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The association between SUSD2 and myocardial ischemia has been explored through a combination of pedigree‐based case reports and large‐scale population studies. In a small kindred with an autosomal dominant presentation of premature myocardial infarction, a novel heterozygous nonsense variant was identified that segregated with the disease phenotype (PMID:32620384). This finding, together with the investigation of a common missense variant in SUSD2 in a population cohort, underscores the potential role of SUSD2 in modifying the risk of ischemic heart disease.
Genetic evidence stems from the identification of a heterozygous nonsense mutation that is reported as c.583G>T (p.Glu195Ter). Although the pedigree details are limited, the segregation of this truncating variant with premature myocardial infarction supports a causal relationship. In addition, a common variant, rs8141797 A>G (p.Asn466Ser), was analyzed in a large cohort of 105,408 individuals (PMID:32620384) and in a meta‑analysis that included 73,983 IHD cases (PMID:32620384), demonstrating a statistically significant association with a reduced risk of myocardial ischemia.
The mode of inheritance for this association is autosomal dominant, as evidenced by its presentation in the kindred. Segregation analysis, although limited in numerical details, indicates that multiple affected relatives carry the pathogenic variant. This supports the genetic etiology whereby even a single truncating event in SUSD2 can contribute to disease manifestation.
Experimental studies provide supportive functional evidence. SUSD2 protein expression has been demonstrated in aortic specimens, particularly in the subendothelial cell layers and around the vasa vasorum, which are key regions implicated in vascular pathobiology. Furthermore, mRNA expression studies have shown that the minor G‑allele of rs8141797 is linked with higher SUSD2 transcript levels in both heart and vascular tissues, offering a molecular rationale for the observed protective clinical effect.
Collectively, both genetic and functional data converge to support a strong association between SUSD2 variants and myocardial ischemia. The evidence reflects robust genetic findings from a rare family‐based mutation complemented by statistically significant associations observed in large population studies, alongside relevant experimental data. Nonetheless, additional studies will be valuable to further elucidate the mechanistic underpinnings and extend these findings beyond the observed cohorts.
Key takeaway: The integration of pedigree-based genetic findings with broad-scale population data and functional expression studies substantiates the clinical utility of assessing SUSD2 variants when evaluating the risk of myocardial ischemia in a diagnostic setting.
Gene–Disease AssociationStrongA heterozygous nonsense mutation segregated within a pedigree with premature myocardial infarction and significant association data from large-scale studies (105,408 participants and meta-analysis of 73,983 IHD cases [PMID:32620384]). Genetic EvidenceStrongThe identification of the truncating variant c.583G>T (p.Glu195Ter) in a familial autosomal dominant context, along with corroborative association studies involving a common missense variant, provides robust genetic support (PMID:32620384). Functional EvidenceModerateFunctional assessment studies demonstrate SUSD2 protein expression in vascular tissues and correlate higher mRNA levels with the protective G‑allele of rs8141797, thereby supporting the gene’s role in myocardial ischemia (PMID:32620384). |