Genetics of Psoriatic Arthritis Remains a Complicated Puzzle, Researchers Say

April 24, 2020

A number of advances have been made in recent years in our understanding of the genetics of psoriatic diseases and psoriatic arthritis specifically. However, those advances have yet to translate into clinically meaningful insights.

Scientists are beginning to understand more and more about the genetics of psoriatic disease, but the coming years likely hold even more significant breakthroughs, according to a new review.

The article, published in Current Rheumatology Reports, details how the scientific community’s understanding of psoriatic diseases has changed as investigators have looked for links between previously identified genetic variants.

Psoriasis is a relatively common skin condition that affects about 3% of adults in the United States. Between 20% and 30% of patients with cutaneous psoriasis will also develop psoriatic arthritis (PsA), which is a distinctive type of inflammatory arthritis, according to corresponding author Proton Rahman, MD, of Memorial University, in Canada. He and colleagues write that cutaneous psoriasis and psoriatic arthritis (PsA) are related but different in complex ways.

“The genetic architecture differs between psoriatic arthritis and cutaneous-only psoriasis with arthritis-specific signals in linkage disequilibrium independent of the published psoriasis signals,” Rahman said.

Both diseases are multifactorial, triggered by a range of factors including genetics and environmental causes. Those triggers lead to the dysregulation of immunological pathways involving the Th1-, Th2-, and Th-17 based cytokines, the authors write. More than 70 genome-wide candidate loci have been identified as associated with psoriatic disease, and some of those have been associated with PsA.

“However, not all these loci have been consistently replicated, and the effect size of any given genetic loci outside the MHC region is modest (odds ratio&thinsp;<&thinsp;1.2),” the authors note. “Also, there is incomplete or limited information on the proposed function and relevance of some genes implicated in psoriatic disease pathology.”

In short, Rahman and colleagues say, these findings do not yet have much clinical utility in terms of diagnosing or managing psoriatic disease.

In reviewing the latest attempts to solve the puzzle, the authors outline some of the complexities that make it difficult to tease out meaningful genetic insights. One of the key challenges, the authors say, is picking out the variants specifically at play in PsA versus psoriatic disease more generally.

Another question for investigators is how much of a role do different factors—genetics versus environment—play in the disease? There is evidence that PsA is more strongly linked to genetic factors, and a number of studies detailed in the review article have sought to understand the genetic differences between PsA and cutaneous psoriasis. Rahman and colleagues also say new strategies ought to bear fruit in the coming years.

“Substantive progress has been made in the genetics of psoriatic disease over the last decade primary due to SNP-based large-scale association studies, as over 70 candidate loci have reached genome-wide statistical significance,” they write.

Future studies with larger cohorts and detailed phenotyping should lead to additional candidate loci, the authors say, particularly in subsets of the disease that are well defined.

“These studies will be complemented by data derived from NGS of the whole exome and/or whole genome which will identify rare variants for multiplex families,” they say. “In addition, integration and computational analysis can provide insight into functional relationships among identified variations and characterize novel signaling pathways.”

Rahman and colleagues say transcript profiling, micro-RNA, circulating RNA, and single-cell sequencing are a major area of focus of current research. Those findings, along with other research, ought to generate significant strides in the scientific community’s understanding of this category of diseases.

“Thus, we are still at the early stages of interrogating the genetic basis of psoriatic disease, and the rapid emergence of affordable high-throughput technology, coupled with advances in big data analysis and integrative medicine, will likely lead to numerous novel candidates, some of which will hopefully lead to improved diagnosis, prognosis, and therapeutic response for psoriatic disease,” they conclude.

Reference

Rahmati, S., Tsoi, L., O’Rielly, D. et al. Complexities in genetics of psoriatic arthritis. Curr Rheumatol Rep. 2020;22(10). doi: 10.1007/s11926-020-0886-x.