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Genetic susceptibility to Barrett's esophagus: From GWAS to biology

Award Number: R01DK128615
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/21/2021
PERIOD OF PERFORMANCE END DATE: 11/30/2026

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Genetic susceptibility to Barrett's esophagus: From GWAS to biology - Barrett’s esophagus (BE) is the only known precursor for esophageal adenocarcinoma (EAC), a highly lethal cancer with rising incidence and median survival <1 year. Substantial health-care resources are devoted to BE screening, surveillance, and treatment. Gastroesophageal reflux-induced injury of the lower esophagus and chronic inflammation are key drivers of BE development, but molecular pathways underlying risk are not well defined. Recent genome-wide association studies (GWAS) led by members of our team identified >20 novel genetic susceptibility loci for BE/EAC, providing new insights into the inherited genetic component of risk. Nevertheless, little progress has been made in bridging associations to biology. Consistent with GWAS of other complex diseases, all BE index variants map to non-coding regions, lack obvious biologic function, and are in linkage disequlibrium with many other SNPs, any of which may be causal. The vast majority of functional variants underlying GWAS signals are believed to map to and alter activity of regulatory elements including enhancers, in an allele-specific manner, and in turn modulate expression of downstream genes involved in risk. Importantly, such regulatory effects may be tissue- and condition-specific. To begin prioritizing candidate functional variants for experimental interrogation, we developed a customized informatics scoring pipeline using comprehensive in-silico annotations from multiple public resources. We selected four high-scoring BE risk loci for evaluation using luciferase reporter assays in esophageal cell lines, and found that two of four regions exhibited allele-specific enhancer activity. CRISPR-mediated deletion of the enhancer region at both loci correlated with downregulation of several candidate risk genes. Motivated by these successes, we seek to expand our integrative framework for elucidating functional consequences of BE-related genetic variation. We hypothesize that such variation is biologically expressed through alterations in transcriptional regulation and downstream gene expression. Our goal is to identify functional variants, risk enhancers, and target genes underlying BE risk, leveraging unique resources and complementary statistical/experimental approaches. In Aim 1, we will define candidate causal variants via Bayesian fine-mapping, using the largest BE GWAS world- wide, and further prioritize leading candidates via functional-potential scores. In Aim 2, we will perform new transcriptome profiling of reflux-exposed gastroesophageal junction tissues and constituent cells, and identify candidate BE risk genes and pathways via eQTL colocalization and network-based analysis. In Aim 3, we will validate candidate functional variants using luciferase reporter enhancer activity assays; identify target genes of risk enhancers via CRISPR-mediated enhancer deletion and RNA-Seq; and interrogate pathways influenced by prioritized target genes in Aims 2 & 3 via CRISPR-mediated gene knockdown/overexpression and RNA- Seq. This study will advance noncoding GWAS signals into functional biological signatures and support future efforts to develop novel preventive/interventional strategies for BE/EAC.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $0 )
2026	2025	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	11/10/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $751,138 )
2025	2025	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	11/18/2024	NON-COMPETING CONTINUATION	$751,138
														Subtotal = $751,138

Issue Date FY: 2024 ( Subtotal = $762,211 )
2024	2024	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVENUE	NEW YORK	NY	10065	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	11/17/2023	NON-COMPETING CONTINUATION	$714,573
2024	2024	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVENUE	NEW YORK	NY	10065	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	5/15/2024	NON-COMPETING CONTINUATION	$47,638
														Subtotal = $762,211

Issue Date FY: 2023 ( Subtotal = $801,778 )
2023	2023	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	1/10/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$801,778
2023	2023	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVENUE	NEW YORK	NY	10065	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	2	2/13/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$508,305
2023	2022	HEALTH RESEARCH, INC.	ELM AND CARLTON ST	BUFFALO	NY	14263	ERIE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	1/9/2023	NEW	$0
2023	2022	HEALTH RESEARCH, INC.	ELM & CARLTON ST	BUFFALO	NY	14263	ERIE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	1	2/13/2023	NEW	-$508,305
														Subtotal = $801,778

Issue Date FY: 2022 ( Subtotal = $762,225 )
2022	2022	HEALTH RESEARCH, INC.	ELM AND CARLTON ST	BUFFALO	NY	14263	ERIE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	12/20/2021	NEW	$762,225
														Subtotal = $762,225

Grand Total All Awards = $3,077,352

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Genetic susceptibility to Barrett's esophagus: From GWAS to biology

Award Number: R01DK128615

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 12/21/2021

PERIOD OF PERFORMANCE END DATE: 11/30/2026

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