Project Grant F32DK145142

GENETIC INSIGHTS INTO TASTE PREFERENCES AND THEIR IMPACT ON METABOLIC DISEASE AND GLP-1 RECEPTOR AGONIST RESPONSE - PROJECT SUMMARY/ABSTRACT THE TYPE 2 DIABETES (T2D) AND OBESITY EPIDEMIC POSE SIGNIFICANT PUBLIC HEALTH AND ECONOMIC BURDEN. WHILE GLUCAGON-LIKE PEPTIDE-1 RECEPTOR AGONISTS (GLP1-RA) SPARKED MUCH OPTIMISM, THEIR EFFECTIVENESS FOR TREATING METABOLIC DISEASE IS HIGHLY HETEROGENEOUS. IDENTIFYING NOVEL GENETIC FACTORS THAT PREDICT METABOLIC DISEASE RISK AND MODULATE GLP1-RA RESPONSES IS CRITICAL TO ATTENUATE THE PUBLIC HEALTH BURDEN OF THESE DISEASES. PARTICULARLY IN HYPERPALATABLE FOOD ENVIRONMENTS, TASTE PREFERENCES ARE POTENTIAL TARGETS. THEY VARY SUBSTANTIALLY, ARE HIGHLY HERITABLE, AND INFORM DIET QUALITY WHICH DRIVES METABOLIC DISEASE. AS GENES INFLUENCING TASTE PREFERENCE ARE IMPLICATED IN EATING BEHAVIOR AND METABOLISM, VARIATIONS IN THESE GENES MAY HELP PREDICT INDIVIDUALS MORE SUSCEPTIBLE TO UNHEALTHY FOOD CHOICES AND METABOLIC DISEASE. MANY PATIENTS ALSO REPORT THAT GLP1-RAS CHANGE TASTE PREFERENCES, PROMOTING HEALTHIER FOOD CHOICES AND TREATMENT SUCCESS FOR SOME, AND TASTE AVERSIONS THAT LEAD TO TREATMENT DISCONTINUATION FOR OTHERS. TASTE PREFERENCES MAY THEREFORE HELP PREDICT WHICH INDIVIDUALS ARE MORE SUSCEPTIBLE TO EACH TYPE OF TASTE CHANGE, PROVIDING TARGETS TO PREDICT GLP1-RA EFFECTIVENESS. GENETICS APPROACHES--SUCH AS GENOME-WIDE ASSOCIATION STUDIES (GWAS), MENDELIAN RANDOMIZATION (MR) AND POLYGENIC SCORES (PGS)--CAN BE USEFUL TOOLS TO CHARACTERIZE THE BIOLOGICAL BASIS OF TASTE PREFERENCES, DEFINE THEIR IMPACT ON METABOLIC DISEASE RISK, AND DETERMINE WHETHER TASTE-RELATED GENETIC FACTORS CAN PREDICT GLP1- RA RESPONSE, PROVIDING FACTORS TO LEVERAGE IN PRECISION MEDICINE AND PHARMACOGENETICS OF METABOLIC DISEASE. THE PROPOSED RESEARCH AIMS TO UNDERSTAND THE IMPACT OF GENETIC DETERMINANTS OF TASTE PREFERENCE ON METABOLIC DISEASE RISK AND GLP1-RA RESPONSE. IN AIM 1 I WILL PERFORM THE LARGEST GWAS OF 5 TASTE PREFERENCES, TO-DATE; THEN I WILL ELUCIDATE THE CAUSAL MECHANISMS THROUGH WHICH GENETIC DETERMINANTS OF TASTE PREFERENCE IMPACT METABOLIC DISEASE. IN AIM 2 I WILL BUILD PGS FOR 5 TASTE PREFERENCES IN TWO CLINICAL STUDIES ON GLP1-RA TO DETERMINE WHETHER GENETIC DETERMINANTS OF TASTE PREFERENCE CAN PREDICT CHANGES IN DIETARY HABITS AND METABOLIC BENEFITS ON A GLP1-RA, THEREBY PROVIDING NOVEL GENETIC PREDICTORS OF GLP1-RA RESPONSE. COMPLETING THIS WORK WILL REVEAL FUNDAMENTAL INSIGHT INTO THE BIOLOGICAL BASIS OF TASTE PREFERENCES AND THEIR IMPACT ON METABOLIC DISEASE RISK AND GLP1-RA RESPONSE, PROVIDING NOVEL GENETIC TARGETS TO IMPROVE THE EFFECTIVENESS OF PRECISION MEDICINE AND PHARMACOGENETIC APPROACHES FOR METABOLIC DISEASE PREVENTION AND TREATMENT. THE NSRA FELLOWSHIP WILL PROVIDE ME WITH COMPREHENSIVE TRAINING IN LARGE-SCALE GENOMICS AND GENETIC CAUSAL INFERENCE. THE CENTER FOR GENOMIC MEDICINE IN MASSACHUSETTS GENERAL HOSPITAL AND THE BROAD INSTITUTE PROVIDE UNPARALLELED ENVIRONMENTS FOR TRAINEES. THE PROPOSED PROJECT, WITH MENTORSHIP SUPPORT, WILL PROVIDE FOUNDATIONAL SKILLS TRAINING, SCIENTIFIC AND CAREER MENTORSHIP, AND PROFESSIONAL DEVELOPMENT TO PREPARE THE CANDIDATE TO APPLY FOR A CAREER DEVELOPMENT AWARD WITH THE LONG-TERM GOAL OF BECOMING AN INDEPENDENT INVESTIGATOR INTEGRATING SENSORY NUTRITION AND GENOMICS TO ADVANCE PRECISION MEDICINE FOR METABOLIC HEALTH. 1