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CC-chemokine receptor 5 polymorphism and age of onset in familial multiple sclerosis. Multiple Sclerosis Genetics
L F Barcellos1, A M Schito, J B Rimmler
1Department of Neurology, University of California at San Francisco 94143-0435, USA.
Abstract:
Multiple sclerosis (MS) is a common disease of the central nervous system characterized by myelin loss and progressive neurological dysfunction. An underlying genetic susceptibility plays a clear role in the etiology of MS, likely acting in concert with an undefined environmental exposure. Full-genome screenings in multiplex MS families have identified several susceptibility regions, supporting a polygenic model for MS. Among these regions, evidence for weak linkage was observed at 3p/3cen suggesting the presence of an MS gene(s) of modest effect. Encoded here are two chemokine receptors, CCR5 and CCR2B. We examined the chromosome 3p21-24 region in 125 MS families (322 total affecteds and 200 affected sib-pairs), and performed genetic analyses of CCR5 and CCR2B loci and two nearby markers (D3S1289 and D3S1300) using both linkage- and association-based tests. No evidence of linkage to MS was observed for any of the tested markers. Affected relative-pair (SimIBD) and sib-pair analyses (ASPEX), and association testing (sib-TDT) for each locus were also not significant. However, age of onset was approximately 3 years later in patients carrying the CCR5delta32 deletion (P=0.018 after controlling for gender effects). Thus, chemokine receptor expression may be associated with differential disease onset in a subset of patients, and may provide a therapeutic target to modulate inflammatory demyelination.
Insights
Genetic analysis of chemokine receptors CCR5 and CCR2B in multiple sclerosis (MS) did not reveal linkage. However, the CCR5delta32 deletion was associated with a later age of onset in MS patients.
Area of Science:
- Neuroscience
- Genetics
- Immunology
Background:
- Multiple sclerosis (MS) is a central nervous system disease involving myelin loss and neurological dysfunction.
- Genetic susceptibility and environmental factors are implicated in MS etiology.
- Previous studies suggested a potential MS susceptibility gene in the 3p/3cen region, encoding chemokine receptors CCR5 and CCR2B.
Purpose of the Study:
- To investigate the role of chemokine receptors CCR5 and CCR2B in the genetic susceptibility to multiple sclerosis.
- To analyze the 3p21-24 chromosomal region for MS susceptibility genes.
- To determine if CCR5 and CCR2B genetic variations influence MS onset or progression.
Main Methods:
- Genetic analysis of 125 MS families using linkage and association tests.
- Examination of CCR5 and CCR2B loci and nearby markers (D3S1289, D3S1300).
- Utilized affected relative-pair analyses (SimIBD, ASPEX) and sib-pair transmission disequilibrium test (sib-TDT).
Main Results:
- No significant evidence of linkage between the studied markers and MS was found.
- Association testing (sib-TDT) for CCR5 and CCR2B loci did not yield significant results.
- Patients with the CCR5delta32 deletion showed a trend towards a later age of onset (approximately 3 years later, P=0.018).
Conclusions:
- The studied chemokine receptor genes (CCR5, CCR2B) do not appear to be major susceptibility genes for MS.
- The CCR5delta32 deletion may be associated with a delayed age of onset in a subset of MS patients.
- Chemokine receptor expression warrants further investigation as a potential therapeutic target for modulating inflammatory demyelination in MS.