1276-P: Transancestral Genomic Analysis Links Dysregulation of Valine Metabolism to the Development of Heart Failure in Type 2 Diabetes
Authors: TANG YALING , PIGEYRE MARIE , SUN XIUQIN , MORIERI MARIO LUCA , SHAH HETAL , PARE GUILLAUME , GERSTEIN HERTZEL C. , TAYLOR KENT , RAMACHANDRAN VASAN S. , ROTTER JEROME I. , RICH STEPHEN S. , MEIGS JAMES B. , MANNING ALISA , MYCHALECKYJ JOSYF , DORIA ALESSANDRO ,   CONSORTIUM NHLBI TRANS-OMICS FOR PRECISION MEDICINE (TOPMED)
Published: May 2022

Persons with type 2 diabetes (T2D) remain at increased risk of heart failure (HF) despite control of known cardiovascular risk factors. The aim of this study was to identify genes and molecular pathways specifically linking T2D to HF. To this end, we conducted a trans-ancestral genome-wide association study (GWAS) using data from ACCORD, ORIGIN, and six TOPMed cohorts (ARIC, CHS, FHS, JHS, MESA, WHI) . Included were a total of 19,8 participants with T2D (11,852 Whites, 4,152 Blacks, 3,157 Hispanics, and 778 Asians) , 1,8 of whom had developed HF, as defined in each study, after being diagnosed with T2D. A novel genome-wide significant trans-ancestral locus was identified on chromosome 7q21 as being associated with HF (lead SNP=rs6462012, OR=1.25[1.15-1.35], p=3.3 × 10-8) . The lead SNP had similar effect in all ethnicities (Whites: OR=1.28[1.16-1.42], p=9.0 × 10-7; Blacks: OR=1.24[1.06-1.42], p=5.0 × 10-3; Asians: OR=2.38[0.66-12.95], p=0.20) , except Hispanics (OR=1.00[0.80-1.26], p=0.98) . This HF locus appeared to be specific to T2D as it was not found among non-diabetic subjects from the six TOPMed cohorts (OR=1.01[0.95-1.08], p=0.71) or in previous GWAS from the general population. Among subjects with T2D included in the GTEx database, the risk allele at this locus was associated with decreased myocardial expression (beta=-0.19, SE=0.07, p=0.02) of the nearby HIBADH gene coding for the enzyme converting 3-hydroxyisobutyrate (a valine metabolite) to methylmalonic acid semialdehyde, while there was no such association among non-diabetic subjects (beta=0.009, SE=0.03, p=0.77) .
In conclusion, we have identified a new HF locus specific for T2D that is linked to branched chain amino acid metabolism, the dysregulation of which has been previously implicated in the development of HF. Further investigation of the mechanisms linking this locus to HF may foster new HF-preventing interventions specifically targeted to the T2D population.

Disclosure
Y.Tang: None. J.I.Rotter: None. S.S.Rich: None. J.B.Meigs: Consultant; Quest Diagnostics. A.Manning: None. J.Mychaleckyj: None. A.Doria: Research Support; Novo Nordisk Foundation. C.Nlbi trans-omics for precision medicine (topmed) : n/a. M.Pigeyre: n/a. X.Sun: n/a. M.Morieri: Advisory Panel; Merck Sharp & Dohme Corp., Consultant; neopharmed gentili, SLAPharma, Other Relationship; Lilly, Novo Nordisk, Servier Laboratories. H.Shah: None. G.Pare: Advisory Panel; Amgen Inc., Bayer AG, Sanofi, Research Support; Bayer AG. H.C.Gerstein: Advisory Panel; Abbott, Eli Lilly and Company, Hanmi Pharm. Co., Ltd., Novo Nordisk, Pfizer Inc., Sanofi, Viatris Inc., Consultant; Kowa Company, Ltd., Other Relationship; DKSH, Eli Lilly and Company, Sanofi, Zuellig Pharma Holdings Pte. Ltd., Research Support; AstraZeneca, Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk, Sanofi. K.Taylor: None. V.S.Ramachandran: None.

Funding
NIH Biodata Catalyst Fellowship (1OT3HL142479-01, 1OT3HL142478-01, 1OT3HL142481-01, 1OT3HL142480-01, 1OT3HL147154) .