Genetics and pathophysiology of systemic lupus erythematosus in global populations

National Institute Of Arthritis And Musculoskeletal And Skin Diseases

Investigators

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Abstract

This unit is focused on understanding how rare genetic variants contribute to systemic lupus erythematosus (SLE) pathogenesis in a diverse cohort of early-onset SLE patients. We also aim to understand the genetic architecture of childhood-onset SLE (cSLE) in a large cohort of patients worldwide. We have established collaborations with cSLE researchers in 4 countries. In doing so, we were able to perform whole genome sequencing on more than 150 childhood and adult onset SLE patients worldwide, and in many cases also collect samples from unaffected relatives. Using this collection, we are beginning to identify rare variants which may be important to refining the heterogenous clinical phenotype of cSLE into precise molecular phenotypes. Additionally, with whole genome data, we can better understand the comprehensive genetic architecture of these patients. With these data, we will be able to define the burden of both rare and common variants in these patients and try to understand the balance in different pediatric age groups and ancestral backgrounds. Defining the genetic architecture of SLE will help us to further understand the role of genetics in disease onset and severity in the pathogenesis of this complex disease. Our study aims to include patients of diverse ages and ancestral backgrounds, as previous studies have focused on mostly patients of European ancestry and of very early onset of disease. In addition, through collaboration, we are aiming to understand more about the clinical spectrum of cSLE. Rare Variant Analysis of childhood-onset SLE Whole genome data have remarkable capacity for discovery of variation causing disease across the genome. Yet whole genome sequencing (WGS) studies yield massive amounts of variant data, and it can be difficult to identify causative variants. Trio analysis of unaffected parents and affected patients or multiplex families allows more effective variant prioritization. We have collected and sequenced 81 cSLE patients and 111 parents, of which 43 were parent/patient trios from diverse ancestral backgrounds. We have prioritized rare variants through bioinformatic pipelines to first focus on those with a large effect on protein function. We have identified the first variants of interest. We have performed WGS on 59 additional SLE patients and unaffected relatives and will begin analysis of these samples. We are currently growing our collaborative network to include more cSLE patients nationally and internationally. Additional sequencing efforts will allow us to increase sample size, which increases potential for discovery but also for validation of important variants. Sequencing patients across a wider age range will help us understand more about the genetic contribution of SLE along the continuum of age at disease onset. Importantly, the foundation for analysis of whole genome data in a diverse cSLE cohort has been established with this initial data analysis. Therefore, subsequent studies will be accelerated by benefitting from the robust methodology we have developed. Genetic Architecture of SLE The pathogenesis of SLE is not fully understood but thought to be triggered by environmental events in a genetically susceptible individual. Whole exome sequencing (WES) and WGS are powerful tools for researchers elucidating genetic variants linked to human diseases. Many genome-wide association studies (GWAS) have been done in SLE, however only a few WES/WGS studies reported rare, highly penetrant genetic variants with a large impact on protein function. In addition to rare variant analysis, whole genome data can be mined for common variants described to confer risk for SLE by GWAS. A cumulative genetic risk score can describe the burden of common risk variants carried within a cohort of patients. Previous studies have determined that earlier onset of disease is associated with higher polygenic risk score (PRS). A study in cSLE showed that a higher score is associated with severe manifestations such as nephritis. No studies compiling a PRS from whole genome data in cSLE patients have been completed to date. This will be the first study to investigate the burden of both rare and common variants in a cSLE patient cohort. The current paradigm for genetic risk in cSLE is that the burden of rare and common SLE risk variants is inversely related in patients, with younger and more severe patients having a higher burden of rare, damaging variants but a low burden of common milder variants. Inversely, adolescent patients and those with milder phenotypes are expected to have a higher burden of common SLE risk variants and few rare variants. However, the actual distribution and balance between rare and common variants in cSLE patients have not been reported. We have performed WGS on 192 SLE patients and unaffected relatives to date. Sequencing patients across a wider age range will help us understand more about the genetic contribution of SLE along the continuum of age at disease onset. Importantly, the foundation for analysis of whole genome data in a diverse cSLE cohort has been established with this initial data analysis. We have completed an assessment of the burden of common risk variants for SLE in our diverse cohort of cSLE patients using a weighted polygenic risk score. We will map the balance of known common and rare SLE risk variants in our cSLE cohort using whole genome data. Exploring the gene-environment interaction in the pathogenesis of childhood-onset SLE by studying the virome While SLE has a strong genetic component, gene-environment interactions may also play a role in disease onset and severity. Ambient environmental exposures vary throughout the course of a lifetime and are notoriously difficult to quantify. Recently, the microbiome has been identified as an important influence in shaping human immune tolerance and thus susceptibility to autoimmunity. The virome is a subset of the microbiome which consists of viruses rather than bacteria. The virome may be important in shaping human immunity, as humans encounter a wide range of viral exposures throughout lifetime. Additionally, there is evidence that viruses may play an important role in the development of autoimmunity. Viral sensing pathways have mechanistic links to the pathogenesis of SLE. Virus nucleic acids are recognized by endosomal toll-like receptors (TLRs), cytosolic RIG-I like receptors (RLRs), and DNA sensors. Genetic changes in these pathways have been described in monogenic SLE, as they result in the activation of type I interferon genes. Viral infections such as Epstein-Barr Virus (EBV) and cytomegalovirus (CMV) have been associated with increased risk of SLE. Studies of the gut virome in children suggest it plays a role in health and disease. Most reports have studied the correlation of a history of prior viral infection such as EBV, with risk of developing SLE. Other studies have investigated DNA or RNA for endogenous retroelements, but have not analyzed whole blood transcriptomes directly for mapped viral sequences. We have completed whole blood RNA sequencing from 43 cSLE patients and 36 healthy relatives from South Africa, Mexico, and the USA; and 151 adult SLE patients and 94 adult HC from the USA. We are currently analyzing the data from this cohort. This investigation may provide an important insight into the genetic-environmental interactions that contribute to the onset and severity of SLE.