2008 Barcelona - European Society of Human Genetics

Molecular and biochemical basis of disease
decreased gene expression in lymphoblastoid cell lines . No association
was observed for the polymorphisms in the OCT2 and OCT3
genes . Additionally, previously suggested effect of the “silence” A411A
polymorphism on the OCT3 splicing could not be validated in exontrapping
experiments .
In conclusion, genetic variants in humanOCT1 but not in OCT2 and
OCT3 genes were associated with alternation in the metabolism of
metformin . The best explanation of our data is that OCT1 is involved to
some extend in tubular reabsorption of metformin .
P06.217
interferon regulatory factor 6 (iRF6) variation contributes to oral
clefts in south America
I. M. Orioli 1 , R. F. Fonseca 1 , A. R. Vieira 2 , E. E. Castilla 3,4 ;
1 ECLAMC at Genetics Department, Federal University of Rio de Janeiro, Rio
de Janeiro, Brazil, 2 Departments of Oral Biology and Center for Craniofacial
and Dental Genetics, School of Dental Medicine, University of Pittsburgh,
Pittsburgh, PA, United States, 3 ECLAMC at Instituto Oswaldo Cruz, Rio de
Janeiro, Brazil, 4 ECLAMC at CEMIC (Center for Medical Education and Clinical
Research), Buenos Aires, Argentina.
Interferon regulatory factor 6 (IRF6) has been associated with nonsyndromic
(NS) oral-facial clefts (OFC) . ECLAMC (Latin American
Collaborative Study of Congenital Malformations) population that was
included in the original IRF6 association study [Zucchero et al ., 2004]
did not show association . Six SNPs within and in the boundaries of the
IRF6 gene were genotyped to test for association with OFC in 304 trios
of affected newborn patients and their parents . The ECLAMC samples
were from Argentina, Bolivia, Brazil, Chile, Ecuador, Colombia, and
Venezuela; there were 168 cases of isolated cleft lip with or without
cleft palate (CL/P), 47 isolated cases with cleft palate only (CPO), and
73 cases with OFC and other defects. The most significant results
were for SNPs rs 17015215 (VAL274I) in all OFC (p=0 .0002), and isolated
CL/P (p=0 .0004), and rs 2013162 in isolated CPO (p=0 .0009) .
Suggestive results were also found for SNPs rs 861019 in all OFC
(p=0 .05), CL/P (0 .05), and CPO (p=0 .02), and rs 17015215 (VAL274I)
(p=0 .048), and rs 2073487 (p=0 .048) in CPO . No association was
found in the OFC group associated with other defects . Our results
demonstrate that variation in IRF6 is a significant genetic contributor to
OFC in South American populations .
P06.218
Allelic variants of iL1R1 and iL1RL2 genes associate with severe
hand osteoarthritis
A. Näkki 1,2 , S. Kouhia 1 , J. Saarela 1 , A. Harilainen 3 , K. Tallroth 3 , T. Videman 4 , M.
C. Battié 4 , J. Kaprio 2 , L. Peltonen 1,5 , U. M. Kujala 6 ;
1 National Public Health Institute, Helsinki, Finland, 2 University of Helsinki, Helsinki,
Finland, 3 ORTON Orthopedic Hospital, Helsinki, Finland, 4 University of
Alberta, Edmonton, AB, Canada, 5 Wellcome Trust Sanger Institute, Hinxton,
Cambridge, United Kingdom, 6 University of Jyväskylä, Jyväskylä, Finland.
Objective. In search for genes predisposing to osteoarthritis (OA), several
genome wide scans have provided evidence for linkage on 2q . In
this study we targeted a 470 kb region on 2q11 .2 presenting the locus
with most evidence for linkage to severe hand OA in our previous genome
wide scan families .
Methods. We genotyped 32 single nucleotide polymorphisms (SNPs)
in this 470 kb region comprising 6 genes belonging to the interleukin
1 superfamily . We monitored for association with individual SNPs and
SNP haplotypes among severe bilateral hand OA cases (n=107) and
also end-stage bilateral primary knee OA cases (n=113) and controls
(n=436) .
Results. In a single SNP analysis with hand OA material, we found a
significant association to a 174 kb region, covered by a single haplotype
block, comprising genes IL1R1 and IL1RL2 (p-value=0 .001) .
Haplotype analysis provided further evidence for the IL1R1 gene .
Conclusion. This study demonstrates a consistent association between
hand OA and gene IL1R1. But since the associated SNPs are
part of a wide LD block, we cannot unequivocally confirm which of
the two genes explains the observed association . IL1R1 and IL1RL2
represent highly relevant candidate genes since they encode proteins
that are known modulators of inflammatory processes associated with
joint destruction .
P06.219
Association of polymorphisms and haplotypes in the 5’ region of
COL A gene with BmD and osteoporotic fractures in Russian
women from Volga-Ural region
L. Selezneva 1 , R. Khusainova 1 , E. Fazlyeva 2 , R. Nurligayanov 3 , E. Khusnutdinova
1 ;
1 Institute of Biochemistry and Genetics, Ufa, Russian Federation, 2 City Clinical
Hospital no. 5, Ufa, Russian Federation, 3 City Clinical Hospital no. 21, Ufa,
Russian Federation.
The collagen type I alpha 1 (COL1A1) gene is a strong candidate for
susceptibility of osteoporosis . We analyzed the possible association of
the COL1A1 genotypes and haplotypes, defined by -1997G/T, -1663indelT
and SpI polymorphisms in 340 Russian postmenopausal women .
Patients with chronic diseases and conditions which may potentially
affect bone mass were excluded . The -1997G/T, -1663indelT and SpI
polymorphisms were in strong linkage disequilibrium (D’ = 0 .66-0 .95) .
The distribution of three common haplotypes in our population was
as follow: -1997*G/-1663*insT/*S - 62 .2%, -1997*T/-1663*insT/*S
- 19 .9%, -1997*G/-1663*delT/*s - 14 .9% . The SpI and -1663indelT
polymorphisms were associated with BMD: homozygote carries of the
SpI*S allele had increased BMD (p=0 .035 for FN-BMD; p=0 .015 for
LS-BMD) and homozygotes for the -1663*insT allele had higher values
of BMD (p=0 .017 for FN-BMD; p=0 .009 for LS-BMD) . There was a significant
association between the -1997*G/-1663*delT/*s haplotype and
FN-BMD (p=0 .01) with reduced BMD values in homozygote carriers
of the haplotype -1997*G/-1663*delT/*s (p=0 .023 from carries of no
copies of the haplotype by Tukey’s post-test) . We found an association
of the -1663*I*D genotype (OR=1 .7; 95%CI 1 .06-2 .71; p=0,024)
and the -1663*delT allele (OR=1 .6; 95%CI 1 .09-2 .4; p=0,015) with
osteoporotic fractures . The association of the -1997*G/-1663*delT/*s
haplotype with fractures was nominally significant (p=0.04), but these
did not reach the threshold for significance when multiple testing was
considered. There was no significant association of the -1997G/T polymorphism
with BMD or fractures in our population . Our results suggest
that the COL1A1 gene is a susceptibility locus for osteoporosis in postmenopausal
Russian women from Volga-Ural region .
P06.220
Epidemiological and genetic studies of otosclerosis with a new
locus Otsc8 in tunisian population
I. Bel Hadj Ali1 , M. Thys2 , N. Beltaief3 , E. Mnif3 , G. Besbes3 , G. Van Camp2 , S.
Ben Arab1 ;
1 2 Faculté de Médecine de Tunis, Tunis, Tunisia, Center of Medical Genetics,
Antwerp, Belgium, 3Hôpital La Rabta, Tunis, Tunisia.
Otosclerosis is a very common hearing impairment among Caucasians
with a prevalence of about 0 .3-0 .4% among white adults . In Tunisia,
clinical otosclerosis has a prevalence of 0 .4 to 0 .8 . Our aim is to perform
an epidemiological, genetic and linkage analyses of otosclerosis
in northern Tunisia .
Segregation analysis were performed and showed that the pattern of
the disease is due to a rare dominant major gene with a high polygenic
component .
Our study showed that in north-eastern areas of Tunisia, the sex ratio
in probands with clinical otosclerosis being twice as often in women
than in men . This probably suggests that an endocrine mechanism
and/or biochemical factor are involved in disease aetiology . However,
in north-western areas, there was no significant difference between
the rates of otosclerosis between sexes .
Geographical distribution of affected subjects according to the ethnic
origin of their parents showed that the areas with the highest concentration
of affected individuals were urban or seaside areas . The frequency
of otosclerosis was lower in rural areas and/or areas far from
the seaside .
Genetic study was undertaken in some genealogies segregating
autosomal dominant otosclerosis and linkage analysis showed that
three families are linked to the known loci responsible of otosclerosis
(OTSC1, OTSC2, and OTSC3) . For the fourth family, the genome wide
linkage analysis was performed and revealed a new otosclerosis locus
named OTSC8 .
The presence of a genetic factor associated with hormonal, biochemical
or environmental factors, probably lead to variable expression of
the otosclerosis according to age and sex .