Projects
The Immunogenetics of Aging
Background
Deterioration of the immune system with aging is associated with an
increased susceptibility to infectious diseases, cancer and autoimmune
disorders.
Many studies have focused on age-associated changes in immune functions
which might contribute to these pathologies. It has been demonstrated
that aging is associated with chronic, low-grade inflammatory activity.
The aging process is very complex and longevity is a multifactorial
trait, which is determined by genetic and environmental factors and
the interaction
of “disease” processes with “intrinsic” ageing
processes. It is hypothesized that the level of immune response as well
as possibly longevity could be associated with genes regulating immune
functions. It is further hypothesized that the diversity of these genes
might influence successful aging and longevity by modulating an individual’s
response to life-threatening disorders. Several studies have focused on
the role of HLA and cytokine gene polymorphisms for human longevity. However,
available data do not allow at present to clarify the role of these genes
due to major methodological problems, such as the typing approach and
focusing on single loci, insufficient sample size, different inclusion
criteria and age limits, inappropriate control matching and neglected
considerations of sex-related effects and the different genetic make up
of studied populations. A broad family-based analysis on the role of genes
with immune functions on longevity in different racial and ethnic groups
would be very informative and would allow clarification of the impact
of these genetic markers in successful aging. However, such family-based
studies are lacking so far in this important area of endeavour.
Goal
To determine the contribution of HLA genes, cytokine genes and other
MHC-encoded loci to successful aging and an increased capacity to
reach the extreme limits of life-span.
Specific Aims/Objectives
The study will comprise two main data sets consisting of: families
with longevity members (octogenarians and nonagenarians) and unrelated
elderly individuals and ethnically matched young controls. The objectives
of the project will include:
1. To collect cells and DNA from these samples and to establish cell
lines whenever possible.
2. To analyze classical HLA class I and class II loci. Additional approaches
will include screening for other relevant genes in the extended HLA
region based on microsatellite markers.
3. To analyze polymorphisms in regulatory and/or coding regions, with
a possible impact on the level of gene expression of pro- and anti-inflammatory
cytokines in elderly and young/middle age individuals
4. To identify (clarify) the role of cytokine genes, classical HLA
class I and class II loci, as well as additional genes within the extended
HLA complex in successful aging and longevity.
5. Based on linkage and association analyses to identify extended immunogenetic
profiles that could be relevant to a better understanding of the mechanisms
of successful aging and increased likelihood of reaching the extreme
limits of life-span.
Families and case-control pairs will be studied through the collaborative
participation of laboratories throughout the world. The participation
of those laboratories previously involved in the field of immunogenetics
and aging is strongly encouraged, as well as the participation of new
laboratories. Investigators previously involved in studies in the international
histocompatibility workshops have access to a wealth of untapped data
and material that could already provide valuable contributions to answering
the questions posed above. Additionally, more individuals could be
recruited during the course of the study.
The study will include three phases:
I. Collection of samples (cells and DNA) from families with longevity
members, unrelated elderly individuals and ethnically matched young
controls and establishment of cell lines whenever possible.
The following selection criteria will be used to identify families
for the study:
- extended families with a family history of at least two generations
with longevity members (octogenarians and nonagenarians) including:
elderly individuals, their children and grandchildren
- sufficient demographic data should be available
- data on family history of diseases should be available
Elderly individuals (in family-based analyses and unrelated case-control
analyses) selected should ideally be characterized according to the
SENIEUR protocol.
Ethnically matched unrelated young controls should ideally be characterized
according to JUNIER protocol.
For all samples sufficient cells and/or DNA should be available for
future studies. Institution approved informed consent should be obtained
prior to inclusion in the study.
II. Generation of DNA-based typing data
1. Genetic loci studied
HLA
Participants are encouraged to analyze major HLA-linked genes. Typing
must be performed using a "qualified" DNA typing system (Methods
and reagents approved by IHWC). Minimal requirement is for completing
an intermediate level of resolution. Laboratories are encouraged whenever
possible to complete high resolution DNA typing and definition of alleles.
The following classical HLA loci should be analyzed:
Class I: HLAA-A, -B, -C
Class II: HLA-DRB1/3/4/5, DQB1, -DQA1, DPA1, -DPB1
Microsatellite markers (protocols for microsatellite testing approved
by IHWC)
Cytokine genes:
Polymorphisms in pro- and anti-inflammatory cytokine (IL-2, IL-6, IL-10,
IL-12, IFN?, TNFa, TGFß) genes with possible correlation to the
level of gene expression will be analyzed. The recommended protocol
and polymorphic positions to be analyzed will be distributed to participants.
2. QC validation (of participating laboratories and/or local methods
and reagents). Reference Panel DNA will be provided for QC testing.
Participating laboratories will be “qualified” for genomic
data submission by testing of a set of coded DNA samples selected from
the IHWG Reference Panel (maintained by the IHWG Cell and Gene Bank).
III. Data generated by individual laboratories will be collected into
a database. Linkage and Association analyses will be performed. Data
will be analyzed using interactive, user-friendly, web-based software
that can be accessed through the internet by all participants.
Co-chairs:
Elissaveta Naumova – Sofia, Bulgaria
Eline Slagboom – Leiden, The Netherlands
Graham Pawelec – Tübingen, Germany
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