Expressions of Intent for IPY 2007-2008 Activities

Expression of Interest Details

PROPOSAL INFORMATION

Haplotype diversity in candidate genes for susceptibility/resistance to infectious disease among circumpolar Aboriginal populations.  (Genes for infectious disease)

Outline
400 words max We will employ a three-pronged approach to assess the contribution of 5 candidate genes (Chemokine receptor 5 (CCR5), Vitamin D receptor (VDR), Killer Immunoglobulin-like receptors (KIR) and the cytokines Tumor Necrosis Factor a (TNFa) and Interferon gamma (IFN?) to the susceptibility/resistance of infectious pathogens in Native North American populations. The identification of gene variants associated with susceptibility to infectious disease among circumpolar Aboriginal groups can contribute to the development of effective treatments for indigenous arctic communities. The three approaches will employ tools from population genetics, direct association studies, and ancient DNA analyses. The genes were chosen because the literature strongly suggests that these genes play a significant role in the active and innate immune response and should be subject to selective forces (pathogens). All genes will be re-sequenced in a diverse panel of circumpolar Aboriginal populations and in specific indigenous communities in North America and Russia that exhibit a high incidence of Tb. 1. The population genetics approach will analyze the distribution, frequency, and relationships among haplotypes in Aboriginal circumpolar groups. The distribution and frequency of haplotypes in these groups should also exhibit a unique pattern at genomic regions that experienced a strong selective pressure (pathogens) during European colonization. These genomic regions likely contain genes associated with resistance to pathogens carried over by European populations during European colonization. 2. The haplotypes identified for the candidate genes in part 1 of the study will then be analyzed in contemporary Aboriginal populations from the circumpolar regions of North American and Russia that exhibit a high frequency of Tb infection. The identification and analysis of haplotypes specific to Native American populations controls for two problems that may exist in previous studies that have typed genetic markers in Aboriginal groups. First, the effects of European admixture in these indigenous communities. By identifying haplotypes that are ancestral to Aboriginal individuals (from part 1) we can exclude haplotypes that are a result of European admixture in the association study. Second, the effects of ascertainment bias because previous genetic markers were largely ascertained from European and Japanese populations. 3. From parts 1 and 2, we will identify haplotypes in the candidate genes that exhibit associations with Tb infection. Once we identify these haplotypes we can directly observe the results of selection for these haplotypes by comparing the frequency of these haplotypes in pre- and post-contact populations. Dr. Larcombe already has permission to analyze DNA from the remains of 20 precontact individuals from indigenous groups in Nunavut. Necessary precautions in ancient DNA analyses will be used.

What significant advance(s) in relation to the IPY themes and targets can be anticipated from this project?
Northern populations currently and historically have infectious disease rates that exceed the national averages. Although socio-economic conditions likely contribute to the burden of disease immunogenetics factors have been implicated in disease susceptibility/resistance. Arctic peoples have unique experiences with infectious diseases given their diverse histories and relationships with non-indigenous groups. The proposed research takes a comprehensive approach to characterizing the immunogenetic variability within and between Arctic populations and how this variation may have been shaped by their history and contributed to their current susceptibility to infectious diseases. The study will develop a set of genetic markers in four genes specific for use in circumpolar Aboriginal patients.

What international collaboration is involved in this project?
This research is a collaboration among researchers in Russia, the U.S., and Canada. The different research groups have complementary analytical skills and have forged relationships with various arctic indigenous communities.

FIELD ACTIVITY DETAILS

Geographical location(s) for the proposed field activities:
Community outreach and samples will be collected from communities in Alaska, Siberia, European Arctic and sub-Arctic regions (the Kola Peninsula and Northern Urals), Nunavut and Manitoba

Approximate timeframe(s) for proposed field activities:
Arctic: 05/08 – 06/08      05/09 – 06/09      05/10 – 06/10
Antarctic: n/a

Significant facilities will be required for this project:
No significant logistic support will be needed.

Will the project leave a legacy of infrastructure?
The project will produce a database of genetic markers of individuals for use in the community. In addition, community outreach and education efforts will leave a legacy of knowledge about infectious disease resistance/susceptibility.

How is it envisaged that the required logistic support will be secured?
National agency
Commercial operator
Own support

Has the project been "endorsed" at a national or international level?

PROJECT MANAGEMENT AND STRUCTURE

Is the project a short-term expansion (over the IPY 2007-2008 timeframe) of an existing plan, programme or initiative or is it a new autonomous proposal?

This project builds on existing research that is examining the immunogenetic profile of northern Canadian Dené and Cree, Alaska Inuit, Siberian Chukchee, European Arctic Saami and North Russia Komi populations.

How will the project be organised and managed?
Three streams of data collection and analysis - U.S., Canada, Russian. Samples all analyzed in similar manner to allow comparison between populations.

What are the initial plans of the project for addressing the education, outreach and communication issues outlined in the Framework document?
We will provide local workshops for secondary, post secondary students and for community members to explain the genetic research in a culturally appropriate mannerA similar workshop has already been established in the Dené community in Manitoba. Preliminary data will be presented at the 14th Circumpolar Conference in Yellowknife in 2008.

What are the initial plans of the project to address data management issues (as outlined in the Framework document)?
Data will be collected, managed, and stored in a database developed for this study. The results of the data will be discussed with participating communities prior to publication.

How is it proposed to fund the project?
The project will be funded through national agencies such as the CIHR and NIH. IPY will provide start up funding for comparison of four target groups – Dené, Chukchee, Saami and a control population (non- polar).

Is there additional information you wish to provide?
None

PROPOSER DETAILS

Dr Pamela Orr
University of Manitoba
GC430-820 Sherbrook Street, Winnipeg, Manitoba Canada
R3E 0W3
Canada

Tel: (204) 78703391
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Other project members and their affiliation

Other Information