig 3 , M. Sandri
2 , S. Friso 2 , F. Pizzolo 2 , L. Schaeffer 3 , J. Heinrich 3 , R. Corrocher 2 , O. Olivieri 2 ,
P. F. Pignatti 1 ;
1 Section of Biology and Genetics - Dept Mother & Child/Biol & Genet, Univ
Verona, Verona, Italy, 2 Dept Clinical and Experimental Medicine, Univ Verona,
Italy, Verona, Italy, 3 GSF-National Research Center for Environmental and
Health, Institute of Epidemiology, Neuherberg, Germany, Neuherberg, Germany.
Background: The delta-5 and delta-6 desaturases, encoded by FADS1
and FADS2 genes, are key enzymes in the conversion of linoleic acid
(LA) to arachidonic acid (AA) . AA is the precursor of a cascade of
mediators, such as eicosanoids, with inflammatory properties. Single
nucleotide polymorphisms (SNPs) in FADS1 and FADS2 have been
associated with different levels of AA and LA, with possible functional
consequences on desaturase activity .
Methods and Results: Thirteen FADS SNPs and AA/LA ratio on red
blood cell (RBC) membranes, a marker of desaturase activity, were
evaluated in 876 subjects with (n=610) or without (n=266) angiographically
documented coronary artery disease (CAD) . AA/LA ratio was
higher in CAD patients (2 .17±0 .41 versus 1 .99±0 .36; P=2 .5×10-10),
and an increased AA/LA ratio resulted an independent risk factors for
CAD (OR 2 .22, 95%CI 1 .37-3 .61 for higher versus lower ratio tertile) .
Furthermore, hs-CRP levels increased progressively across AA/LA ratio
tertiles . In a linear regression model including all the 13 SNPs analysed,
4 resulted to be independent predictors of AA/LA ratio variability .
The subjects carrying the highest number of alleles associated with a
raised ratio, as well as haplotypes with the highest number of such alleles,
presented proportionally more elevated hs-CRP concentrations
and an increased probability of having CAD .
Conclusions: An increased desaturase activity is associated with an
elevated hs-CRP and, in turn, with an increased risk for CAD . Subjects
carrying FADS genotypes associated with an higher desaturase activity
may be prone to a proinflammatory response favouring atherosclerotic
vascular damage .
P06.103
mLPA PcR-analysis for registration of the most frequent
mutations in mEFV gene indigenous to Armenians
V. A. Kadnikova, O. A. Schagina, A. V. Polyakov;
Research Centre for Medical Genetics, Moscow, Russian Federation.
Familial Mediterranean fever (FMF) is an autosomal recessive disease
particularly common in several populations of Mediterranean extraction,
and affecting mainly Turks, Jews, Armenians, and Arabs . It is characterized
by recurrent short episodes of fever, sterile peritonitis, arthritis,
and pleurisy . The gene responsible for FMF, MEFV(MIM# 608107),
was identified by positional cloning in 1997. The product of the MEFV
gene, named pyrin/marenostrin, is expressed in polymorphonuclear
cells and monocytes and it is proposed that it regulates inflammatory
responses at the level of leucocyte cytoskeletal organisation . Thirty
six mutations located in the MEFV gene have been identified so far,
mostly in exon 10, followed by exons 1, 2, 3, 5 and 9 .
We elaborated the multiplex system for MLPA PCR-analysis for most
frequent mutations indigenous to Armenians M694V, M680I, V726A,
F479L, R761H, and E148Q in MEFV gene in exons 10, 5 and 2 . The
MEFV probe mix contains 18 different probes with amplification products
between 82 and 145 bp . Length difference between consecutive
amplification products is 3 or 4 bp.
DNA sample from 57 unrelated Armenian FMF patients were examined
by this multiplex system . 83 chromosomes with different mutations
were revealed So, calculated nformative of this system more then
73% for Armenians living on the Russian Federation territory .
Advantages of this method are: specificity; possibility to work with
small quantity of researching material- method speed; for all mutation
types used two universal ferments: ligase and polymerase; detection
with help of PAAG or capillary electrophoresis; quantitative analysis
genes copy or stripes of genes .