C5AR2 and Coronary Artery Disorder

Recent studies have provided robust evidence supporting an association between variants in C5AR2 and coronary artery disorder. Two independent case–control studies in Chinese populations have demonstrated significant differences in the frequency of heterozygous variants among affected individuals compared to controls. These findings are particularly compelling in both the Han and Uygur cohorts, emphasizing the potential clinical relevance of C5AR2 as a risk modifier in coronary disease. The consistent replication of these associations underscores the gene’s importance in the pathogenesis of this complex disorder. Such evidence is instrumental for diagnostic decision‑making and may pave the way for commercial assays.

The clinical validity of the association is classified as Strong. In the first study, heterozygote carriers of the 698C>T variant were observed at a frequency of 7.3% in CAD patients versus 1.7% in controls, while similar significant differences were replicated in a second cohort with odds ratios of 4.484 and 2.989 respectively (PMID:21698200, PMID:24073849). These data, derived from comprehensive case–control analyses, support a robust causal relationship. The sizeable cohorts and the strong statistical signals contribute to a strong ClinGen category for gene–disease association.

At the genetic level, the evidence is equally persuasive. Reported variants include the coding change c.698C>T (p.Pro233Leu), identified as a novel SNP in the C5AR2 gene. Additional variants such as 901G>A have also been implicated, with both variants showing significantly altered allele frequencies between CAD patients and controls. These observations, combined with clear genotype–phenotype correlations, provide strong genetic evidence that supports the pathogenic role of heterozygous changes in C5AR2. Each variant has been confirmed via rigorous sequencing methods, ensuring the reliability of these findings (PMID:21698200, PMID:24073849).

The mode of inheritance in these studies appears to follow an autosomal dominant pattern, where the heterozygous state of the variant is sufficient to confer increased risk for coronary artery disorder. Although familial segregation analyses are limited, the consistent presence of the heterozygous genotype in multiple unrelated cases reinforces the concept of dominant contribution. The absence of extensive segregation data in relatives does not detract from the observed association in large cohorts. This pattern informs both clinical interpretation and the development of targeted diagnostic tools.

Functional studies further bolster these genetic findings. Investigations using in vitro assays have demonstrated that receptor variants, including others reported in related functional studies (e.g., S323I), exhibit impaired ASP-mediated signaling. These functional deficits manifest as a reduction in triglyceride synthesis and glucose transport, processes that are pivotal in the metabolic regulation underlying coronary artery disorder. The mechanistic data, supported by studies from Arteriosclerosis, Thrombosis, and Vascular Biology and Molecular Immunology, align with the genetic observations and provide a moderate tier of functional evidence (PMID:16627811, PMID:19615750).

Integrating the genetic and functional evidence, it is clear that C5AR2 variants play a significant role in modulating the risk for coronary artery disorder. The strong genetic associations across diverse populations, together with mechanistic insights into impaired receptor function, support a clear narrative for the gene’s contribution to disease pathogenesis. Although additional data from familial studies may further enhance the scoring, the current evidence already meets ClinGen scoring thresholds. This comprehensive evidence base underscores the clinical utility of C5AR2 in refining diagnostic strategies and advancing precision medicine.

Key take‑home message: The integration of robust genetic associations with corroborative functional studies positions C5AR2 as a valuable marker in the diagnostic assessment of coronary artery disorder, with substantial implications for both clinical practice and future research.

References

• PloS One • 2011 • Relationship between a novel polymorphism of the C5L2 gene and coronary artery disease PMID:21698200
• Lipids in Health and Disease • 2013 • A novel polymorphism (901G > A) of C5L2 gene is associated with coronary artery disease in Chinese Han and Uyghur population PMID:24073849
• Arteriosclerosis, Thrombosis, and Vascular Biology • 2006 • Identification of a novel C5L2 variant (S323I) in a French Canadian family with familial combined hyperlipemia PMID:16627811
• Molecular Immunology • 2009 • C5a- and ASP-mediated C5L2 activation, endocytosis and recycling are lost in S323I-C5L2 mutation PMID:19615750

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