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Linkage of rheumatoid arthritis to the candidate gene NRAMP1 on 2q35
M A Shaw1, D Clayton, S E Atkinson
1Department of Medicine, University of Cambridge Clinical School, Addenbrooke's Hospital, UK.
Abstract:
The macrophage resistance gene NRAMP1 regulates priming/activation of macrophages for enhanced TNF alpha, IL 1 beta, and MHC class II expression. Since all of these functions are of potential importance in the induction or maintenance or both of autoimmune disease, samples from the Arthritis and Rheumatism Council's repository of multicase rheumatoid arthritis families were typed for a dinucleotide repeat in the NRAMP1 promoter region and four other 2q34 (TNP1) or 2q35 (IL8R, VIL1, DES) marker genes. Identity by descent (IBD) sib pair analysis using a three locus haplotype NRAMP1-IL8RB-VIL1, or NRAMP1 alone, provided preliminary evidence (maximum lod score = 1.01, p = 0.024) for a gene in this region contributing to suceptibility to rheumatoid arthritis. Candidacy for NRAMP1 as the disease susceptibility gene was supported by a significant bias (p = 0.048) towards transmission of the NRAMP1 promoter region allele 3 in affected offspring.
Insights
The NRAMP1 gene influences macrophage activation, potentially impacting autoimmune diseases like rheumatoid arthritis. Genetic analysis suggests NRAMP1 may contribute to rheumatoid arthritis susceptibility.
Area of Science:
- Immunogenetics
- Rheumatology
Background:
- The NRAMP1 gene regulates macrophage activation, influencing immune responses relevant to autoimmune diseases.
- Key macrophage functions regulated by NRAMP1 include enhanced expression of TNF alpha, IL-1 beta, and MHC class II.
Purpose of the Study:
- To investigate the potential role of the NRAMP1 gene and linked markers in rheumatoid arthritis susceptibility.
- To analyze genetic variations in the NRAMP1 promoter region and nearby genes within rheumatoid arthritis families.
Main Methods:
- Typing of NRAMP1 promoter dinucleotide repeat and four other marker genes (TNP1, IL8R, VIL1, DES) in rheumatoid arthritis family samples.
- Identity by Descent (IBD) sib pair analysis using NRAMP1-IL8RB-VIL1 haplotype and NRAMP1 alone.
- Transmission disequilibrium testing for NRAMP1 promoter alleles.
Main Results:
- Preliminary evidence (lod score = 1.01, p = 0.024) for a rheumatoid arthritis susceptibility gene in the NRAMP1 region using IBD sib pair analysis.
- Significant bias (p = 0.048) in transmission of the NRAMP1 promoter region allele 3 to affected offspring, supporting NRAMP1 candidacy.
Conclusions:
- The NRAMP1 gene is a candidate for contributing to rheumatoid arthritis susceptibility.
- Genetic variations in NRAMP1 may play a role in the development or progression of rheumatoid arthritis.