A new study has identified key rare variants in systemic lupus erythematosus (SLE) in a Chinese population for the first time. Published in Genomics, the study utilised whole-genome sequencing to improve the biomarker identification within the highly heritable disease, where Asian populations are underrepresented in the existing data.
“The novel variants with missense effects in these genes could provide precise therapeutic targets for SLE patients,” the authors write.
Systemic lupus erythematosus prevalence
Systemic lupus erythematosus (SLE) is a chronic but potentially deadly disease. It is characterised by autoimmune intolerance, persistent autoantibody production and inflammation in multiple organs and systems, from the skin to the central nervous system.
SLE is a rare autoimmune disease with high heritability. It affects up to 0.24% of the population globally. It has a higher prevalence in women, as is common for autoimmune diseases, but the specific mechanism causing this disparity remains unclear.
Existing evidence indicates a considerable genetic contribution to SLE susceptibility. First-degree relatives of SLE patients are 20 times more likely to develop SLE compared to the general population.
Previous genome-wide association studies have shown several common variants with small effects in European and East Asian SLE patients. However, common variants with small effects are difficult to map to causal genes, creating an unexplained space in SLE heritability.
In addition, there is still no rare variant study on Chinese SLE patients using whole-genome sequencing technology (WGS). Previous studies on transcontinental populations with SLE have revealed ethnic disparities in the SLE risk. This suggests the importance of accounting for ethnic ancestry in creating a complete profile of SLE genetic variations.
“Most WGS studies were based on non-Asian populations, lowering the effectiveness of early molecular diagnosis and treatment of SLE in Asia,” the authors write.
Family insights
Researchers from Sichuan University designed a family-based WGS study to identify novel rare variants with large effects. WGS is especially cost-effective and powerful for rare disorder research using family-based data.
WGS was performed on 16 Chinese individuals from three families, including seven patients and nine family controls.
Genomics (Chen et al, 2022)
The team used the Genome Aggregation Database to identify rare variants in a broader East Asian population. These population genomic analyses provided insightful genetic background information for the following procedures of SLE-related rare variants identification.
Variant identification
The researchers identified rare protein-coding gene variants with disruptive and sequence-altering impacts in SLE patients. They found that the burden of rare variants was significantly higher than that of common variants in patients. This suggests a larger effect of rare variants on SLE development.
Two genes, including WNT16 and ERVW-1, were found to be the associated with SLE patients in the three Chinese families. WNT16 explained five out of seven patients covering all three families and ERVW-1 explained the other two patients. None of these variants were identified in any of the controls.
The authors caution that it is still under debate whether it is the ethnic ancestry or the socioeconomic status of patients that produces the apparent effect and more studies to fill this knowledge gap should be conducted. They also note that more information on the intersex differences in SLE, especially in relation to rare variants, is needed.
“Our study provides the first direct genetic and in vitro evidence for the pathogenic risk of mutant WNT16 and ERVW-1, which may facilitate the design of precision therapy for systemic lupus erythematosus,” the authors write.
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*In family 1, three SLE cases and four currently unaffected members were sequenced. The husband of WU7 died of chronic pulmonary heart disease, and the mother of WU4 probably died of SLE. B. In family 2, two cases and five unaffected members were sequenced. WU9 is a 25 years old male with an abnormal immunodetection result but without typical SLE symptoms. WU10 and WU11 are twins but only WU10 is suffering from SLE, which was diagnosed at the age of 20. Their mother got a definite diagnosis at 54, even though the onset time could be traced much earlier on the basis of clinical description. C. In family 3, two patients with unaffected familial members were sequenced. NA, not available individual and not sequenced. Star indicates the newly sequenced individual with WGS. The ages of patients during diagnosis are shown next to the patient identifiers.
Written by Poppy Jayne Morgan, Front Line Genomics
Image Credit: Canva
