Novel genetic element ties valine metabolism to heart failure in T2D

A new study presented at the recent 2022 Scientific Sessions of the American Diabetes Association (ADA 2022) has identified a novel genetic locus associated with heart failure (HF) risk among patients with type 2 diabetes (T2D). This locus appears to play a role in the metabolism of valine, a branched chain amino acid.

“Persons with T2D remain at increased risk of 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,” the researchers said.

Drawing from the ACCORD, ORIGIN, and six TOPMed cohorts, the researchers enrolled more than 19,000 patients with T2D, of whom around 1,800 developed HF, as defined in each source study. A transancestral genome-wide association study (GWAS) was then performed on the pooled population to identify potential genetic factors in HF risk.

The GWAS found a genetic locus on chromosome 7q21 that was significantly correlated with HF incidence. The leading single-nucleotide polymorphism (SNP), labelled rs6462012, was associated with a 25-percent increase in the likelihood of developing HF after T2D diagnosis (odds ratio [OR], 1.25, 95 percent confidence interval [CI], 1.15–1.35; p=3.3×10^–8). [ADA 2022, abstract 1276-P]

The researchers then stratified their analysis according to race and ethnicity. Most of the enrolled patients were White (n=11,852), while only 4,152, 3,157, and 778 were Black, Hispanic, and Asian, respectively. Despite large differences in enrolment, the effect of rs6462012 SNP remained mostly comparable and significant across these groups.

White patients harbouring this SNP saw a 28-percent jump in HF odds (OR, 1.28, 95 percent CI, 1.16–1.42; p=9.0×10^–7). A similar effect was reported for Blacks (OR, 1.24, 95 percent CI, 1.06–1.42; p=5.0×10^–3) and Asians (OR, 2.38, 95 percent CI, 0.66–12.95; p=0.20). In contrast, the rs6462012 SNP had no clear impact on Hispanic T2D patients (OR, 1.00, 95 percent CI, 0.80–1.26; p=0.98).

Of note, the researchers reported that the risk allele at this novel locus was significantly correlated with myocardial expression levels of the nearby 3-hydroxyisobutyrate dehydrogenase gene (HIBADH; beta, –0.019; p=0.02), which converts 3-hydroxyisobutyrate, a metabolite of valine, to methylmalonic semialdehyde.

The interaction between the novel HF genetic locus and myocardial HIBADH gene expression was absent among nondiabetic patients (beta, 0.009; p=0.77). Similarly, the effect of this locus on HF appears to be specific to diabetics, as no such correlation was reported among nondiabetic controls in the TOPMed cohorts (OR, 1.01, 95 percent CI, 0.95–1.08; p=0.71).

“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,” the researchers said. “Further investigation of the mechanisms linking this locus to HF may foster new HF-preventing interventions specifically targeted to the T2D population.”