Background Systemic Lupus Erythematosus (SLE) is a severe, multisystem autoimmune disease. Twin and sibling studies indicate a strong genetic contribution (44–69%) to SLE. Although numerous recent GWAS studies have identified gene variants, few have been linked to causal polymorphisms in SLE. It may be that few, rare variants could have large impact on SLE risk. Paediatric SLE patients have earlier onset of disease, suffer aggressive course of illness, and may have a stronger genetic risk than adults. Studying aggressive disease in paediatrics has led to myriad breakthroughs in disease pathogenesis, as demonstrated by familial hypercholesterolemia and atherosclerosis, and fever syndromes and autoinflammation. Whole exome sequencing (WES) is a powerful tool to identify rare coding variants for complex phenotypes such as that of SLE. We have established a multisite international paediatric SLE collaboration at four sites: USA, Canada, South Africa, and Mexico. We will use WES to investigate the genetic variants which may give insight into molecular pathways contributing to SLE.
Materials and methods Paediatric SLE patients at sites in the USA, Canada, South Africa and Mexico will be consented. Whole exome capture/sequencing will be performed on patients with paediatric-onset SLE age ≤10 years and/or SLE with strong familial aggregation, defined as > one first degree relative or two second degree relatives with SLE. Patient and parent samples will be processed and analysed as trios.
We will collect standard information on all cohorts, including demographic information, clinical history, family history, medications, exam findings, laboratory values, SLEDAI and SLICC-DI. Organ damage will be defined as end stage renal disease or SLICC-DI>0.
Raw data will be processed by Whole Exome Sequencing using Illumina HiSeq2500. Bioinformatic analysis will be performed at NIH. We will develop an SLE specific bioinformatics pipeline to process data and analyse variants. Results will be filtered against known variants and parental samples.
Results We currently have access to 50 pSLE patients in the US, 75 pSLE patients in SA, 200 pSLE patients in Mexico, and 500 pSLE patients in Canada from which to recruit patients.
We anticipate analysis of 160 samples (20 patient/parent trios at NIH, 50 in Canada) to be complete at the time of presentation. We expect to recruit 30 SA trios, 135 Mexican trios, 40 US trios, and 200 Canadian trios during the total course of the study. Novel rare variants identified will be reviewed.
Conclusions Novel rare variants identified will be reviewed.
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