Genetics and epigenetics of primary Sjögren syndrome: implications for future therapies

Abstract

In primary Sjögren syndrome (pSS), chronic inflammation of exocrine glands results in tissue destruction and sicca symptoms, primarily of the mouth and eyes. Fatigue, arthralgia and myalgia are also common symptoms, whereas extraglandular manifestations that involve the respiratory, nervous and vascular systems occur in a subset of patients. The disease predominantly affects women, with an estimated female to male ratio of 14 to 1. The aetiology of pSS, however, remains incompletely understood, and effective treatment is lacking. Large-scale genetic and epigenetic investigations have revealed associations between pSS and genes in both innate and adaptive immune pathways. The genetic variants mediate context-dependent effects, and both sex and environmental factors can influence the outcome. As such, genetic and epigenetic studies can provide insight into the dysregulated molecular mechanisms, which in turn might reveal new therapeutic possibilities. This Review discusses the genetic and epigenetic features that have been robustly connected with pSS, putting them into the context of cellular function, carrier sex and environmental challenges. In all, the observations point to several novel opportunities for early detection, treatment development and the pathway towards personalized medicine.

Fig. 1. Clinical features of Sjögren syndrome.

The clinical presentation of primary Sjögren syndrome (pSS) is heterogeneous, and patients can present with various symptoms and organ involvement. a, Lymphocyte infiltration and tissue destruction of the salivary glands, as well as the presence of anti-SSA/Ro autoantibodies are hallmarks of the disease, but other features such as leukopenia and non-erosive arthritis are relatively common. The frequency of the best-described organ manifestations in patients with pSS are represented^,. b, Lymphocytic infiltrate in a haematoxylin-stained minor salivary gland biopsy section analysed as part of the diagnostic procedure for Sjögren syndrome. The infiltrate (filled black arrowhead) surrounds dilated secretory ducts and penetrates into glandular tissue. Some remaining acini are indicated by a white arrowhead. c, Diagnostic features required for classification as Sjögren syndrome include histological findings of at least one focus of lymphocytic sialadenitis in a 4 mm² labial salivary gland biopsy (focus score >1), the presence of anti-SSA/Ro autoantibodies and objective measures of decreased production of tears (ocular staining score or Schirmer’s test) or saliva (unstimulated whole salivary flow rate).

Fig. 2. Studies identifying genetic risk loci of genome-wide significance.

An increasing number of studies on primary Sjögren syndrome (pSS) and selected other autoimmune diseases are registered in the genome-wide association studies (GWAS) catalogue. However, the number of studies that have identified genetic variants of genome-wide significance in pSS is still low compared with other autoimmune diseases. In the timeline, key papers in pSS that identify novel genetic loci at genome-wide significance are indicated, as well as large-scale epigenome-wide association studies (EWAS) that included ≥100 patients with pSS. Some genetic risk loci identified for pSS are also associated with other autoimmune disease. Many of the non-HLA variants associated with pSS are also associated with systemic lupus erythematosus (SLE), whereas fewer variants overlap with rheumatoid arthritis (RA) or multiple sclerosis (MS). Some variants seem to specifically increase the risk of pSS^,.

Fig. 3. Associations between variants within the HLA locus and primary Sjögren syndrome.

A large number of variants that are associated with primary Sjögren syndrome (pSS) are located within the HLA locus on chromosome 6. The graph depicts chromosome position (x axis), odds ratio (OR; bubble size) and significance level (y axis) of these disease-associated genetic variants, which are coloured by study. Dotted lines indicate data generated from cohorts that included only patients with pSS who are positive for anti-SSA/Ro and/or anti-SSB/La autoantibodies. Linkage disequilibrium (expressed in terms of the squared correlation (R²)) between the depicted variants in Utah residents of northern and western European ancestry (a population of the 1000 Genomes Project, Code CEU) is indicated in the bottom triangle (data taken from LDlink). Genes near the associated variants are annotated (using data from the UCSC Genome Browser on Human (GRCh37/hg19)).

Fig. 4. Pathogenic processes implicated by genetic and epigenetic studies.

Genetic and epigenetic studies implicate various genes in the development of primary Sjögren syndrome (pSS). Most of these genes have functions in lymphocyte regulation, Toll-like receptor (TLR) or interferon (IFN) signalling, antigen presentation and tissue homeostasis, pointing to a role for these processes in the pathogenesis of pSS. The position and significance level of methylation signals associated with pSS for various tissues are shown in the upper Manhattan plot, including associations found in blood (red dots), salivary glands (blue dots) and B cells (yellow dots). Genetic variants associated with pSS at genome-wide significance and their annotated genes are shown in the lower Manhattan plot. The genes are linked by coloured cords to the four main pathogenic processes, according to gene function; solid lines indicate a direct function, whereas dotted lines indicate an indirect connection to these processes. Data taken from the studies listed in Tables 1 and 2. APC, antigen-presenting cell; BCR, B cell receptor; Chr, chromosome; EWAS, epigenome-wide association studies; GWAS, genome-wide association studies; ICOS, inducible T cell co-stimulator; ICOSL, inducible T cell co-stimulator ligand; TCR, T cell receptor.

Fig. 5. Potential mechanisms connecting biological sex with risk of primary Sjögren syndrome.

Sex hormones affect biological functions directly and indirectly. The figure illustrates how genetic risk factors can result in discordant effects depending on the sex of the individual. a, Suggested hypotheses to explain this discordance include differential hormonal modulation of immune responses, men requiring a higher number of genetic risk loci to develop disease and differences in X chromosome (X chr) dosage. Genes located on the X chromosome, including important immune genes such as TLR7, can escape X chromosome inactivation (XCI), resulting in higher expression of the protein in women than in men. Other epigenetic modifications can also differ between men and women, including microRNA (miRNA) expression, histone modification and DNA methylation patterns. b, Some single nucleotide polymorphisms (SNPs) associated with primary Sjögren syndrome (pSS) affect the expression of genes in a sex-dependent fashion (known as sex-influenced expression quantitative trait loci (eQTL)). Variants associated with pSS with discordant effects on gene expression between men and women that reach a particular significance threshold (P < 0.05) for sex–genotype interactions are included (data taken from the Genotype-Tissue Expression (GTEx) database). All variants in high linkage disequilibrium with the Sjögren syndrome-associated variants were considered. Variants reported as associated with pSS (Table 1) are included in parenthesis if a sex-eQTL effect was identified for a linked variant. The table summarizes the tissue the effect was identified in, the effect size (expressed as a regression coefficient) in men and in women, and the genotype-by-sex (gen*sex) interaction effect size. AR, androgen receptor; ER, oestrogen receptor; Me, methyl group; Ub, ubiquitin.

Fig. 6. Treatment targets implicated by genetic studies in primary Sjögren syndrome.

The processes implicated by genetic studies in the pathogenesis of primary Sjögren syndrome (pSS) include lymphocyte regulation, antigen presentation, Toll-like receptor (TLR) or interferon (IFN) signalling and tissue homeostasis (including apoptosis and autophagy). Selected pSS risk genes involved in these processes are indicated in boxes. These processes (particularly lymphocyte regulation and TLR or interferon signalling pathways) include targets of current and emerging therapies. APC, antigen-presenting cell; BAFF, B cell-activating factor; BCR, B cell receptor; TCR, T cell receptor.