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Observational Study
. 2022 Aug 1;29(8):1201-1212.
doi: 10.5551/jat.62989. Epub 2021 Sep 15.

Familial Hypercholesterolemia in Patients with Acute Coronary Syndrome: Genetic Insights from EXPLORE-J

Mariko Harada-Shiba  1 , Junya Ako  2 , Atsushi Hirayama  3 , Masato Nakamura  4 , Atsushi Nohara  5 , Kayoko Sato  6 , Yoshitaka Murakami  7 , Ryusuke Koshida  8 , Asuka Ozaki  8 , Hidenori Arai  9
Affiliations
Observational Study

Familial Hypercholesterolemia in Patients with Acute Coronary Syndrome: Genetic Insights from EXPLORE-J

Mariko Harada-Shiba et al. J Atheroscler Thromb. .

Abstract

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.

Keywords: Acute coronary syndrome; Familial hypercholesterolemia; Genetic testing; Japan.

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Figures

Supplementary Fig.1. Diagnosis of patients with FH based on the clinical criteria of JAS, Dutch Lipid Clinical Network, and Simon Broome guidelines
Supplementary Fig.1. Diagnosis of patients with FH based on the clinical criteria of JAS, Dutch Lipid Clinical Network, and Simon Broome guidelines
FH, familial hypercholesterolemia; JAS, Japan Atherosclerosis Society. In total, 398 patients did not meet any of the three diagnostic guidelines. aAll patients carry any pathogenic variants for FH (definite FH).
Fig.1. ROC curve of FH-related parameters on FH judgment via JAS guidelines and FH genetic test for (A) ATT (mm) and (B) LDL-C (max value on/before Visit 1; mg/dL)
Fig.1. ROC curve of FH-related parameters on FH judgment via JAS guidelines and FH genetic test for (A) ATT (mm) and (B) LDL-C (max value on/before Visit 1; mg/dL)
ATT, Achilles tendon thickness; AUC, area under the curve; DF, degree of freedom; FH, familial hypercholesterolemia; JAS, Japanese Atherosclerosis Society; LDL-C, low-density lipoprotein cholesterol; ROC, receiver operating characteristic; SE, standard error.
See this image and copyright information in PMC

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