Hyperlipoproteinemia: genes and variants

Genes linked to Hyperlipoproteinemia

• LPL: Lipoprotein lipase

  It hydrolyzes triglycerides in circulating chylomicrons and very-low-density lipoproteins so tissues can take up released fatty acids. Severe biallelic loss causes familial chylomicronemia, while common variation strongly influences triglyceride levels and cardiovascular risk.

  44 disease-causing and 44 uncertain variants in LPL are linked to Hyperlipoproteinemia.

• APOA5: Apolipoprotein A-V

  It strongly modulates plasma triglyceride levels by promoting efficient clearance of triglyceride-rich lipoproteins. Rare loss-of-function variants can cause severe hypertriglyceridemia and increase susceptibility to familial chylomicronemia-like phenotypes and pancreatitis.

  0 disease-causing and 1 uncertain variants in APOA5 are linked to Hyperlipoproteinemia.

• APOE: Apolipoprotein E

  It redistributes cholesterol and other lipids between tissues by directing remnant lipoproteins to LDL-receptor-family members. The common epsilon4 isoform strongly increases late-onset Alzheimer disease risk and also influences plasma lipids and cardiovascular risk.

  0 disease-causing and 1 uncertain variants in APOE are linked to Hyperlipoproteinemia.

• APOC2: Apolipoprotein C-II

  By activating lipoprotein lipase, it enables hydrolysis of triglycerides in chylomicrons and very-low-density lipoproteins. Biallelic deficiency causes familial chylomicronemia with extreme hypertriglyceridemia and recurrent pancreatitis.

  0 disease-causing and 0 uncertain variants in APOC2 are linked to Hyperlipoproteinemia.

• HMGCR: 3-hydroxy-3-methylglutaryl-coenzyme A reductase

  It controls the rate-limiting step of the mevalonate pathway and therefore strongly regulates endogenous cholesterol production. Statins lower LDL cholesterol by inhibiting this activity, causing the liver to increase LDL-receptor-mediated clearance from blood.

  0 disease-causing and 0 uncertain variants in HMGCR are linked to Hyperlipoproteinemia.

Where Hyperlipoproteinemia variants cluster

• LPL Essential for determining substrate specificity (positions 243–266): 4 of 44 disease-causing changes, 1.8× more than its size predicts.

Known disease-causing variants in Hyperlipoproteinemia

Which prediction tools work for Hyperlipoproteinemia

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• CATVariant: 97 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CADD: 97 out of 100
• PolyPhen-2: 97 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• phyloP: 92 out of 100
• SIFT: 92 out of 100

Same protein, different disease

• Hyperlipidemia, familial combined, LPL related is also caused by LPL variants; they fall partly in the same places as the Hyperlipoproteinemia variants (18 disease-causing).

Diseases related to Hyperlipoproteinemia

• Myocardial infarction, also linked to APOA5, APOE, HMGCR and LPL
• Type 2 diabetes mellitus, also linked to APOE, HMGCR and LPL
• Familial hypercholesterolemia, also linked to APOE and HMGCR
• Alzheimer disease, also linked to APOE and HMGCR
• Age related macular degeneration 9, also linked to APOE
• Hyperlipidemia, familial combined, LPL related, also linked to LPL
• Familial type 3 hyperlipoproteinemia, also linked to APOE
• Diabetes mellitus, also linked to APOE
• Lewy body dementia, also linked to APOE
• Muscular dystrophy, limb-girdle, autosomal recessive 23, also linked to HMGCR
• Limb-girdle muscular dystrophy, also linked to HMGCR
• Dementia, also linked to APOE

Frequently asked questions

Which genes are linked to Hyperlipoproteinemia?

In CATVariant, Hyperlipoproteinemia is linked to 5 analyzed proteins: LPL (Lipoprotein lipase), APOA5 (Apolipoprotein A-V), APOE (Apolipoprotein E), APOC2 (Apolipoprotein C-II) and HMGCR (3-hydroxy-3-methylglutaryl-coenzyme A reductase).

How many genetic variants are linked to Hyperlipoproteinemia?

131 variants: 44 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 46 are of uncertain significance or have conflicting reports.

Which uncertain variants in Hyperlipoproteinemia look disease-causing?

None of the uncertain variants currently reaches the likely-pathogenic range on computable evidence alone.

Which variant effect predictor works best for Hyperlipoproteinemia?

Among tools not trained on clinical labels, CADD separates this disease's known disease-causing variants from harmless ones best (AUROC 0.97, based on 31 disease-causing and 29 harmless variants).

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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