Differential DNA methylation in familial hypercholesterolemia

Area of Science:

• Genetics and Epigenetics
• Cardiovascular Disease Research
• Metabolic Disorders

Background:

• Familial hypercholesterolemia (FH) is a genetic disorder causing high LDL-C.
• A significant portion of FH patients lack identifiable genetic variants in LDLR, APOB, or PCSK9.
• The role of epigenetic modifications, such as DNA methylation, in these mutation-negative FH cases is unclear.

Purpose of the Study:

• To investigate potential associations between DNA methylation patterns and Familial hypercholesterolemia (FH) in patients without identified genetic variants.
• To compare DNA methylation profiles between FH mutation-negative and FH mutation-positive individuals.

Main Methods:

• Included 78 male FH mutation-negative patients and 58 male FH mutation-positive patients with LDLR variants.
• All participants had elevated LDL-C and normal triglyceride levels, without lipid-lowering therapy.
• DNA methylation was analyzed using the Infinium Methylation EPIC 850K array, with statistical analyses including multiple linear regression and machine learning.

Main Results:

• Candidate gene analysis identified one hypomethylated CpG site in CPT1A in FH mutation-negative patients.
• No significant DNA methylation differences were found in other key lipid metabolism genes.
• A machine learning model distinguished between the two groups with an AUC of 0.80, identifying two CpG sites in PRDM16 and GSTT1.

Conclusions:

• FH mutation-negative patients exhibit distinct genome-wide DNA methylation profiles compared to FH mutation-positive patients.
• These findings suggest that epigenetic alterations, rather than major changes in known lipid genes, characterize FH in mutation-negative individuals.
• DNA methylation may contribute to the pathophysiology of FH in the absence of identifiable genetic mutations.