Haplotypes within genes of β-chemokines in 17q11 are associated with multiple sclerosis: a second phase study

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Abstract
We previously defined haplotypes of single nucleotide polymorphisms (SNP) with possible relevance to multiple sclerosis (MS) in 2 CC chemokine ligand (CCL) clusters in chromosome 17q11. The 17q11 region was also identified as a susceptibility locus by a meta-analysis of linkage studies. To confirm and refine the previous finding in a second, high resolution SNP scan in a new set of families. We genotyped 232 SNPs in 1369 individuals in 361 MS families. Transmission of marker alleles and haplotypes from unaffected parents to affected offspring was tested by using the pedigree disequilibrium test, the TRANSMIT 2.5 program, and the family and haplotype based association tests. Distribution of linkage disequilibrium (LD) was assessed by ldmax. In consensus with observations in the first scan, the present study identified haplotypes within CCL3 and CCL15 in the telomeric CCL cluster. There was also an overlap in the findings in the centromeric CCL cluster. Strong and extensive LD was detected both within the centromeric and telomeric CCL gene clusters. The present study replicates our previous findings and further suggests the existence of MS associated haplotypes within genes of CCL3 and CCL15. Haplotypes of interest are also present within the centromeric gene cluster (including CCL2, CCL7, CCL11, CCL8, and CCL13), but extensive LD prevents further refinement of these haplotypes by using the methods applied. Sequencing of the identified chromosomal segments and their flanking regions will be necessary to define specific variants with direct relevance to MS pathogenesis.