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Unravelling the Role of Epigenetics and Cytokines in Type 2 Diabetes among African-ancestry Populations

Award Number: R00DK131018
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: 02/01/2025
PERIOD OF PERFORMANCE END DATE: 01/31/2028

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Unravelling the Role of Epigenetics and Cytokines in Type 2 Diabetes among African-ancestry Populations - PROJECT SUMMARY/ABSTRACT African-ancestry populations in the US and Europe are disproportionately affected by type 2 diabetes (T2D), while rates are rapidly increasing in sub-Saharan Africa. The reasons for this disproportionate burden are poorly understood but are thought to be a complex interplay between genetic and environmental factors, such as lifestyle. Previous work led by the candidate demonstrated that T2D in Africans can partly be traced back to DNA methylation-an important epigenetic mechanism that is a key mediator in the interplay between genetics and lifestyle factors. It also suggested that variations in circulating cytokines, partly driven by African-ancestry specific genetic variants, may play a role in the biology of T2D in Africans. The mentored phase of the Pathway to Independence award enabled the candidate to acquire the necessary knowledge and skills to build on this work. An outstanding mentoring committee guided her in mastering causal inference methods, including the application of Mendelian randomization approaches to epigenetic data, polygenic prediction, and mediation analysis, as well as multi-omics analysis. The Center for Research on Genomics and Global Health (CRGG H) at the National Human Genome Research Institute (NHGRI), renowned for its genetics and genomics research in diverse populations, especially African-ancestry populations, provided an ideal environment for the candidate's training du ring the K99 phase of the project. By inferring causality in the previously observed associations between DNA methylation, circulating cytokines, and diabetes, the candidate was able to identify specific DNA methylation sites causally associated with T2D in Africans through two-sample Mendelian randomization approaches. The candidate also identified three circulating cytokines causally associated with insulin sensitivity and beta-cell function, the hallmarks of T2D pathophysiology. To further improve our understanding of the etiology of T2D in Africans, it is imperative to better understand what drives variation in the circulating cytokines causally associated with T2D in Africans. Given the complex interplay of genetic and environmental factors in T2D etiology, the candidate aims to identify both lifestyle and genetic factors causing variability in these cytokines. To achieve this, the candidate will leverage data from two existing cohorts: sub-Saharan Africans living in Africa from the AADM study and sub-Saharan Africans living in Africa and Europe from the RODAM study. To test the hypothesis that both lifestyle factors and genetic regulatory mechanisms drive variation in circulating cytokines relevant forT2D in Africans, the candidate will accomplish two specific aims. Aim 1 is to infer causality in lifestyle-cytokine associations using Mendelian randomization approaches. Aim 2 will identify regulatory mechanisms of cytokines using multi-omics data. Mechanisms by which loci identified in the candidate's published GWAS analyses exert their effect will be studied using genotype, whole genome sequence, DNA methylation, RNA-seq data, and metabolic data. The training received during the mentored phase significantly enhanced the candidate's skill set, allowing the candidate to develop into an independent investigator and lead a lab at the University of Maryland aimed at studying cardiometabolic diseases among African-ancestry populations.


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 = $242,695 )
2026	2026	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	12/18/2025	NON-COMPETING CONTINUATION	$242,695
														Subtotal = $242,695

Issue Date FY: 2025 ( Subtotal = $248,915 )
2025	2025	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	1/21/2025	EXTENSION WITH OR WITHOUT FUNDS	$248,915
														Subtotal = $248,915

Grand Total All Awards = $491,610

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Unravelling the Role of Epigenetics and Cytokines in Type 2 Diabetes among African-ancestry Populations

Award Number: R00DK131018

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: 02/01/2025

PERIOD OF PERFORMANCE END DATE: 01/31/2028

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