# Insights Into Immune-Related Diseases Born from Population Genomics

> **NIH NIH U01** · UNIVERSITY OF COLORADO DENVER · 2020 · $765,978

## Abstract

The major histocompatibility complex (MHC) of chromosome 6 and the killer cell immunoglobulin-like receptor
(KIR) region of chromosome 19 are among the most variable and medically important regions of the human
genome. The MHC encodes the highly polymorphic human leukocyte antigens (HLA) that are central to immunity
and reproduction, and another 140 genes, many with supporting roles in immunity. A subset of HLA allotypes
interact with KIR, which are expressed by Natural Killer (NK) cells, modulating their activities in initiating and
controlling the immune response. Specific alleles as well as compound genotypes of MHC and KIR have been
implicated in susceptibility or resistance to infectious, allergic, inflammatory, and autoimmune diseases, as well
as to outcomes of hematopoietic cell transplantation and reproductive success.
Asthma is one of the most common inflammatory diseases affecting over 30 million Americans, with 5,000 deaths
per year. Atopic dermatitis (AD) occurs in 20% of children and predisposes to asthma. Together they pose
significant burden on the health and economy of the country, costing an estimated $82 billion per year. Common
to these diseases are a strong genetic component, an environmental or infection trigger, and complex interplay
between innate and adaptive immunity. Accordingly, there are long standing associations with MHC diversity
and asthma susceptibility, which have been confirmed by recent large scale genome studies, but they remain
poorly refined due to the complexity and difficulty of sequencing the region. For the same reasons, the KIR region
has never been studied to high resolution in AD or asthma.
To overcome difficulties in analyzing these complex genomic regions, we developed a targeted sequencing and
bioinformatics approach to analyze MHC and KIR regions at high throughput and resolution. In Aim 1 we will use
the methods to analyze the complete MHC genomic regions from 5,000 patients and 5,000 controls, investigating
each gene as well as their pathways of interaction. We will study well defined cohorts of individuals from diverse
backgrounds, focusing on African ancestry, which associates with the highest prevalence and poorest outcome.
We will sequence the entire MHC with high accuracy to determine the full context of any variants associated with
asthma susceptibility. In Aim 2 we will perform the first high resolution analysis of NK cell diversity in asthma,
supported by directed functional analyses of the activity and specificity of NK cells in disease. By combining high-
resolution analysis of KIR and HLA genes with known functional properties of these interactions, we will be able
to determine the role of NK cell diversity in asthma. To enhance our methodology and solve the most difficult
genomic structural variation, in Aim 3 we will design and implement the first methods to target long-read
sequencing specifically to the MHC and KIR regions, and a bioinformatics pipeline to annotate and analyze the...

## Key facts

- **NIH application ID:** 10008512
- **Project number:** 2U01AI090905-11
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Paul John Norman
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $765,978
- **Award type:** 2
- **Project period:** 2010-07-06 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10008512

## Citation

> US National Institutes of Health, RePORTER application 10008512, Insights Into Immune-Related Diseases Born from Population Genomics (2U01AI090905-11). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10008512. Licensed CC0.

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