# Pinpointing how single-cell states affect genetic regulation of HLA expression in autoimmune diseases

> **NIH NIH F30** · HARVARD MEDICAL SCHOOL · 2022 · $39,014

## Abstract

Project Summary:
 Autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus, are debilitating
and highly prevalent chronic conditions that result from pathogenic inflammatory responses. The major
histocompatibility (MHC) region on chromosome 6, which contains the human leukocyte antigen (HLA) and
other immune-related genes, has the strongest genetic association with autoimmune diseases, but the exact
molecular mechanisms behind MHC disease risk are yet unsolved. Previous research has primarily explored
how coding variants affect HLA protein structure and antigen binding, but recent studies highlight the potential
role of noncoding variants in regulating HLA expression. Increased HLA expression could play a causal role in
disease through higher levels of antigen presentation to autoreactive T cells. There is a critical need to better
understand how a cell’s biological state impacts genetic control of HLA expression.
 The proposed research will test the hypothesis that genetic variation in the MHC region modulates HLA
expression in a cell-state-dependent and disease-relevant manner. The applicant will develop innovative
computational methods to integrate both genetic and single-cell transcriptomic data sampled from inflamed
tissues and controls across multiple human immune-mediated disease contexts, comprising >1,088,000 cells
from 384 individuals. Specifically, the study aims to (1) quantify the effect of genetic variation on HLA
expression in key immune and stromal cell states (T, B, fibroblast, and myeloid cells), (2) identify expression
programs and transcriptional regulators that modulate the effect of HLA regulatory variants, and (3) link HLA
regulatory variation to autoimmune disease risk loci. This work will generate a resource detailing HLA
expression across diverse cell states and identify the specific contexts in which genetic variants regulate HLA
expression. This will deepen our fundamental understanding of mechanisms underlying autoimmune disease
risk and may pave the way for better informed therapeutic strategies.
 The proposed training plan will enable the applicant to: (A) strengthen an understanding of the genetic
and immune basis of human diseases, (B) cultivate strong skills in computational genomics methods
development, (C) develop data science skills in statistical genetics and computational immunology, (D)
improve understanding of the clinical aspects of autoimmune diseases, and (E) develop professional scientific
communication skills. An enriching and supportive training environment and close mentorship by experts in
complex trait genetics, immunology, and single-cell methods development will equip the applicant with
knowledge and skills to become an effective physician-scientist who can contribute to the field of disease-
focused computational immunogenomics.

## Key facts

- **NIH application ID:** 10535216
- **Project number:** 1F30AI172238-01
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** Joyce Blossom Kang
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $39,014
- **Award type:** 1
- **Project period:** 2022-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10535216

## Citation

> US National Institutes of Health, RePORTER application 10535216, Pinpointing how single-cell states affect genetic regulation of HLA expression in autoimmune diseases (1F30AI172238-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10535216. Licensed CC0.

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