Evolution of the search for a common mechanism of congenital risk of coronary heart disease and type 2 diabetes mellitus in the chromosomal locus 9p21.3

Abstract

9.21.3 chromosomal locus predisposes to coronary heart disease (CHD) and type 2 diabetes mellitus (DM2), but their overall pathological mechanism and clinical applicability remain unclear. The review uses publications of the study results of 9.21.3 chromosomal locus in association with CHD and DM2, which are important for changing the focus of clinical practice. The eligibility criteria are full-text articles published in the PubMed database (MEDLINE) up to December 31, 2022. A total of 56 publications were found that met the inclusion criteria. Using the examples of the progressive stages in understanding the role of the chromosomal locus 9p.21.3, scientific ideas were grouped, from a fragmentary study of independent pathological processes to a systematic study of the overall development of CHD and DM2. The presented review can become a source of new scientific hypotheses for further studies, the results of which can determine the general mechanism of the congenital risk of CHD and DM2 and change the focus of clinical practice.

Genome‐wide association study of cardiometabolic multimorbidity in the UK Biobank

“…In other words, CMM SNPs are a subset of CMD SNPs, including both shared and non‐shared SNPs (Condition 4). We found 6q25.3 (LPA and LPAL2, involved in lipid metabolism 27 ), 9p21.3 (CDKN2B‐AS1, known as the best‐replicated locus for CHD 36 ), and 12q24.12 (ACAD10, involved in lipid metabolism 29 ), were shared by all three CMDs 12–14 . Meanwhile, 2q36.3 (IRS1, involved in glucose metabolism 41 ) and 10p13 (CDC123, involved in cell cycle 42 ) were shared between CHD and T2D.…”

“…The 9p21 locus has been identified as the strongest genetic signal for CHD in European individuals since 2007. The genetic risk of T2D shows an approximate result 36 . As for the mechanism, a convincing assumption is about the CDKN2B‐AS gene in 9p21 locus.…”

“…As for the mechanism, a convincing assumption is about the CDKN2B‐AS gene in 9p21 locus. It may influence the cellular growth and proliferation of pancreatic beta cells and smooth muscle cells of the vascular wall through coordinated regulation of transcription, then form the future phenotype of T2D and CHD 36 …”

Epigenetics of hypertension as a risk factor for the development of coronary artery disease in type 2 diabetes mellitus

“…Additionally, the direct vascular and immunomodulatory functions of ANRIL, accelerating several signaling pathways (TNF-α-NF-kB-ANRIL and YY1-IL6/8), contribute to systemic inflammation, indirectly influencing the development of cardiometabolic diseases ( 18 ). This indicates a potential common genetic signature of hypertension, IHD, and T2DM at the level of the chromosomal locus 9p21.3 ( 16 ).…”

“…Moreover, the wide prevalence of risk haplotypes for hypertension, IHD, and T2DM (up to 50% of representatives of many populations) with a strong additive effect leads to at least 15% of cases of IHD and T2DM, making the chromosomal locus 9p21.3 the largest known genomic source of morbidity ( 16 ). The identification of a potential transcriptional regulatory mechanism in this locus, induced by the long non-coding mRNA ANRIL, suggests a common genetic signature for hypertension, CAD, and T2DM, alongside common environmental risks and clinical associations ( 17 ).…”