Skew in the human caveolin 1 gene upstream purine complex homozygote haplotype compartment in multiple sclerosis M. Zarif Yeganeh a , M. Ghaffarpour b , D.D. Farhud c , M. Karimlou d , M. Ghabaee b , A. Haghighi Nazari b , H. Najmabadi a , M. Ohadi a, ⁎ a Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Evin, Tehran, Iran b Iranian Center of Neurological Research, Imam Khomeini Hospital, Tehran University of Medical Sciences, Terhan, Iran c Genetics Clinic, Valie Assr Sq. 16 Keshavarz Blvd. Tehran, Iran d Department of Biostatistics, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran abstract article info Article history: Received 27 June 2009 Received in revised form 6 September 2009 Accepted 9 September 2009 Keywords: Multiple sclerosis Caveolin 1 Haplotype Homozygote Purine complex Caveolin 1 (CAV1) is a component of the myelin sheath and the expression of the gene encoding this protein is increased during myelination in Schwann cells and oligodendrocytes. We sought to investigate the homozygote haplotype compartment in a recently identified polymorphic purine complex at the upstream region of the human CAV1 gene in multiple sclerosis (MS). In a case/control study design, the region was characterized in 126 cases of MS diagnosed based on the Revised McDonald diagnostic criteria, and 460 controls. We report a skew in the homozygote haplotype compartment in the cases versus controls both in a qualitative and quantitative respect. Excess homozygosity for haplotypes was observed in the MS cases (corrected p < 0.012, OR = 2.54, CI 1.14–5.64). Furthermore, we observed eight homozygote haplotypes in the MS cases that were non-existent in the controls (p < 0.0003, OR = 20.27, CI 2.50–163.8). For the first time, our data highlight the CAV1 upstream purine complex as a novel susceptibility genomic locus in the pathophysiology of MS. Of utmost importance, the region has been conserved across species, including mouse, guinea pig, rhesus macaque, and human. The functional effect of this region remains to be clarified in the future studies. © 2009 Elsevier B.V. All rights reserved. 1. Introduction Multiple sclerosis (MS) is a chronic inflammatory demyelinating autoimmune disease affecting the central nervous system (CNS). Caveolin 1 (CAV1) is a component of the myelin sheath and the expression of the gene encoding this protein is increased during myelination in Schwann cells and oligodendrocytes (Mikol et al., 2002). The oligodendrocyte- myelin glycoprotein is present in lipid rafts and CAV1-enriched membranes (Boyanapalli et al., 2005). Furthermore, the CAV1 protein is a component of the blood brain barrier which is damaged in the process of the pathogenesis of MS (Virgintino et al., 2002). In line with the notion of gender dimorphism in multiple sclerosis (Nicot, 2009), membrane- associated estrogen receptor and CAV1 are present in the CNS myelin and oligodendrocyte plasma membranes (Arvanitis et al., 2004), indicating a potential role for those proteins in myelin maintenance or functions. The expression of CAV1 is increased in EAE & EAN animal models of MS (Shin et al., 2005; Kim et al., 2006). We have recently reported a novel polymorphic purine stretch of tetranucleotide motifs at the upstream region of the human CAV1 gene (Heshmati et al., 2009). Haplotypes resulting from three polymorphic motifs, GGAA (n1) , GAAA (n2) , and GGAA (n3) , across this stretch were shown to be associated with late-onset Alzheimer's disease (AD) in our study. Characterization of the homozygote haplotype compartment in the region unraveled homozygote haplotypes that were present only in the AD cases (Zarif Yeganeh et al., 2009). In view of the evidence implicating CAV1 involvement in the pathophysiolgoy of MS, we investigated this region in a group of patients afflicted with MS and compared the results with controls. Furthermore, we characterized the region in a group of non- neurological phenotype including patients afflicted with breast cancer. The purpose of this inclusion was twofold: Firstly, to examine the hypothesis that this region may be involved in the well-established role of CAV1 in breast cancer tumorigenesis (Williams et al., 2004). Secondly, to examine the specificity of the CAV1 upstream purine complex in the pathogenesis of neurological conditions such as MS. 2. Materials and methods 2.1. Subjects Our study was conducted in two steps. In step I, one hundred twenty six unrelated subjects receiving the diagnosis of MS based on Revised McDonald criteria, and 123 unrelated controls were included for sequencing the entire CAV1 upstream purine region. In step II, an Journal of Neuroimmunology 216 (2009) 103–107 ⁎ Corresponding author. E-mail address: mohadi@uswr.ac.ir (M. Ohadi). 0165-5728/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.jneuroim.2009.09.007 Contents lists available at ScienceDirect Journal of Neuroimmunology journal homepage: www.elsevier.com/locate/jneuroim