CTLA4 exon 1 and promoter polymorphisms in patients with multiple sclerosis Introduction Multiple sclerosis (MS) is a chronic autoimmune disease of central nervous system white matter resulting in extensive inflammation, demyelination and axonal damage. In a vast majority of patients, the disease consists of alternating recurrent attacks followed by a period of a variable degree of recovery (relapsing remitting, RR), whereas in a minority of patients, the disease shows a more progressive course (primary progressive, PP). Both familial occurrence of MS and the higher rate in monozygotic twins as compared with dizygotic twins point toward the importance of genetic factors (1). Following a series of genome-wide screens in MS, substantial evidence has emerged for the potential involvement of many genes, each contributing a small to moderate effect to the overall disease process (2). Genes coding proteins that play crucial roles in regulating the immune response, such as cyto- kine, chemokines and costimulatory ⁄ coinhibitory molecules, are considered with be of high rele- vance in autoimmune diseases such as MS. This has initially justified searches for MS association with cytokines ⁄ chemokines genes in different ethic groups including one study in an Iranian population (3). Cytotoxic T lymphocyte antigen 4 (CTLA4), the cell designation 28 antigen (CD28) and their ligands, B7-1 and B7-2, form the major pathway for the activation of T cells. While the CD28–ligand interaction brings about an increase in T cell response, the CTLA4–ligand interaction has an inhibitory effect on T cell activation (4, 5). The CTLA4 gene is located on chromosome 2q33 recognized as a candidate locus by linkage genome scan (6). Several polymorphisms in the Acta Neurol Scand 2009: 120: 424–429 DOI: 10.1111/j.1600-0404.2009.01177.x Copyright Ó 2009 The Authors Journal compilation Ó 2009 Blackwell Munksgaard ACTA NEUROLOGICA SCANDINAVICA Yousefipour G, Erfani N, Momtahan M, Moghaddasi H, Ghaderi A. CTLA4 exon 1 and promoter polymorphisms in patients with multiple sclerosis. Acta Neurol Scand 2009: 120: 424–429. Ó 2009 The Authors Journal compilation Ó 2009 Blackwell Munksgaard. Objective – The polymorphisms of exon 1 (+49 A ⁄ G) and promoter regions ()1722 T ⁄ C, )1661 A ⁄ G and )318 C ⁄ T)of cytotoxic T lymphocyte antigen 4 (CTLA4) and also haplotypes constructed from mentioned loci were investigated amongst 153 Iranian patients with definite multiple sclerosis (MS) and 190 healthy controls. Methods – The polymorphisms were genotyped by PCR-restriction fragment length polymorphisms and PCR-amplification refractory mutation system. The 4-locus haplotypes were estimated by Arlequin software (University of Berne, Berne, Switzerland). Results – Preliminary results showed significant increase of +49 G allele and )1661 AG genotype, as well as TGCA haplotype among patients than controls (P < 0.036, P = 0.009 and P < 0.010, respectively). The distribution of )1722 T ⁄ C, )1661 A ⁄ G, )318 C ⁄ T and +49 A ⁄ G (TACA) haplotype, from the contrary, was observed to be significantly increased among controls (P < 0.001). Conclusions – After Bonferroni correction, the results provide preliminary evidence that CTLA4 genetic variation at )1661 locus may render Iranian individuals to be more susceptible to MS, whereas harboring TACA haplotype might be protective. G. Yousefipour 1 , N. Erfani 2 , M. Momtahan 1 , H. Moghaddasi 1 , A. Ghaderi 2 1 Department of Neurology, Shiraz University of Medical Sciences, Shiraz, Iran; 2 Shiraz Institute for Cancer Research, Shiraz University of Medical Sciences, Shiraz, Iran Key words: )1661 A ⁄ G; cytotoxic T lymphocyte antigen 4; exon 1; haplotype; multiple sclerosis; polymorphism Abbas Ghaderi, Department of Immunology, Shiraz Institute for Cancer Research, Shiraz University of Medical Sciences, P.O. Box: 71345-3119, Shiraz, Iran Tel.: +98 711 2303687 Fax: +98 711 2304952 e-mail: Ghaderia@sums.ac.ir Accepted for publication February 2, 2009 424