Prevalence and clinical relevance of familial hypercholesterolemia-causing mutations in Germany

Background: Familial hypercholesterolemia (FH) is a monogenic disease characterized by pathogenic mutations in genes involved in low-density lipoprotein cholesterol (LDL-C) metabolism. Optimal strategies for identifying FH in the general population are still unknown.  

Objective: To assess the prevalence of genetic FH (genFH) in a contemporary population-based sample of adult Hamburg residents and to evaluate its association with hypercholesterolemia phenotype.

Methods: In 7,373 participants of the population-based Hamburg City Health Study (HCHS) the FH genes LDLR, APOB, PCSK9, LDLRAP1, and APOE were analyzed to identify genFH, based on short-read whole-genome sequencing. LDL-C concentrations were adjusted for intake and intensity of lipid-lowering medication and categorized using the following thresholds: ≥130/≥160/≥190 mg/dL. Severe hypercholesterolemia was defined by LDL-C ≥190 mg/dL.

Results: Among 7,373 adults, median age was 62.0 (quartiles 54.0-69.0) years, and 49.1% of these were women. Twenty-three individuals had heterozygous genFH (prevalence 0.31%; 95%CI: 0.21% to 0.47% [corresponding to 1:321]), all caused by mutations in the LDLR gene. Median treatment-corrected LDL-C was higher in subjects with genFH (191 mg/dL, quartiles 149-210 mg/dL) compared to 128 mg/dL (quartiles 105-153 mg/dL) in those without genFH.

Severe hypercholesterolemia was observed in 476 of 7,275 (6.5%) subjects with available LDL-C values. Of those, only 2.3% (n=11) were positive for genFH. Moreover, 9.1% of carriers of FH-causing variants had LDL-C values below 130 mg/dL, 32.8% below 160 mg/dL and only 50% of subjects with genFH had severe hypercholesterolemia (Table).

Applying a phenotypic LDL-C threshold of ≥190 mg/dL, ≥160 mg/dL and ≥130 mg/dL to screen for genFH would result in numbers needed to screen of 43, 99 or 174, respectively.

Conclusion: The prevalence of genetically verified FH in this contemporary German population-based cohort was very similar to the worldwide prevalence of FH (0.31% versus 0.32%, respectively). Only half of the adult individuals with genFH had severe hypercholesterolemia, and only (2.3%) of individuals with LDL-C ≥190 mg/dL had genFH. More robust evidence of genotype-phenotype associations of FH mutations is needed to accurately infer at-risk individuals from genetic screening.

Table: Prevalence of genFH, according to accompanying LDL-C concentration – n (%).

Natalie Arnold und Cristian Riccio, sowie Andreas Ziegler und Raphael Twerenbold trugen gleichermassen zur Veröffentlichung bei.