2008 Barcelona - European Society of Human Genetics

Molecular and biochemical basis of disease
P06.169
Absence of causative coding variants in the mEis1 gene in 245
French-canadian Restless Legs syndrome patients
L. Xiong1 , M. Dubé1 , A. Levchenko1 , J. St-Onge1 , S. Girard1 , C. Gaspar1 , G.
Turecki2 , J. Montplaisir1 , G. A. Rouleau1 ;
1 2 University of Montreal, Montreal, QC, Canada, McGill University, Montreal,
QC, Canada.
Introduction: Restless legs syndrome (RLS) is a common sensorimotor
disorder with a substantial genetic contribution . Recently, a genome-wide
association study reported significant association between
common variants within the MEIS1 gene and the RLS phenotype . The
odds ratio of the risk allele ranges from 1 .8 to 3 .0 . The MEIS1 gene
encodes a homeobox protein involved in limb development, establishment
of the intrasegmental spinal motor neuron identity and connectivity,
and patterning of sensory organs in the embryonic peripheral
nervous system, as well as hematopoiesis .
Patients and methods: We systematically sequenced 245 clinically
well-defined RLS patients for the entire coding and UTR regions of
the MEIS1 gene . All samples were Caucasians with 95% of French-
Canadian (FC) origin; and 77% were severe or very severe cases with
mean age of 53±12 yrs and disease onset 30±16 yrs . 77% of patients
had positive family history and 83% were also positive for periodic
leg movements during sleep . In total, 13 exons/17 fragments (NM_
002398 .2, 3180 bps) were sequenced . All sequence variants detected
in patients were genotyped in 285 FC controls .
Results: In total, 19 variants were detected, five intronic and 14 exonic,
including 13 variants within the 3’UTR region and one synonymous
SNP (rs13005707) in exon 7 . Eight rare variants and eleven common
variants showed no association with the disease phenotype .
Conclusion: No causative coding variants were found in the MEIS1
gene in 245 RLS patients . Further deep-sequencing of the non-coding
region and studies of the expression and function of the MEIS1 gene
are underway .
P06.170
Effect of polymorphisms in the dopaminergic system genes on
the mental fatigue
M. A. Kulikova, M. A. Timofeeva, N. V. Maluchenko;
Moscow State University, Moscow, Russian Federation.
Mental fatigue (MF) represents a failure to initiate and sustain tasks
that require self-motivation and internal cues in the absence of demonstrable
cognitive failure or motor weakness . So development of the
mental fatigue is the significant problem for people who work with big
amount of data and constantly need focused attention .
Molecular mechanisms of MF origin still are not clear . It is known that
basal ganglia play a key role in the development of MF (Chaudhuri et
al ., 2000) . Dopamine is one of the most prevalent neurotransmitters in
the basal ganglia . Therefore we suppose that alterations in the functioning
of dopamine system provided by genes variations may influence
the development of the MF . We tested the hypothesis that allelic
variation of the DRD2 and DAT genes located mostly in the striatum
could be associated with differences in the onset of MF .
In current investigation 160 volunteers (78 males and 82 females) participated
. Subjects were genotyped for TaqI A RFLP of the DRD2 gene
and 40-bp VNTR polymorphism of the DAT gene . Psychophysiological
indexes were measured before and after mental load consisted
in the monotonous passing of personality questionnaires during three
hours .
Case-control analyses suggested a strong association between the
A1+10/10 genotype and increased mental fatigue (P < 0 .05) . In conclusion,
mental fatigue seems to be related to allelic variations within
the DRD2 and DAT genes .
P06.171
Effect of genes from the serotonin system on the mental fatigue
M. Timofeeva1 , M. Kulikova2 , N. Maluchenko2 ;
1Russian Research Institute of Sport and Physical Education, Moscow, Russian
Federation, 2Moscow State University, Moscow, Russian Federation.
Fatigue is an important factor affecting sporting and mental performances
. It is complicated process which includes peripheral and central
components . Central fatigue occurs in central nervous system as a
result of mental as well as physical activity .
There are evidences that serotonin is implicated in central fatigue de-
velopment . Serotonin turnover in the brain increases in response to
physical exercise . Decreased motivation, tiredness, loss of motor coordination
- markers of central fatigue, are associated with the rise of
brain serotonin concentration . But the role of serotonin in the development
of mental fatigue is unclear .
In the current study we investigate associations of serotonin system
genes polymorphism with the mental fatigue . In the study students
of Moscow State University took part (N=160, male=78, female=82) .
Volunteers were exposed to intensive mental workload (logical tasks
and monotonous persistent completion of psychological tests) during
3 hours . Before and after workload the psychophysiological state was
estimated with the help of “NS-Psychotest” (Neurosoft, Russia) . Additionally
volunteers completed self-ratings of mental fatigue and of
functional state .
It was detected that carries of both ss-genotype of the 5HTTLPR and
CC-genotype of the 5-HT2A polymorphism (T102C) reported higher
level of mental fatigue after performing fatigue task compared with carries
of ll(5HTTLPR) genotype and of TT(T102C) genotype .
ss-genotype of the 5-HTTLPR as well as CC-genotype of the 5-HT2A
are associated with reduced expression of both genes and therefore
could cause increasing concentrations of extracellular serotonin in the
brain. These findings suggest a role of serotonin transmission efficiency
in mental fatigue .
P06.172
Joint analysis of individual-level data data from 17 studies on
the association of the IL promoter polymorphism -174G>c with
glucose levels, interleukin-6 levels, and body-mass index
C. Huth 1,2 , T. Illig 1 , C. Herder 3 , C. Gieger 1,2 , H. Grallert 1 , Y. H. Hamid 4 , O. Pedersen
4 , T. Hansen 4 , V. Lyssenko 5 , L. Groop 5 , H. Ireland 6 , J. W. Stephens 7 , I. Wernstedt
Asterholm 8 , J. Jansson 8 , H. M. Stringham 9 , M. Boehnke 9 , J. Tuomilehto
10,11 , J. Fernandez-Real 12,13 , A. Lopez-Bermejo 12,13 , L. Gallart 14 , J. Vendrell 14 , S.
E. Humphries 6 , F. Kronenberg 15 , H. E. Wichmann 1,2 , I. M. Heid 1,2 ;
1 Institute of Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany,
2 Institute of Biometry and Epidemiology, University of Munich, Munich,
Germany, 3 German Diabetes Center, Leibniz Institute at Heinrich Heine University
Düsseldorf, Düsseldorf, Germany, 4 Steno Diabetes Center, Copenhagen,
Denmark, 5 Department of Clinical Sciences, University Hospital Malmö, Malmö,
Sweden, 6 Centre for Cardiovascular Genetics, Royal Free and University College
Medical School, London, United Kingdom, 7 Medical School, University of
Wales, Swansea, United Kingdom, 8 Institute of Neuroscience and Physiology,
Sahlgrenska Academy at Gothenborg University, Gothenburg, Sweden, 9 Department
of Biostatistics, University of Michigan, Ann Arbor, MI, United States,
10 Diabetes Unit, National Public Health Institute, Helsinki, Finland, 11 Department
of Public Health, University of Helsinki, Helsinki, Finland, 12 Section of Diabetes,
Endocrinology and Nutrition, Girona, Spain, 13 CIBER “Fisiopatología de la
Obesidad y Nutrición” CB/06/03/010, Girona, Spain, 14 Research Unit, University
Hospital Joan XXIII, Tarragona, Spain, 15 Division of Genetic Epidemiology,
Innsbruck Medical University, Innsbruck, Austria.
Background: Several studies have investigated associations between
the -174G>C polymorphism (rs1800795) of the IL6 gene and phenotypes
related to type 2 diabetes mellitus (T2DM), but presented inconsistent
results . This joint analysis aimed to clarify whether IL6 -174G>C
was associated with the quantitative phenotypes circulating glucose,
body-mass-index (BMI), and circulating interleukin-6 (IL-6) .
Methods: Individual participants’ data from all published and unpublished
studies of the IL6-T2DM consortium on Caucasian subjects with
available BMI were collected. As study-specific estimates did not show
heterogeneity (P>0 .1), they were combined by using the inverse-variance
fixed-effect model.
Results: The main analysis included 9440, 7398, 24,117, or 5659 nondiabetic
and manifest T2DM subjects for fasting glucose, 2-h glucose,
BMI or circulating IL-6, respectively . The IL6 -174 CC- and GC-genotypes
were significantly associated with -0.091mmol/L (P=0.014) lower
fasting glucose . There was no evidence for association between IL6
-174G>C and BMI or IL-6 levels . In an additional analysis of 641 subjects
known to develop T2DM later on, the IL6 -174 CC-genotype was
associated with higher baseline IL-6 levels (+0 .75pg/mL, P=0 .004),
which was consistent with higher IL-6 levels in the 966 manifest T2DM
subjects (+0 .50pg/mL, P=0 .044) .
Conclusions: Our data on the widely debated IL6 -174G>C polymorphism
suggest an association with quantitative glucose, and exploratory
analysis indicated modulated IL-6 levels in pre-diabetic subjects,