Project Grant K43TW011926

PREVALENCE AND TEMPORAL DYNAMICS OF CLONAL MUTATIONS ASSOCIATED WITH THE RISK OF HEMATOLOGICAL CANCER IN A COHORT OF CLINICALLY HEALTHY NIGERIANS - PROJECT SUMMARY/ABSTRACT THE BURDEN OF NON-COMMUNICABLE DISEASES, ESPECIALLY HEMATOLOGICAL MALIGNANCIES AND CARDIOVASCULAR DISEASES (CVDS), IS RISING IN AFRICA. CLONAL HEMATOPOIESIS OF INDETERMINATE POTENTIAL (CHIP) IS AN AGE-RELATED RISK FACTOR FOR ALL-CAUSE MORTALITY, BLOOD CANCER AND CVDS, PROMPTING HUGE INTERESTS IN THE DEVELOPMENT OF DRUGS TARGETING CHIP MUTATIONS TO INTERCEPT PROGRESSION TO MALIGNANCIES. HOWEVER, INDIVIDUALS OF AFRICAN DESCENT ARE A MINORITY IN THESE CHIP STUDIES HENCE THE NEED TO UNDERSTAND THE SPECTRUM AND FREQUENCY OF CHIP VARIANTS IN AFRICAN POPULATIONS. MY LONG-TERM RESEARCH GOAL IS TO GENERATE A PAN-AFRICAN DATABASE OF SOMATIC MUTATIONS ASSOCIATED WITH THE RISK OF DEVELOPING MYELOID LEUKEMIA. RECENT GENOME-WIDE ASSOCIATION ANALYSES HAVE IDENTIFIED GERMLINE LOCI PREDISPOSING INDIVIDUALS TO INCREASED RISK OF CHIP ACQUISITION. THESE INCLUDE THE RS144418061 INTERGENIC VARIANT NEAR TET2 FOUND ONLY IN AFRICAN-ANCESTRY POPULATIONS. THE CENTRAL HYPOTHESIS IS THAT THERE IS A HIGH BURDEN OF CHIP VARIANTS IN NORMAL-AGING AFRICANS COMPARED TO AGE-MATCHED HEALTHY CAUCASIANS. TO ADDRESS THIS, I PROPOSE THE FOLLOWING SPECIFIC AIMS: AIM 1 DETERMINES THE FREQUENCY OF CHIP MUTATIONS IN A COHORT OF CLINICALLY HEALTHY NIGERIANS. WHOLE BLOOD SAMPLES FROM HEALTHY NIGERIAN VOLUNTEERS =40 YEARS WILL BE COLLECTED AND ERROR-CORRECTED TARGETED SEQUENCING WILL BE CARRIED OUT TO GENOTYPE 54 GENES KNOWN TO BE FREQUENTLY MUTATED IN MYELOID MALIGNANCIES. AIM 2 DESCRIBES TEMPORAL TRENDS AND CLINICAL OUTCOMES OF CHIP ACQUISITION OVER A THREE-YEAR PERIOD. EACH SUBJECT WILL BE FOLLOWED UP FOR THREE YEARS AND THE TEMPORAL DYNAMICS OF CHIP CLONAL DOMINANCE OVER THE PERIOD WILL BE DETERMINED. IN ADDITION, HEMATOLOGICAL CHANGES CORRELATING WITH THE CHIP ARCHITECTURE WILL BE DESCRIBED. IT IS SUSPECTED THAT VARYING BEHAVIORAL AND CLINICAL STATES WILL IMPACT THE RATE OF CHIP PROGRESSION IN DIFFERENT INDIVIDUALS. AIM 3 WILL DETERMINE THE INFLAMMATORY MARKERS ASSOCIATED WITH CHIP BURDEN IN THE STUDY POPULATION. HERE, LUMINEX-BASED HUMAN CYTOKINE/CHEMOKINE ASSAY WILL BE ADOPTED TO TEASE OUT INFLAMMATORY SIGNALS CORRELATING WITH CHIP BURDEN. THIS K43 PROJECT WILL GENERATE INFORMATION ON CHIP MUTATIONS IN NORMAL-AGING NIGERIANS. THIS ALIGNS WITH THE STUDY I AM CURRENTLY LEADING ON CHIP BURDEN IN NIGERIANS WITH VARYING COMORBIDITIES. MY CAREER DEVELOPMENT GOAL OF THIS K43 APPLICATION IS TO GAIN SKILLS ON ERROR-CORRECTED SEQUENCING, VARIANT CALLING AS WELL AS DATA ANALYSIS AND GENERATE SUFFICIENT DATA FOR A COMPETITIVE HYPOTHESIS-DRIVEN R01 SUBMISSION BY THE FIFTH YEAR OF THIS AWARD. THIS WILL ENABLE ME TO BUILD RESEARCH CAPACITY FOR BLOOD CANCER GENETICS IN NIGERIA AND ESTABLISH MY INDEPENDENCE AS AN AFRICA-BASED MEDICAL GENETICIST. MY TRAINING AND RESEARCH ACTIVITIES WILL BENEFIT FROM A STRONG COMMITTEE OF MENTORS COMPRISING ESTABLISHED US AND AFRICA-BASED RESEARCHERS IN HEMATOLOGY, POPULATION GENETICS, BIOINFORMATICS AND COMPUTATIONAL ANALYSIS. I WILL MAXIMIZE MY TIME AT THE NIGERIAN INSTITUTE OF MEDICAL RESEARCH CARRYING OUT HEMATOLOGICAL ANALYSIS AND SEQUENCING WHILE TAKING ADVANTAGE OF HANDS-ON TRAINING ACTIVITIES, IMPORTANT DATA SCIENCE AND RESEARCH LEADERSHIP COURSES AVAILABLE AT THE NATIONAL INSTITUTES OF HEALTH.