# Transancestral fine mapping and functional dissection of autophagy-related SLE risk loci

> **NIH NIH R01** · MEDICAL UNIVERSITY OF SOUTH CAROLINA · 2020 · $701,196

## Abstract

Systemic lupus erythematosus (SLE) is a chronic, heterogeneous autoimmune disease that disproportionally
affects women and the disease is often more severe with end-organ damage in non-white populations. Few
effective treatments exist for SLE, largely because the etiology is incompletely understood; however, the
disease is likely to occur in genetically susceptible individuals upon environmental triggers. Multiple genome
wide association studies (GWAS) and replication studies have identified ~100 (80 published and 20 in the
publishing process) SLE susceptibility loci (P<5x10-8) using mainly European- and Asian-derived populations.
Our recent Korean GWAS and other published studies of Asians have implicated a number of autophagy-
related gene loci in SLE, similar to several other autoimmune diseases. Autophagy is an intracellular process
that transports damage cytoplasmic organelles, macromolecular aggregates, or intracellular pathogens to the
lysosome for degradation and recycling. Autophagy cross talks with the immune system and controls
inflammation through effects on various immune cells to regulate immune homeostasis and to modulate host
defenses. Fine mapping autophagy-related gene loci associated with SLE is necessary to gain understanding
how these genetic variants affect different aspects of autophagy pathways in specific immune cell types, which
may serve as a new drug target for SLE treatment. Due to linkage disequilibrium (LD), each risk locus contains
multiple variants, and in some cases, multiple genes that could impact biologic functions relating to SLE
pathogenesis. In Aim 1, we propose to utilize LD structure differences between Asian and African-derived
ancestries to conduct transracially fine-mapping and bioinformatics analysis of seven SLE risk loci related to
autophagy (ATG16L2-FCHSD2-P2RY2, PRDM1-ATG5, DRAM1, CDKN1B, CLEC16A, NCF2 and HIP1) using
the Global Screening Array (GSA) that contains headroom for custom variants in SLE cases and controls of
non-white minorities (4000 Asians and 3000 African Americans [AA]). By comparing haplotype structures and
applying Bayesian approaches, we will obtain the best credible set of variants to pursue further. In Aim 2, we
will refine credible variant list by using bioinformatics and molecular approaches to identify functional variants.
This will include sorting immune cell subsets from 100 AA SLE patients and 100 AA controls (matched for age
and gender) for RNA-seq and qRT-PCR to correlate allelic genotypes with differential gene expression and
splicing as well as conducting molecular biology assays. The best candidates will be further tested in Aim 3 to
conduct immunophenotyping, RNA-seq and autophagy functional assays to assess the consequences of gene-
edited immune cell lines and induced pluripotent stem cells (iPSCs), which will determine the pertinent cell
subset from SLE patients and controls to conduct autophagy functional assays for confirmation of genotypic
effects. Our resul...

## Key facts

- **NIH application ID:** 9898320
- **Project number:** 5R01AR071410-03
- **Recipient organization:** MEDICAL UNIVERSITY OF SOUTH CAROLINA
- **Principal Investigator:** Christopher J Lessard
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $701,196
- **Award type:** 5
- **Project period:** 2018-04-09 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9898320

## Citation

> US National Institutes of Health, RePORTER application 9898320, Transancestral fine mapping and functional dissection of autophagy-related SLE risk loci (5R01AR071410-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9898320. Licensed CC0.

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