What methods can be used to determine the genetic contribution to rheumatic disease?

From the Guidelines

Genetic testing, such as next-generation sequencing (NGS) and Sanger sequencing, can be used to determine the genetic contribution to rheumatic disease, particularly in cases where suggestive clinical features are present. According to the most recent evidence 1, NGS platforms are now widely used and are replacing the Sanger sequencing “gene by gene” approach. The choice of genetic testing method depends on the specific condition being investigated, with NGS being generally recommended for its comprehensive coverage.

Some key methods for determining the genetic contribution to rheumatic diseases include:

• Next-generation sequencing (NGS) for its ability to scan the entire genome and identify genetic variants associated with rheumatic conditions
• Sanger sequencing for cost-effective analysis of a single gene, particularly in patients with a known familial disease or classic disease features
• Whole exome sequencing and whole genome sequencing for comprehensive genetic information to identify rare variants
• Chromosomal microarray analysis by comparative genomic hybridization array or by single nucleotide polymorphism array to detect large deletions
• PCR and sequencing using specific deletion breakpoint primers to screen reported large deletions in selected ethnic backgrounds

It's essential to note that HLA-B27 testing may be helpful in specific clinical settings, such as when spondyloarthritis is suspected 1. However, the current evidence suggests that there is no genetic test that can be routinely recommended for all rheumatic diseases. The experts acknowledge the current lack of evidence for the practical utility of genetics in undifferentiated peripheral inflammatory arthritis (UPIA), but highlight the potential usefulness of HLA-B27 testing in specific clinical settings.

In cases where a genetic diagnosis cannot be made following routine genetic workup, patients should be referred to a research centre of excellence with expertise in the molecular diagnosis of systemic autoinflammatory diseases (SAIDs) 1. This approach ensures that patients receive the most accurate diagnosis and appropriate management for their condition.

From the Research

Methods to Determine Genetic Contribution to Rheumatic Disease

The genetic contribution to rheumatic disease can be determined using various methods, including:

• Genome-wide association studies (GWAS) to identify susceptibility loci 2
• Genetic association studies to investigate the relationship between specific genes and rheumatic diseases 3
• Mapping of the human genome to understand the genetic basis of rheumatic diseases 4
• Identification of genetic variants implicated in rheumatic disease susceptibility, such as single nucleotide polymorphisms (SNPs) 3
• Investigation of the role of human leukocyte antigens (HLA) in genetic susceptibility to rheumatic diseases 4, 2

Genetic Factors Involved in Rheumatic Disease

Several genetic factors have been implicated in rheumatic disease, including:

• HLA-B27, which contributes to genetic susceptibility to ankylosing spondylitis and related spondyloarthropathies 4
• Other genes, such as MHC, IL-1RA, IL-6, IL-10, and CYP2D6, which may also be involved in rheumatic disease susceptibility 4
• Genetic variants, such as TGF-β1 and IL-1β, which have been associated with susceptibility to rheumatic heart disease 3

Study Designs and Technologies

Various study designs and technologies have been used to investigate the genetic contribution to rheumatic disease, including:

• Candidate gene studies to investigate the relationship between specific genes and rheumatic diseases 3
• Genome-wide screens to identify chromosomal areas of interest 4
• Bioinformatics and advanced statistical methods to analyze large-scale genetic data 5
• International collaboration and the use of large-scale, publicly available data to facilitate comprehensive studies 2