Is high cholesterol genetic?

Is High Cholesterol Genetic?

Yes, high cholesterol can be genetic, most notably in familial hypercholesterolemia (FH), an autosomal dominant inherited disorder affecting approximately 1 in 500 people, caused by mutations in genes regulating LDL cholesterol metabolism. 1

Monogenic Forms of Hypercholesterolemia

Familial Hypercholesterolemia (FH)

FH is the most clinically significant genetic cause of high cholesterol, resulting from mutations in three primary genes:

• LDLR gene (LDL receptor): Accounts for the majority of FH cases, with approximately 700 different mutations identified worldwide, causing deficient or defective LDL receptors and impaired clearance of circulating LDL particles 1
• APOB gene (apolipoprotein B-100): Causes familial defective apolipoprotein B-100 (FDB) in approximately 3% of FH patients in the UK, North Europe, and USA, producing a milder phenotype than LDLR-FH 1
• PCSK9 gene (protein convertase subtilisin/kexin type 9): Causes increased degradation of LDL receptors, reducing receptor numbers on cell surfaces 1

Clinical presentation of heterozygous FH includes:

• LDL cholesterol typically 5-10 mmol/L (200-400 mg/dL) 1
• Premature coronary heart disease: angina, heart attacks, or death typically occurring in men between 30-50 years and women between 50-70 years 1
• Tendon xanthomas in some cases 1
• Family history of hypercholesterolemia and premature cardiovascular disease 1

Familial Combined Hyperlipidemia (FCH)

FCH is the most common severe hyperlipidemia, with a prevalence of approximately 1 in 100, and is more polygenic/multifactorial than FH. 1 A major gene determining the FCH phenotype has been identified as upstream regulatory factor 1 (USF1), a major controller of lipid and glucose homeostasis, though no specific mutation within USF1 has been identified—rather, a common haplotype composed of several SNPs is associated with FCH risk. 1

Polygenic Hypercholesterolemia

Beyond monogenic disorders, hypercholesterolemia has substantial polygenic contributions:

• Nearly 80 genes involved in lipid metabolism with single nucleotide variants (SNVs) are associated with hypercholesterolemia and serum lipid traits 2
• Genome-wide association studies have identified SNVs associated with total cholesterol, HDL cholesterol, and LDL cholesterol in nearly 120 additional genes not previously known to be involved in lipid metabolism 2
• Over 90% of these SNVs are located outside coding regions of genes, suggesting unrecognized processes and mechanisms of lipid homeostasis 2

Genetic evidence demonstrates causal relationships:

• Genetically elevated remnant cholesterol shows a 2.8-fold causal risk increase for ischemic heart disease per 1-mmol/L increase 1
• Genetically elevated triglyceride levels are strongly associated with ischemic heart disease, independent of HDL and LDL cholesterol levels 1
• Mutations in LPL (lipoprotein lipase gene) lead to lifelong high triglycerides and increased ASCVD risk, with heterozygous individuals being 4.9-fold more common among patients with ischemic heart disease 1

Genetic Testing Recommendations

The American Heart Association recommends genetic testing for FH genes (LDLR, APOB, PCSK9) in the following scenarios: 1

Genetic testing should be offered when:

• Children with persistent LDL-C ≥160 mg/dL or adults with persistent LDL-C ≥190 mg/dL without secondary causes, with at least one first-degree relative similarly affected or with premature CAD 1
• Children with persistent LDL-C ≥190 mg/dL or adults with persistent LDL-C ≥250 mg/dL without secondary causes, even without positive family history 1

Genetic testing may be considered when:

• Children with persistent LDL-C ≥160 mg/dL with an LDL-C ≥190 mg/dL in at least one parent or family history of hypercholesterolemia and premature CAD 1
• Adults with no pretreatment LDL-C available but personal history of premature CAD and family history of both hypercholesterolemia and premature CAD 1
• Adults with persistent LDL-C ≥160 mg/dL with family history of hypercholesterolemia and either personal or family history of premature CAD 1

Cascade genetic testing should be offered to all at-risk family members of individuals found to have a pathogenic variant in an FH gene. 1 This approach enables higher diagnosis rates, more effective cascade testing, initiation of therapies at earlier ages, and more accurate risk stratification. 1

Clinical Implications

The genetic diagnosis of FH has critical management implications:

• Patients with FH require aggressive statin therapy initiated at young ages, with children ≥10 years old being candidates for treatment 1, 3
• High-intensity statin therapy should be initiated immediately upon diagnosis, targeting ≥50% LDL-C reduction from baseline 3, 4
• Early treatment of FH significantly reduces lifetime cardiovascular risk 3
• Family screening is essential to identify other affected individuals through reverse-cascade screening 3

Important caveats:

• Using currently available routine clinical genetic diagnostic techniques, mutations can be demonstrated in 80-90% of clinically diagnosed FH patients 1
• A substantial proportion of adults with hypercholesterolemia do not have mutations in the four major FH genes (LDLR, APOB, PCSK9, LDLRAP1), indicating polygenic inheritance in many cases 2
• An LDL cholesterol level ≥3.5 mmol/L (135 mg/dL) predicts the presence of familial hypercholesterolemia with 0.98 posttest probability in children from FH kindreds 1
• Secondary causes of hypercholesterolemia (hypothyroidism, diabetes mellitus, renal disease, nephrotic syndrome, liver disease, medications) must be excluded before attributing hypercholesterolemia to genetic causes 1