Rare Genetic Mutations Linked to Lupus Risk

Blood sample positive with systemic lupus erythematosus (SLE)

Rare gene variants have been linked to systemic lupus erythematosus (SLE)  by a group of scientists led by Carola G. Vinuesa, Ph.D., of the Australian National University. The research was published May 17 in Nature Communications.

SLE is a highly heterogeneous autoimmune disease thought to be caused by the effects of many common variant gene loci. This new research, however, describes rare coding variants that are found in most SLE patients but not in healthy controls. These variants are believed to be drivers of the immune dysregulation that characterizes this disease.

The group described the functional consequences of rare and low frequency BLK and BANK1 missense variants, which are proteins that interact and are present alone, or in combination, just in lupus patients. These variants impair suppression of IRF5 and type-I IFN in human B cell lines and increase levels of pathogenic lymphocytes in mouse models of lupus.

SLE varies both in terms of clinical presentation and underlying pathophysiology. Studies of patients and animal models suggest multiple mechanisms contribute to symptoms, including B-cell hyperreactivity and breaks in B-cell tolerance caused by B-cell intrinsic and extrinsic factors.

Little is still known about the genetics underlying SLE. Concordance for the disease in monozygotic twins is approximately 50%, but overall inheritance follows complex non-Mendelian patterns and variants found using genome-wide association (GWAS) studies have so far not been able to explain a genetic cause for the disease.

This latest study’s authors write: “The prevalent hypothesis to explain the observation of common allelic frequency and modest effect size is that it is the cumulative or epistatic effect of multiple GWAS single-nucleotide polymorphisms (SNPs) in addition to environmental factors that result in predisposition to SLE.”  But it has also been suggested that rare genetic variants with strong effects can also cause SLE.

The Australian scientists set out to uncover such variants by studying a group of 69 patients with the condition and 97 healthy elderly people without a history of chronic disease.  The SLE cohort included patients with pediatric-onset, adolescent-onset and adult-onset disease.  Most of the patients in both groups were predominantly of European ethnicity.

All of the controls and about 13% of the SLE patients underwent whole-genome sequencing (WGS). The rest of the SLE patients had whole-exome sequencing (WES).  The researchers then looked for rare (minor allele frequencies, or MAFs, below 0.005 specific to the individuals’ ethnicity)  missense and splice site variants. They found that most SLE patients had rare gene coding variants in SLE-associated genes. The most common variants seen were in the genes BLK, LYST, TYK2, UHRF1BP1 and IKBKE. 

To evaluate the role of rare variants in this condition, they then did complementary functional studies, starting by looking at the single nucleotide variants (SNVs) in BLK, because they had observed a relatively high frequency of rare variants in that gene. Six SNVs where identified in that gene.  Further studies found that BANK1 SNVs also increases risk of SLE. “SLE patients are likely to harbor two or more rare variants in genes implicated in SLE by GWAS or involved in the regulation of T1 IFN,” the authors wrote.

SLE affects 20 to 150 out of 100,000 people in the United States. The condition is about twice as prevalent in African American women as white women, and can is a serious condition for women of child bearing age.  Because it is so hard to diagnose and treat, progress such as this in uncovering its genetic underpinnings is especially important.

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