The publication of the human genome sequence in 2001 represented one of the major milestones in the history of biology and much effort has since been devoted to describing and understanding human variation. The International HapMap project has constructed an extensive database of human variation in European, African and Asian genomes, characterizing over 1.5 million single nucleotide polymorphisms (SNPs). The combination of these SNP catalogs (containing SNPs with an allele frequency commonly higher than 5%) with high-throughput genotyping technologies and arrays allowed for the production of genome-wide-association studies (GWAS) for many human common diseases, especially auto-immune diseases, such as rheumatoid arthritis and systemic lupus erythematosus, and several other rheumatic diseases such as psoriatic arthritis, ankylosing spondylitis and osteoarthritis. These experiments were inspired by the ‘common disease-common variant’ hypothesis, which claimed that common alleles underlie most common human diseases. However, it has become apparent that a significant amount of heritability remains unexplained for most of these complex diseases. The “missing heritability” problem resulting from these GWAS has triggered interest in the potential role of rare variants in complex disease, as indicated by the’ common disease-rare variant’ (CDRV)hypothesis. Direct sequencing rather than genotyping is required for exploration of the CDRV hypothesis in complex diseases, as a result of the expected high allelic heterogeneity, to identify all rare risk alleles across a population. The advent of next generation sequencing (NGS) technologies has dramatically reduced the time and cost of population sequencing, setting the stage for widespread exploration of the CDRV hypothesis. Whole genome, whole exome, and targeted region sequencing to identify rare risk alleles across a population have become feasible with these technologies. Data from NGS of whole human exomes are being successfully applied to identify mutations in genes underlying rare Mendelian disorders. A promising area for application of NGS technologies is to identify rare variants in genes and loci in which common polymorphisms have previously been associated with rheumatic diseases. Sequencing of these loci may unravel rare variants whose accumulation will explain a portion of the missing heritability in the genetics of complex rheumatic diseases. Despite many challenges that lie ahead in applying these technologies to rheumatic disease, rare variants are likely to be a critical piece of the puzzle that needs to be solved to understand the genetic basis of rheumatic diseases and to use this information to develop better therapies.
Another promising area for application of NGS technologies is that of pharmacogenetics, the study of variations in genes encoding drug transporters, drug-metabolizing enzymes and drug targets, and their translation to differential responses to drugs. Pharmacogenetics is a rapidly progressing field in rheumatology and its applications, particularly to methotrexate, and the newer, more expensive biologic agents, might make personalized therapy in rheumatic diseases possible.
Disclosure of Interest None Declared