Gender effects in relapsing–remitting multiple sclerosis: Correlation between clinical variables and gene expression molecular pathways

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Abstract

Gene expression profiles were assessed in patients with relapsing–remitting multiple sclerosis (RRMS) to identify gender effects. Clear gender differences in time to second relapse and time to EDSS = 6.0 progression in patients with late onset of the disease (>40 years) were evident, and occurred more rapidly in female RRMS patients. Identified molecular biological mechanisms were related to increased immune activation associated with prominent inhibition of apoptosis that enhanced inflammatory processes and were more evident in female RRMS patients. Our findings open possibilities to explore gender-dependent immunomodulatory treatments that will be based on gene expression mechanisms that set the difference between male and female RRMS patients.

Introduction

The prevalence of multiple sclerosis (MS) is much greater in women, similarly to increased female incidence in other autoimmune diseases [1]. This female predisposition to develop autoimmune diseases may be related to notable immunological findings in healthy women demonstrating that women have higher absolute numbers of CD4+ lymphocytes relative to men [2]. Cell-mediated host responses also exhibit sexual dimorphism, and female mice have been shown to mount more vigorous T-cell responses to exogenous and allogeneic antigens than males [3]. Secretion of cytokines like interferon-γ (IFN-γ), interleukin 1 (IL-1) and IL-10 is enhanced in vitro in the presence of estrogen, while IFN-γ, IL-4 and IL-5 decrease in the presence of androgens [4], [5], [6].

The epidemiologic data and population surveys in MS consistently indicate that women are at least twice as often affected than men whatever the ethnic origin of the population studied [7]. Several factors have been indicated to specifically contribute to the gender differences in MS. These include genetic susceptibility, various influences of sex hormones and specifically their effects on cytokines. AT haplotype on chromosome 16 chemokine gene cluster was proposed as a protective factor towards the development of MS, particularly in males [8]. Similarly, polymorphisms of IFN-gamma [9], TGFB1 [10], and BDNF [11] genes were associated with increased MS susceptibility, especially in males, while APOE polymorphisms was reported [12] to increase disease severity in females.

The asymmetry patterns between female and male MS patients are likely attributable to genetic programs that operate early in life and contribute to the ongoing neurodevelopmental processes active later, driven by genetic programming as well as by experience. Teasing apart the relative contribution of these alternate influences requires the analysis of informative data. Alterations at the gene expression level may help account for gender-related changes even in the absence of gross differences in clinical variables. These gene expression modifications can explain differentially modified penetrance of a genetic trait between females and males and can provide detailed information about specific regulations of gender differences at the cellular level within the broad spectrum of the disease. Better understanding of these phenomena may have implications on the management and treatment of MS patients. In the current study we evaluated gender-related differences in a large cohort of relapsing–remitting MS patients and studied gene expression signatures related to gender discriminating variables.

Section snippets

Settings

The Multiple Sclerosis Center at Sheba Medical Center, Tel-Hashomer, Israel, was founded in 1995 to provide long-term multidisciplinary treatment and care for patients diagnosed with MS from referral areas all over the country. Patients' demographic and clinical data are archived by an advanced computerized electronic record-keeping software system. Patients' records are updated by the Center's neurologists prospectively, during each clinic visit and telephone interactions are recorded as well.

Age of onset

Of the 2012 RRMS included in the analysis, 1387 were females (68.9%) and 625 (31.1%) were males, resulting in female:male ratio of 2.21:1. The distribution of patients by gender according to the age of onset is presented in Fig. 1A. According to age of onset, the female-to-male gender ratio increased from 1.0 at 10 years, (childhood MS) to 2.2 at 15 years (juvenile MS), reaching a peak of 2.8 at 20 years; this increased ratio gradually decreased to 1.3 at 60 years, suggesting an age-related

Discussion

Gender differences are probably a composite of hormonal elements, environmental factors, and overall lifestyle components that affect overall health. These differences are not only determined by gender-related differences in sex steroid levels, but also by gender-specific tissue and cellular characteristics that mediate gender-specific responses to a variety of stimuli. Our data demonstrated that though female and male RRMS patients have many similarities in various clinical variables, there

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