# Comprehensive functional genomic analysis of the multi-disease associated CDKN2A/B locus

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $617,273

## Abstract

ABSTRACT
The incidence of cardiovascular disease (CVD), Type 2 diabetes (T2D) and cancers all dramatically increase as
a function of age. The underlying mechanisms of these diseases, which vary, are incompletely understood.
Genome-wide association studies (GWAS) have identified many SNPs that are associated with these conditions.
One of the strongest associations comes from the CDKN2A/B locus on chromosome 9p21.3 which has been
associated with multiple age-related diseases, as well as overall human lifespan. Within this 200 kb locus, there
are three encoded proteins, p16INK4a, p14ARF and p15INK4b, and one antisense non-coding RNA, the inhibitor of
CDK4 (INK4) locus (AS/ANRIL). To date, it has not been firmly established which, if any, of these genes are the
risk genes for the associated diseases. There are ~193 disease-associated, noncoding SNPs in linkage
disequilibrium (LDs) across this 200 kb region, represented by 18 lead SNPs used for GWAS analysis. While
the mechanisms underlying the contribution of these SNPs to specific diseases are not fully understood, a single
genetic region associated with multiple different age-related diseases suggests that this locus may modulate
these conditions by promoting aging itself, perhaps via induction of cellular senescence as a common
mechanism. In this application, we propose to apply an experimental approach using high throughput techniques
we have recently developed including Reel-seq and FREP/SDCP-MS, to systematically dissect this locus. We
will first identify the disease-associated functional SNPs (fSNPs), as well as the regulatory elements across the
58 kb core region primarily associated with cardiovascular diseases using Reel-seq. Next, we will identify the
regulatory proteins that specifically bind to all the fSNPs, as well as the regulatory elements, using FREP/SDCP-
MS. A range of relevant cell types related to atherosclerosis will be used to generate the nuclear extract required
for our screens. We will demonstrate the role of these regulatory proteins by confirming their direct effects on
p16INK4a, p14ARF, p15INK4b and AS/ANRIL expression, and subsequently on cell cycle regulation and cellular
senescence. A range of complementary techniques such as RNAi, CRISPR/cas9 gene editing, will be employed.
Such analysis will provide the first in-depth understanding of this critical genomic region, as well as a unique
strategy to uncover unifying biochemical pathways that simultaneously regulate atherosclerosis, as well as
potentially multiple other age-related diseases.

## Key facts

- **NIH application ID:** 10491270
- **Project number:** 5R01AG065229-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** TOREN FINKEL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $617,273
- **Award type:** 5
- **Project period:** 2021-09-30 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10491270

## Citation

> US National Institutes of Health, RePORTER application 10491270, Comprehensive functional genomic analysis of the multi-disease associated CDKN2A/B locus (5R01AG065229-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10491270. Licensed CC0.

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