Familial Hypercholesterolemia: Prevalence and Discrepancy between Genotype and Phenotype. Findings of the Population-based Hamburg City Health Study

BACKGROUND: Familial hypercholesterolemia (FH) is among the more common monogenic diseases, yet population-based data on genetically confirmed FH (genFH) and its association with LDL cholesterol (LDL-C) in Germany are lacking.

METHODS: In the Hamburg City Health Study (registration: Clinical Trials.gov, NCT03934957), five FH-associated genes were exam - ined for pathogenic mutations with whole genome sequencing and compared with LDL-C levels that had been corrected for lipidlowering medication. Severe hypercholesterolemia was defined as an LDL-C level of 190 mg/dL or above.

RESULTS: There were 7373 adult participants (49.1% women; median age 62 years), of whom 23 had FH, corresponding to a prevalence of 0.31% (95% confidence interval [CI]: [0.21; 0.47]), or a prevalence ratio of 1:321 [1:213; 1:476]. All genFH cases were due to mutations in the LDLR gene. The median treatment-adjusted LDL-C level was higher in genFH cases (191 mg/dL) than in persons without genFH (128 mg/dL; p <0.001). Eleven of the participants with genFH had severe hypercholesterolemia. Among the 7253 participants without genFH, 465 had severe hypercholesterolemia. Only 2.3% (n = 11) of the severely hypercholesterolemic participants had genFH. Forty-three people would need to be genetically tested to identify one genFH case if an LDL-C threshold of ≥190 mg/dL is selected, 98 people at ≥160 mg/dL, and 175 people at ≥130 mg/dL.

CONCLUSION: The prevalence of genFH in this German study was 0.31%, which corresponds to the global average. As only half of the persons from our adult cohort identified as having genFH had severe hypercholesterolemia, population-based genetic screening would seem to be of questionable benefit.