# Regulation of Inflammation by IL1RN polymorphisms

> **NIH NIH R21** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2021 · $223,740

## Abstract

ABSTRACT
There is significant literature that IL1RN polymorphisms affect clinical outcomes in a variety of diseases,
including osteoarthritis, diabetes, juvenile arthritis and obesity. The precise mechanisms that impart IL1RN's
effects are unknown. We have shown that the IL1RN TTG haplotype (rs419598, rs315952 and rs9005) predicts
both age-related radiographic severity [Kellgren-Lawrence grade (KL), medial joint-space width (JSW)] and is
associated with a 3-fold increased risk for incident knee OA. Moreover, this pro-inflammatory genotype is not
limited to OA but can be demonstrated in patients with rheumatoid arthritis (RA) and in obese patients who carry
the IL1RN TTG risk haplotype. There are a number of functional elements in the IL1RN gene, and it is unclear
which of these confers increased inflammatory function by modulating IL1RN expression and influencing other
genes in the haplotype block. The central objective of this grant, therefore, will be to define the effects of the
IL1RN risk haplotypes in vitro and in vivo using transgenic technologies. In Aim 1: Use synthetic human
haplotypes to determine which functional elements are critical for the inflammatory phenotype conferred by the
IL1RN risk haplotype, in vitro. We will construct risk and protective haplotypes in the context of the flanking
human genes using “Assemblon” technology, which allows the construction and precision delivery of mammalian
gene loci of up to 200 kb in length. Using this technology, we will select informative mouse embryonic stem cell
(mESC) lines and will be differentiated in vitro to monocytes and macrophages which will be assayed for
expression of IL1RN and the other genes in the haplotype block, cytokine production, surface marker
expressions. Aim 2: Generate a humanized mouse expressing the IL1RN TTG-2 risk or TTG-0 non-risk
haplotypes for study in the surgically induced destabilization of the medial meniscus (DMM) model of OA. Since
recent studies also indicate an association of IL1RN genetic polymorphism in obesity and insulin resistance, we
will study high-fat diet-induced obesity models in transgenic humanized mice. These studies will elucidate novel
mechanisms by which the IL1RN risk haplotype influences cellular responses and inflammatory gene regulation,
and will reveal previously unrecognized various functional linked genes, which are crucial for the inflammatory
function of the risk haplotype.

## Key facts

- **NIH application ID:** 10110339
- **Project number:** 1R21AR078466-01
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Steven B Abramson
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $223,740
- **Award type:** 1
- **Project period:** 2021-03-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10110339

## Citation

> US National Institutes of Health, RePORTER application 10110339, Regulation of Inflammation by IL1RN polymorphisms (1R21AR078466-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10110339. Licensed CC0.

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