European Human Genetics Conference 2007 June 16 – 19, 2007 ...

Concurrent Symposia
S07. Vertebrate miRNA diversity
E. Cuppen;
Hubrecht Laboratory, Utrecht, The Netherlands.
MicroRNAs are 20- to 23-nucleotide RNA molecules that can regulate
gene expression. Currently over 400 microRNAs have been experimentally
identified in mammalian genomes, whereas estimates go up
to 1000 and beyond. We have used bioinformatic and experimental
(microarray-based detection and massively parallel sequencing) approaches
to get insight in the vertebrate microRNA repertoire and evolutionary
dynamics.
Analysis of the microRNA content of human and chimpanzee brain
regions resulted in the identification of hundreds of novel microRNAs
genes, many of which are not conserved beyond primates, indicating
their recent origin. Others are expanded in one species through duplication
events, suggesting that evolution of microRNAs is an ongoing
process and that along with ancient, highly conserved microRNAs,
there are a number of emerging microRNAs that could contribute to
evolutionary processes and differences in human and chimpanzee
brain function.
S08. SLE susceptibility genes
T. J. Vyse;
Imperial College, Molecular Genetics and Rheumatology Section, London,
United Kingdom.
SLE is a generalised autoimmune disease affecting a wide range of
tissues including skin, joints, bone marrow and kidneys, which afflicts
~10,000 individuals in the UK. The disease is characterised by the
production of autoantibodies to nuclear and cell-surface antigens. The
cause of the disease is poorly understood although genetic factors
contribute. The strategy adopted is to use both family-based and casecontrol
methods to ascertain genetic association with SLE. To achieve
this we have established large collections of SLE cases (n=500) and
families (n=850). We have analysed approximately 100 different genes
(based on functional and positional candidacy) and found convincing
evidence to support the role of genetic variation in five of these in SLE
susceptibility.
How nuclear autoantigens are targeted in SLE has been a subject of
controversy. Nucleic acids can bind Toll-like receptors on antigen presenting
dendritic cells, which stimulates an interferon response and
thereby augments dendritic cell function. Interferon regulatory genes
(IRFs) are key molecules within this amplification loop and we have
shown that patients with lupus are almost twice as likely to carry genetic
variants in IRF5 that generate more transcripts, in part due to
differential polyadenylation. Autoantibodies in SLE are of the IgG isotype
and bind with high affinity to their targets, implicating the adaptive
immune system in pathogenesis. We examined a number of candidate
genes acting at the T-B lymphocyte interface and identified associations
with SLE at the CTLA4 locus and a stronger signal arising from
the tumour necrosis factor family member, OX40L. Finally, the IgG Fc
receptor locus on human chromosome 1q23 has been extensively
studied in autoimmunity genetics. We have provided strong evidence
that the locus does contribute to the risk of SLE as a result of copy
number variation. Reduction in neutrophil FCGR3B expression predisposes
to end organ damage in the kidney, probably through defective
removal of immune complexes.
In conclusion, we have identified lupus susceptibility genes operating
in both the adaptive and innate immune systems. Gene effects promote
initial autoantigen targeting, aberrant regulation of the immune
response and finally accentuate end organ damage.
S09. New pathways in pathogenesis of allergic asthma: ADAM
and end organ susceptibility genes
J. Holloway;
Human Genetics and Infection, Inflammation & Repair Divisions, School of
Medicine, University of Southampton, Southampton, United Kingdom.
While asthma is an inflammatory disorder of the airways usually associated
with atopy, an important additional component is involvement
of the epithelium and underlying mesenchyme acting as a trophic unit
(EMTU). In addition to allergens, a wide range of environmental factors
interact with the EMTU, such as virus infections, environmental
tobacco smoke and pollutants, to initiate tissue damage and aberrant
repair responses that are translated into remodelling of the airways.
While candidate gene association studies have revealed polymorphic
variants that influence asthmatic inflammation, positional cloning of
previously unknown genes is identifying a high proportion of novel
genes in the EMTU and revealing mechanistic pathways behind the
remodelling response. A disintegrin and metalloproteinase (ADAM)33
is one such susceptibility gene strongly associated with asthma that
is preferentially expressed in the airway mesenchyme. Furthermore,
recent results suggest that variation in the gene may play a significant
role in other diseases that involve tissue remodelling in response to
chronic inflammation, and that this variation may act early in life, altering
developmental processes, rendering tissue innately susceptible to
remodelling.
S10. Genetic and environmental factors in celiac disease
L. M. Sollid;
Institute of Immunology, Rikshospitalet, University of Oslo, Norway.
Coeliac disease (CD) is an intestinal disorder which develops as a
result of interplay between genetic and enviromental factors. Particular
HLA genes together with non-HLA genes predispose to the disease.
The concordance rate among monozygotic twins is about 75%
whereas the concordance rate among HLA identical siblings is about
30%. This suggests the involvement of non-HLA genes, but the many
attempts to identify non-HLA genes has been met with limited success.
There is evidence for susceptibility genes located on chromosomes
5q32, 2q33 and 19p13. By contrast, the HLA susceptibility genes in
CD are well characterised. The primary HLA association in the majority
of CD patients is with DQ2 and in the minority of patients with
DQ8. DQ2 (DQA1*05/DQB1*02 can be encoded in cis in DR3DQ2
individuals and in trans in individual being DR5DQ7/DR7DQ2 heterozygous).
Among the multifactorial disorders with involvement of HLA
genes CD is unique, as a critical environmental factor has been identified,
namely dietary gluten. Evidence suggests that CD4+ T cells are
central in controlling a multifaceted immune response to gluten that
causes the characteristic disease pathology. Gluten reactive T cells
can be isolated from small intestinal biopsies of coeliac patients but not
from non-coeliac controls. DQ2 or DQ8, but not other HLA molecules
carried by patients, are the predominant restriction elements for these
T cells. Lesion derived T cells mainly recognise deamidated gluten
peptides, and this the deamidation is mediated in vivo by transglutaminase
2 (TG2). A number of distinct T cell epitopes exist within gluten.
DQ2 and DQ8 bind the epitopes so that the glutamate residues introduced
by TG2 are accommodated in pockets of the binding site which
have preference for negatively charged side chains. Notably, TG2 can
also generate complexes between gluten and TG2. These complexes
may permit gluten reactive T cells to provide help to TG2 specific B
cells thereby explaining the occurrence of gluten TG2 auto-antibodies
which is a characteristic feature of CD patients exposed to gluten.
S11. The genetic architecture of Skin pigmentation
M. D. Shriver;
The Pennsylvania State University, Department of Anthropology, University
Park, PA, United States.
No abstract available as per date of printing. Please check www.eshg.
org for updates in the online database.
S12. Novel Insights into melanoma genetics
B. C. Bastian 1 , J. C. Curtin 1 , J. Bauer 1 , A. Viros 1 , J. Fridlyand 1 , P. Kanetsky 2 , T.
Landi 3 , D. Pinkel 1 ;
1 University of California, San Francisco, Comprehensive Cancer Center, San
Francisco, CA, United States, 2 University of Pennsylvania, Philadelphia, PA,
United States, 3 National Cancer Institute, Bethesda, DC, United States.
Melanocytic neoplasms display significant phenotypic variation.We
used a genetic approach to compare primary melanomas from mucosal
membranes, the non-hair bearing skin of the palms and soles (acral
melanomas), and sun-exposed skin with and without signs of chronic
sun-induced damage (CSD and non-CSD). We found differences in
the degrees of genomic instability, the specific genomic regions that
are gained and lost, frequencies of mutations in specific genes, and
effects of genetic variants in the germline on melanoma risks. Melanomas
on acral skin and mucosa had distinct patterns of frequent amplifications
and deletions involving very small segments of the genome,
indicating a unique type of genomic instability. By contrast amplifications
were rare in melanomas arising on some-exposed skin. Among
these, BRAF mutations occurred in~ 60% of non-CSD melanomas but