Familial Hypercholesterolemia (FH) Subtypes

Familial hypercholesterolemia (FH) is a hereditary illness marked by persistently raised low-density lipoprotein cholesterol (LDL-C) and a significantly increased risk of atherosclerotic cardiovascular disease (ASCVD). FH was diagnosed by phenotypic features or the presence of a pathogenic mutation in an FH gene. However, genetic studies currently imply that FH is divided into four distinct subtypes: the existence of a monogenic FH variation, a high LDL-C polygenic score, or “polygenic FH,” and the presence of a polygenic FH variant. LDL-C>190 mg/dl with a positive family history without a known genetic etiology or real “phenotypic FH.” Researchers looked for FH subtypes in 134,444 unrelated people whose exome sequences were available in the Biobank. 

They identified 358 people (1 in 376; 0.27%) with a pathogenic mutation in their exome sequence as having monogenic FH, 2,800 as having polygenic FH (1 in 48; 2.1%), 2,246 as having high lipoprotein (a) (1 in 60; 1.7%), and 3,146 as having phenotypic FH (1 in 43; 2.3% ). The remaining 125,894 samples were classed as controls since they did not have an FH subtype. The cohort was divided into statin-treated and untreated individuals. When compared to controls, those with an FH subtype were 2.8 times more likely to be administered a lipid-lowering prescription at the baseline interview. Those with monogenic FH were at the greatest risk for 10-year incident ASCVD in the statin-treated group (n=21,875). As evaluated by the hazard ratio, monogenic FH had a 2.7 (95% CI: 1.6-4.3) times greater ASCVD risk than controls (HR). Individuals with high lipoprotein and phenotypic FH had a higher risk of ASCVD (HR = 1.5 (95% CI: 1.1-2.1) and HR = 1.6 (95% CI: 1.3-2.1), respectively. On the other hand, those with polygenic FH do not have higher rates of incident ASCVD than controls among treated persons. The risk of ASCVD in FH subtypes was higher in the untreated group (n=112,569) compared to controls. Among the four categories, those with increased lipoprotein (a) had the greatest risk of incident ASCVD (HR=2.9, 95% CI: 2.4-3.7). Finally, they discovered variations in ASCVD risk among FH subtypes. The findings highlighted the relevance of considering subtypes when assessing ASCVD risk in patients with the FH phenotype.


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