2008 Barcelona - European Society of Human Genetics

Molecular and biochemical basis of disease
P06.147
A haplotype of the lipopolysaccharide-binding protein gene is
associated with susceptibility to severe sepsis
C. Flores 1,2 , E. Espinosa 3 , L. Pérez-Méndez 1,2 , N. Maca-Meyer 1 , R. Sangüesa 3 ,
A. Muriel 4 , J. Blanco 2,4 , M. Muros 2,5 , J. G. N. Garcia 6 , J. Villar 2,7 ;
1 Unidad de Investigación, Hospital Universitario N.S. de Candelaria, Santa
Cruz de Tenerife, Spain, 2 CIBER de Enfermedades Respiratorias, (CIBERes),
Spain, 3 Department of Anesthesia, Hospital Universitario N.S. de Candelaria,
Santa Cruz de Tenerife, Spain, 4 Intensive Care Unit, Hospital Universitario
Río Hortega, Valladolid, Spain, 5 Department of Clinical Biochemistry, Hospital
Universitario N.S. de Candelaria, Santa Cruz de Tenerife, Spain, 6 Pulmonary
and Critical Care, Department of Medicine, University of Chicago, Chicago,
IL, United States, 7 Multidisciplinary Organ Dysfunction Evaluation Research
Network, Research Unit, Hospital Universitario Dr. Negrín, Las Palmas de Gran
Canaria, Spain.
The lipopolysaccharide-binding protein (LBP) is an acute phase protein
that plays a dominant role in the genesis of sepsis by initiating
signal transduction pathways leading to the activation of the inflammatory
host response . A single nucleotide polymorphism (SNP) of the
LBP gene has been previously associated with an increased risk for
sepsis but gene-wide association studies are lacking . Here we evaluated
the association of common variants across the entire LBP gene
with susceptibility to severe sepsis by genotyping 10 selected SNPs,
including a subset of tagging SNPs that efficiently captured common
variation across the gene, in 176 severe cases of sepsis and 364
population-based controls . Although individual SNPs resulted non-significantly
associated after adjusting for multiple testing, a haplotype
extending ~1.2 kb in the 5’-flanking region of LBP gene, crucial for
in vitro gene inducibility by cytokines, showed a significant association
with susceptibility to severe sepsis (p=0 .001, permuted p=0 .025) .
Homozygous carrier patients of the haplotype had an elevated risk for
severe sepsis (odds ratio: 2.21; 95% confidence interval: 1.39-3.51;
p=0 .0006) and this result was unaffected by covariate and population
stratification adjustments. These patients also showed a consistent
elevation of mean serum LBP concentrations across days examined .
Taken together, these results support that common variation in LBP
gene contributes to susceptibility to severe sepsis .Supported by grants
from FUNCIS (37/02) and Ministerio de Educación y Ciencia, Spain
(SAF 2004-06833)
P06.148
Effects of LcAt polymorphisms on HDL-c levels in turkish
population.
D. Agirbasli 1 , M. A. Agirbasli 2 , M. Sumerkan 2 , C. Aral 1 , S. Aksoy 3 , S. Karabulut
1 , B. Cirakoglu 1 ;
1 Department of Medical Biology and Genetics, Marmara University Medical
School, Istanbul, Turkey, 2 Department of Cardiology, Marmara University Medical
School, Istanbul, Turkey, 3 Siyami Ersek Cardiovascular Hospital, Istanbul,
Turkey.
High density lipoprotein cholesterol (HDL-C) protects from vascular
diseases. Genetic and environmental factors influence HDL-C levels.
Low HDL-C is common among Turks . Nearly 50 % of the population
has HDL-C levels below 35 mg/dl . Lecithin cholesterol acyltransferase
(LCAT) takes part in reverse cholesterol transport and HDL-C maturation.
The objective of our study is to evaluate the effects of 3 polymorphisms
in LCAT gene on HDL-C levels . Study consists of 50 subjects
with low HDL-C levels (65 mg/dl) . We studied 511C/T polymorphism (exon 4),
4886C/T (exon 6), 608C/T (exon 5) . Although single locus effects of
the 3 polymorphisms of LCAT gene were not significantly related to the
HDL levels, when combined effects are studied, the subjects with total
of less than 2 high risk alleles had significantly higher HDL-C levels
compared to subjects with 2 or more high risk alleles (56±27 vs 44±
23, p=0.04). Multiple linear regression was performed to find the predictors
of HDL-C . The variables were body mass index (BMI), glucose,
age, smoking (number of pack years), number of high risk alleles . Age
and smoking were the strongest predictors of HDL-C . However, after
controlling for age and smoking, there was a negative correlation
between the number of high risk alleles and HDL-C levels with borderline
statistical significance (p=0.07).
These 3 genetic polymorphisms are susceptibility loci and are neither
necessary nor sufficient for prediction of HDL-C, but co-existence of
high risk alleles may contribute to low HDL-C levels .
P06.149
A study of LRRK2 mutations in Parkinson‘s disease patients
from the Volga-Ural region of Russia
I. Gilyazova1 , E. Simons2 , E. Khusnutdinova1 , I. Khidiyatova1 , G. Breedveld2 , B.
Oostra2 , R. Magzhanov1 , V. Bonifati2 ;
1Institute of Biochemistry and Genetics,Ufa Science Centre, RAS, Ufa, Russian
Federation, 2Erasmus MC Rotterdam, Rotterdam, Netherlands Antilles.
Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene have been
shown to cause both autosomal dominant and sporadic Parkinson’s
disease (PD) . The common G2019S mutation shows wide geographical
distribution while G2385R and I2020T variants are suggested to
be risk factors for sporadic PD in Asian populations . The frequency
of these mutations in the Volga-Ural region of Russia remained to be
established . To determine the prevalence of G2019S, G2385R, I2020T
mutations in the Volga-Ural region, we recruited 341PD patients (129
Russians, 156 Tatars and 56 Bashkirs) and 360 controls (103 Russians,
131 Tatars, 126 Bashkirs) and conducted genetic analysis of
these mutations . All patients exhibited at least two of the four principal
signs of PD: resting tremor, rigidity, bradykinesia, or postural-reflex impairment
. Exclusion criteria included prior history of multiple cerebrovascular
events or other causes of parkinsonian symptoms . Controls
were matched for age, ethnic origin and area of residence . Heterozygous
G2019S was detected in one late-onset Bashkir patient with
akinetic-rigid-trembling form (1 .79%) . Interestingly, that this patient
doesn’t carry a SNP in intron 13 (IVS13+104 G/A) which is in strong
LD with the mutation and tags the commonest haplotype shared by all
patients with this mutation in the Mediterranean populations .
The “Asian” risk factor, G2385R, was rare, but found in 2 Tatar PD patients
(1 .28%) . We observed no I2020T mutations in this study sample .
All mutations were confirmed by direct sequencing. These data have
implications both for understanding the molecular mechanisms of PD,
and for directing the genetic screening in clinical practice .
P06.150
Genetic Diagnosis and investigations of Disease LHON and
cPEO
M. Houshmand;
NIGEB, Tehran, Islamic Republic of Iran.
Leber hereditary optic neuropathy (LHON) is a maternally inherited
form of retinal ganglion cell degeneration leading to optic atrophy in
young adults . To investigate any possible association between LHON
primary mutations and
mtDNA haplogroups, the nucleotide sequence of the HVS-I region of
mtDNA was determined in 30 unrelated Iranian patients with LHON
harboring one of the primary mutations and 100 normal controls with
the same ethnicity . Our analysis revealed a relatively high proportion of
haplogroup J in LHON patients (53 .3%) compared to normal controls
(20%). In addition, a slightly significant increase of normal controls of
haplogroup L has been confirmed (14% in normal controls vs. 0% in
LHON patients at p 5 0 .03), whereas other haplogroups did not show
contribution to LHON contingency. We identified twelve nucleotide
substitutions . Eleven of twelve nucleotide substitutions had already
been reported as polymorphism . One of the nucleotide substitutions
(A14290G) has not been reported . The A14290G nucleotide substitution
does not change its amino acid . Different sizes of mtDNA deletions
were detected in 16 patients (69 .6%) . Each of the 5 .5, 7, 7 .5 and 9 kb
deletions existed only in 1 patient . Common deletion (4977bp) and 8
kb deletion were detected in 5 and 3 patients respectively . Multiple
deletions were also present in 4 patients . Out of 23 patients included
in our study, two cases (8 .7%) had Twinkle gene mutation (G1423C)
and 5 patients (21 .7%) did not show any deletions in mtDNA or the
Twinkle gene mutation .
P06.151
A visual aura locus for migraine on chromosome 9q31
P. Tikka-Kleemola 1 , S. Vepsäläinen 1,2 , V. Artto 1,2 , M. Kaunisto 1,3 , V. Anttila 1,4 , E.
Hämäläinen 1,4 , M. Färkkilä 1,2 , M. Kallela 1,2 , M. Wessman 1,3 , A. Palotie 1,4 ;
1 University of Helsinki, Biomedicum Helsinki, Helsinki, Finland, 2 Department of
Neurology, Helsinki University Central Hospital, Helsinki, Finland, 3 Folkhälsan
Research Center, Helsinki, Finland, 4 The Wellcome Trust Sanger Institute,
Hinxton, United Kingdom.
Migraine is the most common cause of chronic episodic severe headache
affecting approximately 15 % of the adult population . It has a