Reducing Premature Coronary Artery Disease in Malaysia by Early Identification of Familial Hypercholesterolemia Using the Familial Hypercholesterolemia Case Ascertainment Tool (FAMCAT): Protocol for a Mixed Methods Evaluation Study

Abstract

Background Familial hypercholesterolemia (FH) is predominantly caused by mutations in the 4 FH candidate genes (FHCGs), namely, low-density lipoprotein receptor (LDLR), apolipoprotein B-100 (APOB-100), proprotein convertase subtilisin/kexin type 9 (PCSK9), and the LDL receptor adaptor protein 1 (LDLRAP1). It is characterized by elevated low-density lipoprotein cholesterol (LDL-c) levels leading to premature coronary artery disease. FH can be clinically diagnosed using established clinical criteria, namely, Simon Broome (SB) and Dutch Lipid Clinic Criteria (DLCC), and can be identified using the Familial Hypercholesterolemia Case Ascertainment Tool (FAMCAT), a primary care screening tool. Objective This study aims to (1) compare the detection rate of genetically confirmed FH and diagnostic accuracy between the FAMCAT, SB, and DLCC in the Malaysian primary care setting; (2) identify the genetic mutation profiles, including novel variants, in individuals with suspected FH in primary care; (3) explore the experience, concern, and expectation of individuals with suspected FH who have undergone genetic testing in primary care; and (4) evaluate the clinical utility of a web-based FH Identification Tool that includes the FAMCAT, SB, and DLCC in the Malaysian primary care setting. Methods This is a mixed methods evaluation study conducted in 11 Ministry of Health primary care clinics located at the central administrative region of Malaysia. In Work stream 1, the diagnostic accuracy study design is used to compare the detection rate and diagnostic accuracy of the FAMCAT, SB, and DLCC against molecular diagnosis as the gold standard. In Work stream 2, the targeted next-generation sequencing of the 4 FHCGs is used to identify the genetic mutation profiles among individuals with suspected FH. In Work stream 3a, a qualitative semistructured interview methodology is used to explore the experience, concern, and expectation of individuals with suspected FH who have undergone genetic testing. Lastly, in Work stream 3b, a qualitative real-time observation of primary care physicians using the “think-aloud” methodology is applied to evaluate the clinical utility of a web-based FH Identification Tool. Results The recruitment for Work stream 1, and blood sampling and genetic analysis for Work stream 2 were completed in February 2023. Data collection for Work stream 3 was completed in March 2023. Data analysis for Work streams 1, 2, 3a, and 3b is projected to be completed by June 2023, with the results of this study anticipated to be published by December 2023. Conclusions This study will provide evidence on which clinical diagnostic criterion is the best to detect FH in the Malaysian primary care setting. The full spectrum of genetic mutations in the FHCGs including novel pathogenic variants will be identified. Patients’ perspectives while undergoing genetic testing and the primary care physicians experience in utilizing the web-based tool will be established. These findings will have tremendous impact on the management of patients with FH in primary care and subsequently reduce their risk of premature coronary artery disease. International Registered Report Identifier (IRRID) DERR1-10.2196/47911

A case report of heterozygous familial hypercholesterolaemia with LDLR gene mutation complicated by premature coronary artery disease detected in primary care

“…She was then offered and counselled for genetic testing, the gold standard for diagnosing FH. 10 Targeted next-generation sequencing of the three FH candidate genes ( LDLR , APOB , and PCSK9 ) was conducted. 10 Subsequently, she was confirmed to carry a heterozygous pathogenic variant in the LDLR gene (rs769446356) located in intron 2 (noncoding area), in keeping with the American College of Medical Genetics and Genomics (ACMG) recommendation.…”

“… 10 Targeted next-generation sequencing of the three FH candidate genes ( LDLR , APOB , and PCSK9 ) was conducted. 10 Subsequently, she was confirmed to carry a heterozygous pathogenic variant in the LDLR gene (rs769446356) located in intron 2 (noncoding area), in keeping with the American College of Medical Genetics and Genomics (ACMG) recommendation. 11 This patient was then counselled by the primary care physician regarding the genetic diagnosis, the need to intensify her lipid-lowering medication (LLM), and to screen her first-degree relatives.…”

Age and Sex Differences in LDL Cholesterol Distribution in Adults in Malaysia: A Cross-Sectional Study (2010–2021)

“…In younger individuals, cholesterol testing/assessment may be initiated due to existing cardiovascular risk factors (such as a family history of cardiovascular diseases or raised LDL-c). The data was not nationally representative as the selection of the clinics was purposely undertaken for the FAMCAT study, 7 and involved three out of 14 states and federal territories in Malaysia. Additionally, only data on age and sex were extracted from the EMR for this study, it was therefore impossible to assess the relationship between age and/or sex and LDL-c levels, adjusting for other confounding variables such as dietary habits, physical activity, and medication use, which are known to impact LDL-c levels.…”

“…The study setting and population have been previously described in detail. 7 Descriptive analyses were conducted to describe the mean LDL-c levels overall and by sex stratified by 10-year age band. Baseline characteristics were presented as frequencies with percentages, means with standard deviation (SD) or medians with interquartile ranges.…”