Gender-specific influence of the chromosome 16 chemokine gene cluster on the susceptibility to Multiple Sclerosis

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Abstract

Macrophage-derived chemokine (MDC/CCL22) plays a role in Experimental Autoimmune Encephalomyelitis (EAE), the animal model of Multiple Sclerosis (MS). MDC/CCL22 gene is part of a chemokine cluster, which includes also thymus and Activation-Regulated Chemokine (TARC/CCL17).

The frequency of the C/T and C/A Single Nucleotide Polymorphisms (SNPs) in the promoter and coding sequence of CCL22 as well as the C/T SNP in the promoter of CCL17 were determined in 370 patients with Multiple Sclerosis (MS) compared with 380 controls.

A trend towards a decreased allelic frequency of the A allele of the CCL22 C/A SNP as well as of the T allele of the CCL17 C/T SNP was found in patients compared with controls. The frequency of the AT haplotype was significantly decreased in MS patients (P = 0.017, OR: 0.49, CI: 0.28–0.87). Stratifying patients according to gender, the observed association was even more pronounced in male patients compared with male controls (P = 0.004, OR = 0.18, 95% CI: 0.06–0.50), whereas no significant differences were observed in females.

Therefore, the presence of the AT haplotype in chromosome 16 chemokine cluster is likely to confer a decreased risk of developing MS, particularly in males.

Introduction

Multiple Sclerosis (MS) is an inflammatory autoimmune disease of the Central Nervous System (CNS) in which myelin proteins are supposed to act as autoantigens. The initial step of MS pathogenesis is the aberrant activation of specific populations of autoreactive T lymphocytes in the periphery, followed by T cell recruitment into the brain [1]. This process leads to the activation of several inflammatory molecules, including cytokines and chemokines, which in turn cause demyelination, eventually resulting in axonal damage [2]. Among chemokines, Interferon-γ-inducible Protein-10 (IP-10/CXCL10) levels were shown to be increased in Cerebrospinal Fluid (CSF) of patients with symptomatic attacks of inflammatory demyelination, whereas Monocyte Chemoattractant Protein-1 (MCP-1/CCL2) levels were decreased [3], [4]. Stratifying according to MS subtypes, IP-10/CXCL10 levels were significantly elevated in CSF from Relapsing Remitting (RR) and Secondary Progressive (SP)-MS patients, whereas levels in Primary Progressive (PP)-MS patients were similar to controls [5]. A number of additional chemokines binding to receptors preferentially expressed on Th1 lymphocytes have been detected in the CNS of MS patients [3], [6], [7]. However, recent evidence pointed out that chemokines binding to receptors expressed on Th2 cells are important as well during the development of MS. Macrophage-derived chemokine (MDC/CCL22), which interacts with CCR4 receptor, preferentially expressed on Th2 lymphocytes, is likely to play a role in MS pathogenesis, as in the CNS of EAE-affected mice the expression of this chemokine and its receptor correlates with clinical manifestations and development of inflammatory lesions [8]. In particular, in mouse models of RR-EAE, both MDC/CCL22 and CCR4 have been detected during acute attacks but returned to baseline upon remission, whereas in chronic-relapsing form of EAE, MDC/CCL22 and its receptor are weakly expressed at disease onset and increase with the progression of the disease [8].

Multiple Sclerosis is a multifactorial disease, and genetic factors play a primary role in determining the pathological events and in changing the disease phenotype from patient to patient. Up to now, many efforts have been made to identify genetic variation having a potential role in human diseases [9]. The strongest and most consistent evidence for a susceptibility gene in MS is within the major histocompatibility complex (MHC) on chromosome 6p21.3. Association with the HLA-DR2 haplotype (DRB11501–DQB10602) has been repeatedly demonstrated in several populations, including Italians [10], [11]. Although the MHC region contributes significantly to the risk, much of the genetic effect in MS remains to be explained as the clinical heterogeneity and complex etiology of the disease represent confounding factors. Besides HLA, several allelic variants have been proposed as candidate for MS, including adhesion molecules and chemokines [12], [13], [14], [15]. Recently, the chemokine gene cluster composed by MDC/CCL22, fraktalkine/CX3CL1 and Thymus and Activation-Regulated Chemokine (TARC/CCL17) has been proposed as a susceptibility locus for inflammatory disorders, and several polymorphisms have been described in this region [16], [17]. To date, three SNPs with a possible effect on the rate of transcription or the function of the protein have been reported in this region: a C/T transversion in the promoter of CCL22 (C-308T, rs223889), a C/A SNP at position 5 of the coding region of CCL22, resulting in a substitution of an alanin with an aspartate at position 2 of the protein (rs4359426), and a C/T substitution in the promoter of CCL17 (C-431T, rs223828). Neither association nor functional studies have been extensively carried out in Caucasian population yet, except for rs223889 and rs223828, which have been investigated with regard to susceptibility for inflammatory bowel disease [16].

Frequency data available so far for rs4359426 accounts for a limited number of individuals of Caucasian descent and show a minor allele frequency (MAF) of 4%. The MAF for the rs223889 and rs223828 reported by Fisher et al. [16] are 27% and 8% respectively, which are very similar to the ones reported in NCBI data bank for Caucasians (MAF: 26% and 6%, http://www.ncbi.nlm.nih.gov).

Given the potential importance of these allelic variants in chromosome 16 chemokine gene cluster in the pathogenesis of MS, a case-control association study in a population of Italian MS patients and matched healthy subjects has been performed, in order to determine whether their presence could influence the susceptibility or exert a protective effect towards the development of the disease.

Section snippets

Subjects

Three-hundred seventy patients with MS (122 males and 248 females, age ± S.E.M.: 41.1 ± 0.72, age at disease onset ± S.E.M.: 31.2 ± 0.62) were consecutively recruited at Multiple Sclerosis Centers in Northern Italy, Ospedale Maggiore Policlinico (Milan) and Ospedale Maggiore (Novara). All patients underwent a standard battery of examinations, including medical history, physical and neurological examination, screening laboratory test, brain Magnetic Resonance Imaging (MRI). Diagnosis was made in

Results

Three-hundred seventy patients with MS and 380 matched controls were genotyped for the C/T and C/A SNPs in the promoter and coding sequence of CCL22 as well as the C/T SNP in the promoter of CCL17. Both MS and controls were in Hardy–Weinberg equilibrium for all the SNPs tested and the distribution of the three polymorphisms in controls was similar to the one previously reported in Caucasians (http://www.ncbi.nlm.nih.gov). No differences in either allelic or genotypic frequency of the C/T SNP in

Discussion

According to the present results, the presence of the AT haplotype in chromosome 16 chemokine cluster is likely to confer a decreased risk of developing MS. Most interestingly, the effect of this allele is likely to be gender-specific, as it was found in males only, decreasing the risk to develop the disease by more than 5 fold. However, these findings must be interpreted cautiously because the significant P value emerges from a difference of 15 males carriers of the AT haplotype.

This is the

Acknowledgements

This work was supported by grants from Associazione “Amici del Centro Dino Ferrari”, IRCCS Ospedale Maggiore Milano, Monzino Foundation, Regione Piemonte/CIPE 2003 and Ing. Cesare Cusan.

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