Project: Immunogenetics of Aging

Immunogenetics of Aging

Project Leaders: Elissaveta Naumova, Milena Ivanova and Graham Pawelec

Detailed project description:

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 immune 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.

The aim of the component “Immunogenetics of Ageing” is to identify new biomarkers for successful aging and an increased capacity to reach the extreme limits of life-span by analysis of immune response genes. Within 18th IHIW we plan to confirm the possible biomarkers, defined in previous workshops, in a larger cohort of healthy elderly, elderly patients with age-associated diseases and controls (young and middle age) from different populations

The study will include unrelated elderly individuals (octogenarians and nonagenarians) and families with longevity members. Comparisons with young and middle – aged controls will be performed. The project will be focused on the following candidate biomarkers: classical HLA loci (HLA-A,-B,-C,-DRB1/3/4/5, -DQB1,-DQA1, -DPA1, -DPB1), genes in the extended MHC region such as MICA and MICB, polymorphisms in pro- and anti-inflammatory cytokine genes (IL-2, IL-6, IL-10, IL-12, IFNγ, TNFα, TGFβ) with possible correlation to the level of gene expression, KIR, BCR and TCR. Linkage and Association analyses and correlation with functional parameters, defining immune risk profiles will be performed.

Milestones in years:

2020: Creation of uniform way to enter second-field HLA typing data, data for other genetic polymorphism:  cytokine genes, KIR, BCR and TCR irrespective of the vendor. Inclusion of  many laboratories/ European and non-European populations. Start of samples and data collection

2021: Continuing sample and data analyses

2022: Finalizing analyses

Patient/sample description (if applicable, details, inclusion/exclusion criteria):

The study focus on unrelated elderly individuals (octogenarians and nonagenarians) and families with longevity members.

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 or nearly – SENIEUR protocols.

Ethnically matched unrelated young controls should ideally be characterized according to JUNIER protocol. Ethnically matched middle aged controls will also be included in the study.

Data required (number, type of data, inclusion/exclusion criteria):

  1. Second filed HLA typing for HLA-A, -B, -C, -DRB1, -DQB1, -DQA1, -DPB1 loci
  2. MICA and MICB genotype
  3. Polymorphisms in pro- and anti-inflammatory cytokine (IL-2, IL-6, IL-10, IL-12, IFNγ, TNFα, TGFβ) genes with possible correlation to the level of gene expression/ cytokine level
  4. Cytokine levels
  5. KIR genotypes
  6. TCR and BCR
  7. Viral status: CMV, EBV, HCV, HBV
  8. Data on date of birth, ethnicity, place of birth, health status

Samples required (if applicable, number, type of samples, inclusion/exclusion criteria):

If no molecular typing at second field level of HLA, MICA, MIC; cytokine gene polymorphism; KIR genes, TCR or BCR are available, DNA is required to perform the typing of corresponding immunogenetic markers. If cytokine levels of viral status are not analysed, serum samples are required.

We expect to collect at least samples/data from at least 6 European and 4 non-European populations. The minimal requirements would be at least 100 elderly subjects and 200 controls (100 young and 100 middle aged) from each population.

Reagents/additional assays required:

For a proportion of laboratories we expect to require additional HLA NGS analyses, genetic test for some of the other immunogenetic markers, analyses of cytokine profiles. Such analysis could be performed in a central facility (approximately 500 samples for HLA NGS typing; 500 samples for KIR typing; 500 samples for cytokine  gene polymorphisms, BCR, TCR; 500 samples for cytokine levels)

Data infrastructure required:

Uniform way to enter data irrespective of the vendor.