2008 Barcelona - European Society of Human Genetics

Normal variation, population genetics, genetic epidemiology
University of Lisbon, Lisboa, Portugal.
There is growing evidence that certain mtDNA haplogroups determine
a genetic susceptibility to various disorders bringing out the interest
in the possible role of mtDNA background on the phenotype expression
of mitochondrial genetic disorders . An association between haplogroup
T and asthenospermia has been reported and several sublineages
of haplogroup U were associated with differences in sperm
motility and vitality . The deletion of some DAZ copies gene in 10-15%
of azoospermic and oligospermic patients has been reported but also
present in fertile men belonging to certain Y-haplogroups. The findings
of one study have rarely been replicated by studies in other populations
and conflicting associations have been reported. Our focus in this
case-control study is to investigate the existence of other influences,
besides a weak mtDNA background, promoting male infertility . The occurrence
of a specific mtDNA variant associated to a certain Y-chromosome
haplogroup could represent a vital link that will compromise
the sperm function and be responsible for male infertility . A group of
99 infertile men and other one composed by 90 subjects with proven
fertility were selected and analysed . The frequency of the combination
mtDNA-haplogroup H (especially with the CRS sequence) and Yhaplogroup
R was higher in fertile than in infertile men seemingly to
be favorable to fertility . On the other hand, a considerable number of
infertile men belonging to mtDNA-haplogroup H (CRS) and to Y-haplogroup
I, associated to a specific DAZ gene deletion pattern- 2+4d,
suggests a non favorable combination to male fertility .
P07.085
Genetic risks factors for melanoma development in Latin
America
F. Cuellar 1,2 , A. Larre-Borges 3,4 , B. Carlos 5,6 , J. Puig-Butille 1,2 , V. Godinez 7,6 , J.
Salas 8,6 , Z. Ogbah 1,2 , J. Malvehy 1,2 , S. Puig 1,2 ;
1 Hospital Clinic, IDIBAPS, Barcelona, Spain, 2 GenoMEL, Barcelona, Spain,
3 Hospital de Clinicas, Montevideo, Uruguay, 4 GenoMEL, Latinamerica, Uruguay,
5 Centro Medico Nacional IMSS, Mexico City, Mexico, 6 GenoMEL, Latinamerica,
Mexico, 7 Facultad de Medicina UNAM, Mexico city, Mexico, 8 Hospital
Universitario UANL, Monterrey, Mexico.
Introduction: Genetics of Melanoma network (GenoMEL) is focused in
melanoma genetic susceptibility in Europe, Australia, North America
and Israel . Nowadays GenoMEL is obtaining samples and data from
Latin America .
Objective: To Study well-known genes for melanoma (MM) susceptibility
(CDKN2A/ p14arf, CDK4, MC1R) in familial and multiple primary
MM in Latin America .
Methods: In a total period of three years (2001-2009) patients with
genetic susceptibility for MM from Latin America .
Results: Until now we have analysed 16 pedigrees (25 individuals)
from Mexican and Uruguayan pedigrees and identified the I49T, M52T
CDKN2A mutations in Mexico and E88X, -34G>T, G101W in Uruguay .
The percentage of CDKN2A mutation was 100% in families with 4 MM
cases (1/1 family), 25% in 3 MM (1/4), 55 .5% in 2 MM (5/9), and no
mutation in 2 MPM without familial history .
Conclusion: CDKN2A mutations are responsible of MM susceptibility
in familial MM in Latin America . CDKN2A mutations with founder effect
(G101W, -34G>T) were detected in Uruguay . Nonsense germline
E88X CDKN2A mutation was detected in two unrelated Uruguayan
families . M52T mutation detected in Mexico was not previously described
. One MPM Mexican patient was believed homozigote for I49T
by sequencing but later MLPA showed deleted exon 1 alfa .
P07.086
Variants in the Vitamin D Receptor Gene and melanoma Etiology
L. P. Fernandez1 , E. Barroso1 , R. L. Milne1 , G. Pita1 , M. Tanic1 , J. A. Aviles2 , P.
Lazaro2 , J. Benitez1 , G. Ribas1 ;
1 2 Spanish National Cancer Research Centre (CNIO), Madrid, Spain, Hospital
Gregorio Marañon, Madrid, Spain.
The aetiology of malignant melanoma (MM) remains unclear but it is
known that both genetic and environmental factors influence the development
of sporadic disease . The main reason for the increasing
incidence of MM in the general population is greater sun exposure .
Epidemiologic studies confirm that UV radiation is the main factor involved
in the pathogenesis of the disease . Among phenotypic factors,
fair pigmentation and low tanning ability are the most important risk
factors . In recent years there has been a increasing interest in the
role of vitamin D and its active metabolites in MM susceptibility . Sunlight
induces production of vitamin D that has been associated with
antiproliferative and pro-differentiative effects in both melanocytes and
cutaneous melanoma cells mediated through the vitamin D receptor .
In this study we explore the interaction between sunlight exposure and
vitamin D receptor gene polymorphisms in the etiology of MM .
This case-control study included 131 consecutive Spanish MM patients
from the Dermatology Unit of the Gregorio Marañón Hospital and
245 control subjects frequency matched for sex and age . Phenotypic
information was collected using a standardized questionnaire .
Four SNPs in the vitamin D receptor gene (VDR) were genotyped .
SNPs on exons or in the putative promoter region were selected . We
were able to identify several individual SNPs and haplotypes associated
with tumoral characteristics such as breslow index and melanoma
location . We also discuss the role of VDR variants as possible markers
for MM and its agresiveness .
P07.087
An Empirical comparison of meta-Analyses of Published Gene-
Disease Associations Versus consortium Analyses
A. C. J. W. Janssens 1 , A. M. González-Zuloeta Ladd 1 , S. López-Léon 1 , J. P. A.
Ioannidis 2 , B. A. Oostra 1 , M. J. Khoury 3 , C. M. van Duijn 1 ;
1 Erasmus MC, Rotterdam, The Netherlands, 2 University of Ioannina School
of Medicine, Ioannina, Greece, 3 Centers for Disease Control and Prevention,
Atlanta, GA, United States.
Background: Consortia of investigators currently compile sufficiently
large sample sizes to investigate the effects of low-risk susceptibility
genetic variants . It is not clear how the results obtained by consortia
compare with those derived from meta-analyses of published studies .
We performed meta-analyses of published data for 16 genetic polymorphisms
investigated by the Breast Cancer Association Consortium
and compared sample sizes, heterogeneity, and effect sizes .
Methods and findings: PubMed, Web of Science, and HuGENet databases
were searched for breast cancer case-control association
studies. Summary odds ratios (ORs) and 95% confidence intervals
were calculated for three genetic models (homozygotes, heterozygotes,
and per-allele comparisons), using random effects analyses .
The strength of the epidemiological evidence was evaluated on the
basis of recently proposed criteria . We found that meta-analyses of
published data and consortium analyses were substantially based on
different data . Published data by non-consortium teams amounted on
average to 26 .9% of all available data (range 3 .0%-50 .0%) . The correlation
coefficient of the I2 heterogeneity estimates of the two approaches
was 0 .47 (p=0 .001), and that of the OR estimates was 0 .44
(p=0 .002) . The meta-analyses of published data and the consortium
analyses both showed statistically significant decreased breast cancer
risks for CASP8 D302H, and all meta-analyses were graded as having
“strong” evidence .
Conclusion: Meta-analysis of published gene-disease associations
may still have an important role in the synthesis of knowledge on the
genetic basis of human diseases . The expense and complexity of
consortium-based studies should be considered vis-à-vis the potential
methodological limitations of synthesis of published studies .
P07.088
Recessive congenital methemoglobinemia type i in Yakutia: the
frequency of disease gene and age of the mutation
N. Galeeva, V. Spitsin, A. Polyakov;
Research Centre for Medical Genetics, Moscow, Russian Federation.
Recessive congenital methemoglobinemia (RCM) type I is defined
by cyanosis due to methemoglobinemia and an isolated deficiency of
NADH-cytochrome b5 reductase (b5R) in erythrocyte . This disease is
rare in the world but frequent in Sakha Republic (Yakutia) of Russia .
In research based on clinical evidence frequency of RCM in Yakutia
amounted to 1:5677 .
In previously investigation has been showed that all RCM cases here
were caused by single mutation c .806 C>T in DIA1 gene that suggested
presence founder effect for this disease in Yakutia . Allelic frequency
of the mutation amounted to 0 .025 and calculated frequency of
disease amounted to 1:1600 .
The date of diffusion of the mutation has been calculated by linkage
disequilibrium between disease locus and markers closed to it . The
age of mutation is approximately 310 years .