CC-chemokine receptor 5 polymorphism and age of onset in familial multiplesclerosis

Multiple sclerosis (MS) is a common disease of the central nervous system c haracterized by myelin loss and progressive neurological dysfunction. An un derlying genetic susceptibility plays a clear role in the etiology of MS, l ikely acting in concert with an undefined environmental exposure. Full-geno me screenings in multiplex MS families have identified several susceptibili ty regions, supporting a polygenic model for MS. Among these regions, evide nce 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 (3 22 total affecteds and 200 affected sib-pairs), and performed genetic analy ses of CCR5 and CCR2B loci and two nearby markers (D3S1289 and D3S1300) usi ng 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 CCR5 Delta 32 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 ma y provide a therapeutic target to modulate inflammatory demyelination.