Sex differences and genomics in autoimmune diseases

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Abstract

Autoimmune diseases (AIDs) are believed to be multifactorial diseases that commonly involve multiple organ systems. About three fourth of the patients afflicted with AIDs are women suggesting that sex differences impact the incidence of AID. However, the proportion of females to males suffering from AID varies depending on the disease. The response to some AID therapeutics also differs in females versus males, suggesting that enrollment of adequate numbers of women and men is important in clinical trials for development of AID drugs. It is known for a long time that genetic factors are important contributors to AID susceptibility. Currently available information suggests that multiple genes with modest association to AID contribute to susceptibility to AID. Also, the associations may differ for the various ethnicities. The major histocompatibility (MHC) locus appears to be a major genetic factor that confers susceptibility to multiple AIDs, even though the locus is complex and has the highest density of genes in the human genome. Thus, the association of different AIDs could be with different genes in the MHC locus. Among the non-MHC genes, some of the risk alleles are shared between different AIDs, but may not be common to all AIDs. For example, genetic polymorphisms in the Protein Tyrosine Phosphatase-22 (PTPN22) gene have reproducibly shown to have association with systemic lupus erythematosus (SLE), Graves’ disease (GD), rheumatoid arthritis (RA) and multiple sclerosis (MS), but not with psoriasis. Identification of factors responsible for risk for developing AID and the of the pathways underlying these diseases are likely to help understand subsets of disease, identify responders to a specific treatment and develop better therapeutics for AID.

Highlights

► Patients with autoimmune diseases are predominantly women. ► Impact of sex differences on autoimmune diseases examined. ► Association of genetic factors including contribution of HLA, non-HLA genes and X chromosome. ► Unique as well as an overlap of some susceptibility alleles in multiple autoimmune diseases observed.

Introduction

Autoimmunity refers to the misdirected attacks made by the body’s immune system against itself as a result of a failure in recognizing self antigens correctly. This phenomenon is usually a harmless process, but has the potential to lead to a broad spectrum of multiple, complex autoimmune diseases (AID). More than 5% of the US population is afflicted by AID and at least eighty illnesses caused by autoimmunity are known [1]. Multi-organ involvement is commonly observed in AID and the damage to the primary target-organ usually drives the clinical presentation and characterizes the disease.

Genetic and environmental factors are believed to be the triggers for progression of harmless autoimmunity to autoimmune disease. Sex also appears to be an important determinant since 75–80% of the patients suffering from AID are women. Autoimmune diseases also are one of the top 10 leading causes of death in women in a variety of age groups up to 65 [2], [3], [4]. This review article will focus on the impact of genomics/genetics and sex differences in autoimmunity, particularly in AID.

Section snippets

Sex differences and autoimmunity

Female predominance in AID has been known for more than a century. However, the proportion of females with AID varies depending on the disease; from 18:1 in thyroiditis/hypothyroidism to 1:1 in psoriasis to 1:2 in ankylosing spondylitis (AS). There are a few examples of AID where the proportion of males to females is high (1: (2–9)), such as Goodpasture’s syndrome (Table 1). Autoimmune diseases, more prevalent in men, are characterized by acute inflammation, appearance of autoantibodies and a

Genomics/genetics in autoimmunity

The pathogenesis of AID is considered to be multifactorial. However, genetic factors are established to be important contributors to susceptibility in developing autoimmune diseases based on several findings including the observation that rates of concordance for many autoimmune diseases is higher in monozygotic twins than in dizygotic twins [20] (Table 1). In addition, epidemiological studies show variable prevalence rates of autoimmune diseases in different geographical areas and provide

Autoimmune diseases

In the United States, autoimmune diseases are the third most common category of disease, after cancer and cardiovascular disease [3]. Since our focus is on sex and genomics in autoimmune diseases, we selected to review a spectrum of AIDs which differed in the prevalence of the disease in females versus males.

Conclusions

It is well-known that the prevalence of most AIDs is higher in women than in men. However, the reasons underlying increased risk of developing AID in women are still not understood. Better understanding of epigenetic factors, including the role of microRNAs, may shed more light on the mechanisms involved in AIDs. The impact of hormones and other environmental factors on development of AID further makes it challenging to understand the etiology of AIDs.

The advent of genomic technologies such as

Disclosure

The views expressed are those of the authors and do not necessarily reflect US FDA policy. No official endorsement is intended nor should be inferred.

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