2009 Vienna - European Society of Human Genetics

Evolutionary and population genetics, and Genetic epidemiology
candidate gene UDP-glucuronosyltransferase (UGT1A1). The activity
of this enzyme is significantly influenced by a TA-repeat polymorphism
in the promoter of the gene. In a prospective study individuals with
genotype (TA)7/(TA)7 had significantly higher bilirubin levels and approximately
one third the risk of CVD as carriers of the wild type (TA)6
allele. In the present study we performed a conditional linkage study to
investigate whether this polymorphism explains the observed linkage
peak and extended our analysis by a genome-wide association study
on bilirubin levels in 1345 individuals.
Results: After adjustment for the bilirubin variance explained by this
polymorphism, the LOD score on chromosome 2q dropped from 3.8 to
0.4, demonstrating that this polymorphism explains the previous linkage
result. For the genome-wide association study, the closest marker
to UGT1A1 was in the top ranking SNPs. The association became
even stronger when we considered the TA-repeat polymorphism in the
analysis (p=2.68x10-53). Five other SNPs in other regions reached
genome-wide significance without obvious connection to bilirubin metabolism.
Conclusions: Our studies suggest that UGT1A1 may be the major
gene with strong effects on bilirubin levels and the TA-repeat polymorphism
might be the key polymorphism within the gene controlling
bilirubin levels. Since this polymorphism has a high frequency and a
substantial impact on the development of CVD, the gene might be an
important drug target.
P10.33
Polymorphism of some cytokines genes in connection with age
gradation
V. V. Pauk, I. A. Tuktarova, T. R. Nasibullin, O. E. Mustafina;
Institute of Biochemistry and Genetics, Ufa, Russian Federation.
Aim of study was to investigate IL6 (-572G/C), IL10 (-627C/A), IL12B
(1159A/C) and TNFA (-308G/A) gene polymorphisms in connection
with age gradation.
Total group (1627 individuals, from 1 to 109 years old, ethnic Tatars,
Russia) was divided into young (1-20), middle-age (21-55), aged (56-
74), senile (75-89) and long-living (90-109) persons. Gene polymorphism
was analyzed by PCR-RFLP. Fisher’s two-tailed exact test was
used for age groups comparison.
Among aged persons IL6(-527)*G/*G genotype frequency was
higher than in middle-age group (80.0% vs. 69.28%, P=0.004). IL6(-
527)*G/*C genotype frequency was lower in group of long-livers than
in middle-age group (15.79% vs. 27.9%, P=0.006). IL6(-527)*C/*C
genotype frequency was lower in aged (0%, P=0.005) and senile
groups (0.56%, P=0.03) than in middle-age group (2.82%). In middleage
group IL10(-627)*C/*C genotype frequency (56.09%) was higher
in comparison with aged (47.83%, P=0.034), senile (43.53%, P=0.005)
and long-livers groups (43.28%, P=0.015). Accordantly, in this group
IL10(-627)*C/*A genotype frequency (34.56%) was lower than in aged
(42.61%, P=0.03), senile (45.54%, P=0.002) and long-livers groups
(46.27%, P=0.021). IL12B(1159A/C)*C/*C genotype frequency is
higher in senile group than in middle-age group (6.78% vs. 3.21%,
P=0.049). In aged and senile groups TNFA(-308)*G/*G genotype frequencies
were 71.39% and 79.37%, TNFA(-308)*A/*G genotype frequencies
- 26.08% and 18.53% accordantly (P=0.02).
Thus, genotypes frequencies changes of studied genes in various age
groups are traced. This data allow considering cytokines genes as associated
with life span.
The research was particular supported by Grant RFH 08-06-00426a.
P10.34
Genetic study of 45 big hearing loss pedigree and GJB2 gene
mutations frequency in a province of iran
E. Farrokhi1 , S. Shirmardi2 , A. Khoshdel1 , S. Amani1 , M. Soleimani2 , M. Kasiri2 ,
J. Rahbarian2 , N. Parvin3 , N. Shahinfard3 , Z. Noaparast4 , A. Salehifard1 , M.
Afzal1 , M. Shirani5 , M. Hashemzadeh1 ;
1Cellular and Molecular Research Center,Shahrekord University of Medical Sciences,
Shahrekord, Islamic Republic of Iran, 2Ministry of Welfare Chaharmahal
va Bakhtiari province, Shahrekord, Islamic Republic of Iran, 3Medical Plants
Research Center, Shahrekord University of Medical Sciences, Shahrekord,
Islamic Republic of Iran, 4Ministry of Welfare, Tehran, Islamic Republic of Iran,
5School of Public Health, Zabol University of Medical Sciences, Zabol, Islamic
Republic of Iran.
Background and aim: Hearing loss is the most common sensorineural
disorder in human. This disorder is heterogeneous and happens due
to genetic or environmental causes or both. Mutations in the GJB2
gene have been involved in deafness in many populations. This study
aims to investigate genetic epidemiology and frequency of GJB2 gene
mutations in 45 big deaf pedigrees.
Methods: In this genetic epidemiology study we have investigated 45
big deaf pedigrees concerning inheritance patterns consanguinity and
diversity of deafness severity among siblings using data collected by
questionnaires and audiograms. We examined also the frequency and
profile of GJB2 gene mutations in 45 probands using direct sequencing
strategy.
Results: Our study revealed 73% of consanguinity in the deaf pedigrees
studied from which first cousins marriage was the more common
with the rate of 49%. The most common type of first cousins marriage
was found between first cousin who were the children of two brothers.
We found autosomal recessive and X-linked recessive pattern in 94-
97% and 3-6% of the pedigrees studied respectively.
We found also 57% of diversity (mild to profound) of deafness severity
among deaf siblings GJB2 mutations were found in 11% of population
studied including 35delG, 167delT, 299-300delAT and 363delC.
Conclusion: A high rate of consanguineous marriage determined in this
study could rise the rate of autosomal recessive patterns up to 94-97%
of the overall pedigree and would be the main cause of congenital
deafness. This study revealed a low contribution of GJB2 gene mutations
in Chaharmahal va Bakhtiari Province.
P10.35
GJB2 carrier screening with ultrasonographic measurement of
epidermal thickness.
V. I. Guerci 1 , P. Guastalla 2 , D. Stefanidou 3 , D. L. Grasso 4 , A. Fabretto 1 , F. Faletra
1 , A. P. D’Adamo 5 , L. Ronfani 6 , P. Gasparini 1,5 ;
1 Dipartimento di Scienze della Riproduzione e Sviluppo, Trieste, Italy, 2 Radiology
Unit, IRCCS Burlo Garofolo, Trieste, Italy, 3 Sinfony, Bologna, Italy, 4 ENT
Unit, IRCCS Burlo Garofolo, Trieste, Italy, 5 Genetics Unit, IRCCS Burlo Garofolo,
Trieste, Italy, 6 Epidemiology Unit, IRCCS Burlo Garofolo, Trieste, Italy.
Inherited hearing loss (IHL), affecting 1/1000 children, represents an
important public health issue and implies disability, expensive interventions
and rehabilitation. The most frequent cause of IHL, due to
mutations in GJB2 gene, presents a high carrier frequency worldwide.
There are no means to identify them apart from expensive DNA- methods.
Recently high epidermal thickening due to GJB2 carrier status
was suggested. We used skin ultrasonography measurement of epidermal
thickness in a series of controls and obligate carriers. 273 individuals
were tested by ultrasonography using a linear band probe to
determine their epidermal thickness. Variance and linear regression
analyses were carried out. Regression coefficients were used to obtain
scores of thickness corrected by age and sex. Carriers presented significant
increase in epidermal thickness as compared to controls, GJB2
status explaining 50% of this variability. Results led to the development
of a screening protocol with 98% of sensitivity and 93% specificity, in
subjects aged 20-80, with a likelihood ratio of a positive test of 14 to 1.
Better results were obtained studying people in reproductive age. The
availability of a simple, non-invasive, rapid, sensitive, and cheap ultrasonographic
protocol opens new perspectives for carrier screening in
the population. Present data further supports the role of skin thickness
as major selective advantage for GJB2 carriers.
Bibliography
D’Adamo et al. Does epidermal thickening explain GJB2 high carrier
frequency and heterozygote advantage? Eur J Hum Genet. 2008 Dec
3.
Guastalla et al. Epidermal sonography can detect epidermal thickening
in GJB2 carriers. Radiology. Radiology; 2009.Feb3.
P10.36
Genome-wide interaction Analysis Guided by A Priori
information
C. Herold, T. Becker;
Institute for Medical Biometry, Informatics and Epidemiology, Bonn, Germany.
Complex diseases are caused by interacting genetic and environmental
factors. Due to computational burden, genome-wide association studies
(GWAS) are typically limited to single-marker analysis. We present