Genetics and Functional Genomics of Spondyloarthritis

Abstract

Spondyloarthritis (SpA) is a chronic inflammatory disorder with high heritability but with complex genetics. It encompasses several entities that share common clinical features. Most of the genetic studies in SpA have been restricted to ankylosing spondylitis (AS), the prototypical form of SpA. However, there is growing evidence of shared genetic background between all the SpA subtypes and also with some other immune-mediated diseases. The most important part of SpA heritability comes from the HLA-B27 allele in the major histocompatibility complex (MHC) that explains around 25% of the attributable heredity. Several other loci outside of the MHC have been shown to be involved in the disease. However, all these non-MHC loci explain only a small additional fraction of disease predisposition. Thus, a substantial fraction of SpA genetic basis remains poorly understood. Gene expression profiling is a complementary approach to elucidate the underlying mechanisms and pathways that drive the disease. Several expression profiling studies have been undertaken in SpA. However, results have been quite disappointing with little overlap between the studies largely due to the small sample sizes, resulting in limited power to discover small effects. In this review, we summarize current knowledge on genetic findings concerning SpA and we describe strategic approaches for identification of additional variants, with a focus on rare variants in familial forms. We also provide an overview of gene expression studies in SpA and discuss the possibilities offered by high-throughput RNA sequencing technologies, in particular in sorted cells. Finally, issues in establishing molecular mechanisms underlying genetic association hits and potential translational applications will be addressed.

HLA-B27 alters BMP/TGFβ signalling inDrosophila, revealing putative pathogenic mechanism for spondyloarthritis

“…Strikingly, flies transgenic for AS-associated HLA-B*27:04 and HLA-B*27:05, in combination with hβ2m, exhibited crossveinless and small-eye phenotypes. In contrast, coexpression of HLA-B*07:02 allele (which is known to be protective from AS)33 with hβ2m, used as a control condition, did not affect fly development. These results underscore HLA-B27- expressing Drosophila as a new promising model to investigate HLA-B27 pathogenic effects, even if it bears some limitations owing to the lack of adaptive immune system.…”

Optimization of HLA-B*27 ALLELE Genotyping by PCR-SSP

“…HLA-B*27 allelic genotyping has become important in clinical practice for the treatment and management of spondyloarthropathies. In AS, HLA-B*27 is the most important genetic marker and some alleles such as HLA- B*27:05 , B*27:02 , B*27:04 , and B*27:07 , have been associated with the disease ( 4 , 9 ). Through the standardized PCR-SSP technique, it was possible to genotype the HLA-B*27 alleles frequent in the Brazilian population.…”

“…Studies have shown that HLA-B*27:05 , HLA-B*27:04 , and HLA-B*27:02 are associated with AS in the Caucasian, Chinese, and Mediterranean populations, respectively ( 4 ). The HLA-B*27:06 and HLA-B*27:09 alleles were not found to be associated with AS ( 4 , 9 , 10 ).…”

“…The identification of the HLA-B*27 alleles is relevant in the clinical follow-up, diagnosis, and treatment of AS ( 9 ). This work aimed to optimize HLA-B*27 genotyping using PCR-SSP, an easy-to-use and affordable technique.…”

Immune checkpoint inhibitor–induced inflammatory arthritis as a model of autoimmune arthritis

“… SNPs in genes outside of the MHC locus have also been linked to an increased risk for developing SpA, including those in ERAP1 and IL23R (reviewed elsewhere ref. 145). …”