Haplotype analysis of the preprotachykinin-1 (TAC1) gene in multiple sclerosis

The potential relevance of chromosome 7q21 - 22 in susceptibility to multiple sclerosis ( MS) has been highlighted in genome-wide linkage screens as well as in association studies of 7q-specific polymorphic microsatellites. Especially, recent, independently performed studies have provided evidence for significant association of the markers D7S554 and D7S3126 with MS in Sardinian, Northern Irish and Spanish - American cohorts. The gene most closely located to these markers is the neuropeptide preprotachykinin-1 (TAC1) gene. Both its position and the array of biological functions exerted by its expression products make it a logical primary choice for further scrutiny as the putative chromosome 7q21 - 22 MS susceptibility gene. We report identification of eight polymorphisms in this gene by means of a sequencing approach. A Northern Irish case - control was typed for six of these polymorphisms. One of these, an intron 1 single-nucleotide polymorphism ( SNP), showed significant association with MS ( P = 0.009). Two-marker haplotypes composed of allelic combinations of TAC1 promoter - intron 1 SNPs were highly significantly associated with MS and more so with the relapsing-remitting form of this disease. While independent reproduction of these data in other data sets is indicated, our work is suggestive for a role of the TAC1 gene in MS.