Research Topic

Genetics of Familial Hypercholesterolemia: New Insight

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About this Research Topic

Familial hypercholesterolemia (FH) is a common monogenic cause of inherited metabolic disease in the world. It is estimated that at least 1 in 250 to 270 individuals suffer from a life-long two-to-three-fold elevation of serum low-density lipoprotein cholesterol (LDL-C) due to the heterozygous form of ...

Familial hypercholesterolemia (FH) is a common monogenic cause of inherited metabolic disease in the world. It is estimated that at least 1 in 250 to 270 individuals suffer from a life-long two-to-three-fold elevation of serum low-density lipoprotein cholesterol (LDL-C) due to the heterozygous form of familial hypercholesterolemia (HeFH). In a rare homozygous form of FH (HoFH), serum LDL-C levels often exceed over 13 mmol/L.

In untreated HeFH, the risk of early-onset coronary artery disease (CAD) is increased by 50% in men and 30% in women, compared to the general population. CAD in untreated HeFH has been reported as early as 17 years of age in males and 25 years of age in females. HoFH, in turn, may cause death in childhood or early adulthood, due to premature atherosclerotic disease (ASCVD) and calcifications in the aortic root. It can be rightly stated that without treatment, FH is closely associated with increased premature ASCVD and cardiovascular deaths.

HeFH is caused by mutant alleles in the LDLR, APOB , or PCSK9 gene. 90% of HeFH cases are due to mutations in the LDLR gene, and over 1700 different LDLR mutations have been reported so far. Additionally, in the clinically suspected HeFH patients who are mutation-negative for LDLR, APOB, or PCSK9 genes, there is an accumulation of common small-effect LDL-C-raising alleles, which has been defined as “polygenic HeFH”. FH is vastly under-diagnosed in many countries worldwide. Next-generation sequencing (NGS) is a promising technique of FH diagnostics. Cascade testing of the index patients’ families are undertaken, to identify first, second and third-degree relatives with the disease.

However, currently, many countries don’t have FH disease-specific registry. It is important to have more national or international FH registries, to monitor diagnoses, treatment, and follow-up of FH patients. A lifelong statin treatment starting in childhood is the current clinical practice in the treatment of HeFH. Statins can be combined with other lipid-lowering therapies, such as ezetimibe (cholesterol absorption inhibitor), to achieve recommended LDL-C lowering target concentrations, as defined in published guidelines. For adult HeFH patients with significant ASCVD risk, PCSK9 inhibitor is a newer therapy option and could be combined with a statin and ezetimibe. HoFH treatment includes plasma apheresis, statin, and newer novel therapies.

This Research Topic aims to focus on improving diagnostics and treatment of FH and as well as offering new research areas. We welcome original research, reviews, and opinion articles covering the following areas:

• New and novel mutations in FH
• Epigenetics and FH
• Diagnostics in FH: Next-generation sequencing, single nucleotide polymorphisms, mutation-negative FH
• Advances in cascade testing in FH
• New drugs and their hypolipidemic response in FH based on genetic evaluation
• Genetic risk stratification in FH
• Potential new risk factors like lipoprotein(a) in FH
• Concomitant genetic factors, which increase ASCVD risk in FH
• Importance of FH registries
• Dietary response and FH genetics
• Genetics of FH in developed and low and middle-income countries
• Specific genetic issues related to HoFH

Topic Editor Kirsten Bjørklund Holven has received research grants from Tine SA, Mills DA, Olympic Seafood, Amgen, Sanofi, and Kaneka, and personal fees from Amgen, Sanofi, and Pronova. All other topic editors declare no competing interests with regards to the Research Topic subject


Keywords: familial hypercolesterolemia, genetics, diagnostics, mutation, cascade testing


Important Note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.

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