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Published on: September 15, 2018
Familial Hypercholesterolemia in Patients with Acute Coronary Syndrome: Genetic Insights from EXPLORE-J
Mariko Harada-Shiba1, Junya Ako2, Atsushi Hirayama3
1Department of Molecular Pathogenesis, National Cerebral and Cardiovascular Center Research Institute.
Insights
Genetic testing reveals a higher prevalence of familial hypercholesterolemia (FH) in Japanese patients with acute coronary syndrome (ACS). Current diagnostic criteria show low sensitivity, underscoring the need for genetic analysis and family history in FH diagnosis.
Area of Science:
- Cardiovascular Genetics
- Medical Diagnostics
Background:
- Familial hypercholesterolemia (FH) diagnosis is crucial for cardiovascular health.
- Genetic testing offers definitive FH diagnosis but faces accessibility limitations in some regions, like Japan.
- Approximately 30% of FH cases remain undiagnosed due to unidentified mutations.
Purpose of the Study:
- To investigate the prevalence of FH-causing genetic mutations in Japanese patients presenting with acute coronary syndrome (ACS).
- To evaluate the diagnostic sensitivity of the Japanese Atherosclerosis Society (JAS) 2017 guidelines in this patient cohort.
- To highlight the challenges in diagnosing FH during the acute phase of ACS.
Main Methods:
- The EXPLORE-J study prospectively enrolled patients with ACS across multiple centers.
- Genetic screening was performed, and variants in LDLR, LDLRAP1, and PCSK9 genes were classified as pathogenic, indeterminate, or nondetectable.
- Diagnostic criteria were applied both with and without genetic data incorporation.
Main Results:
- Of 431 patients genetically screened, 5.8% had pathogenic FH variants (LDLR: 10, PCSK9: 15).
- The Japanese Atherosclerosis Society (JAS) 2017 guidelines identified only 1.9% of patients with FH; this increased to 7.7% when genetic data were included.
- No patients with pathogenic FH variants met the clinical criteria of the JAS 2017 guidelines.
Conclusions:
- A higher prevalence of FH genetic mutations exists in Japanese ACS patients than previously recognized.
- The JAS 2017 guidelines demonstrate low sensitivity for diagnosing FH in ACS patients, especially in the acute phase.
- Integrating genetic testing and family history is essential for accurate FH diagnosis in ACS patients.
Aim:
Genetic testing can provide a definitive diagnosis of familial hypercholesterolemia (FH). However, accessibility of genetic testing may be limited in certain countries where it is not considered "standard of care," including Japan. In addition, mutations responsible for FH cannot be identified in approximately 30% of patients.
Methods:
EXPLORE-J is a multicenter, prospective, observational study of patients presenting with acute coronary syndrome (ACS). The genetic data were analyzed and adjudicated as pathogenic, indeterminate, or nondetectable pathogenic variant.
Results:
Of 1,944 patients, 431 underwent genetic screening. Overall, most patients had nonpathogenic variants of LDLR, LDLRAP1, or PCSK9 (n=396, 91.9%). Of the 25 (5.8%) patients with pathogenic variants, variants of the LDLR gene and the PCSK9 gene were seen in 10 and 15 patients, respectively. Indeterminate variants were observed in 10 (2.3%) patients. Of the 431 patients, eight (1.9%) met the criteria for a diagnosis of FH using the Japanese Atherosclerosis Society (JAS) 2017 guidelines. When genetic data were incorporated, 33 (7.7%) patients met the JAS guidelines. No patients with FH pathogenic variants satisfied the JAS clinical criteria for a diagnosis of FH.
Conclusions:
The results revealed a higher prevalence of genetic mutations of FH among Japanese patients with ACS and a low sensitivity of the FH diagnostic criteria of the JAS 2017 guidelines. These findings highlight the difficulties of FH diagnosis in patients with ACS in the acute phase and suggest the importance of genetic testing and family history.
