Effects of Different Types of Pathogenic Variants on Phenotypes of Familial Hypercholesterolemia

Abstract

Objective: It has been shown that pathogenic variants are associated with poor clinical outcomes in patients with familial hypercholesterolemia (FH). However, data on the effect of different types of pathogenic variants on FH phenotype is limited.Methods: We retrospectively investigated the associations between genotypes and phenotypes, including low-density lipoprotein (LDL) cholesterol level and the occurrence of major adverse cardiac events (MACEs), defined as cardiovascular death, myocardial infarction, unstable angina, or coronary artery revascularization, in patients with FH (N = 1,050, male/female = 490/560). Based on genotype, the patients were divided into the following three groups: patients without pathogenic variants, patients with missense variants, and patients with protein-truncating variants (PTVs). Cox proportional hazard model was used to identify the factors associated with MACEs.Results: The median follow-up duration was 12.6 years (interquartile range = 9.5–17.9 years). There were 665 patients with FH-mutation (277 patients with missense variants and 388 patients with PTVs) and 385 patients without FH-mutation. Over the follow-up duration, 175 MACEs were observed. We identified 89 different pathogenic variants in the 665 patients with FH. LDL cholesterol level was found to be significantly higher in patients with PTVs (256 mg/dl) than in patients with missense variants (236 mg/dl) and patients without pathogenic variants (216 mg/dl). It was also found that PTVs and missense variants are significantly associated with MACEs (hazard ratio [HR] = 1.58, 95% confidence interval [CI] = 1.08–2.08, p = 0.0033 and HR = 3.24, 95% CI = 2.12–4.40, p = 3.9 × 10−6, respectively), independent of classical risk factors.Conclusion: Pathogenic variants, especially PTVs, are significantly associated with poor outcomes in patients with FH. Genetic testing is useful for the diagnosis and risk stratification of patients with FH.

Early diagnosis and treatments in childhood are associated with better prognosis in patients with familial hypercholesterolemia

“…It is also noteworthy that almost half of our study subjects had nonsense mutation in LDLR , which we believe are associated with severe form of FH. In fact, we have shown that phenotype of FH with nonsense mutation in LDLR is severer than that of FH with missense mutation [20] .…”

Does low-density lipoprotein fully explain atherosclerotic risk in familial hypercholesterolemia?

“…The greater the effect on lifetime LDL-C, the greater the effect on risk independent of observed LDL-C. For example, when considering specific types of FH variants, loss-of-function variants of LDLR are associated with higher LDL-C compared to other FH variants. Likewise, such variants have been found to associate with greater atherosclerotic risk independent of baseline LDL-C compared to other variant types [37 ▪ ,38 ▪ ]. This greater magnitude of independent risk seen among carriers of LDLR null variants reflects a greater impact on lifetime LDL-C compared to other variant types.…”

Genetic Counseling and Genetic Testing for Familial Hypercholesterolemia

“…Genotype–phenotype correlations exist in some diseases and genes [ 29 ], such as in FH. For example, the phenotype of FH caused by nonsense variants in the LDLR is much worse than that caused by missense variants [ 30 ]. Another association study revealed that the effect size for “FH-variant” coronary artery disease was inversely associated with their allele frequency [ 31 ], which is in accordance with the concept that rarer genetic variants tend to have larger effect sizes on diseases [ 32 ].…”

“…In addition to the presence of FH variants, the type of pathogenic variants as well as other genetic situations, including polygenic risk scores comprising common genetic variations, are all associated with the phenotype [ 44 ]. We have shown that patients with FH caused by a protein-truncating variant had poorer prognosis than patients with FH caused by a missense variant ( Figure 3 ) [ 30 ]. Accordingly, genetic backgrounds need to be considered during risk assessment in patients with FH [ 45 ].…”

“…Currently, there are two major ways to screen for FH, cascade screening and universal screening. by a protein-truncating variant had poorer prognosis than patients with FH caused by a missense variant (Figure 3) [30]. Accordingly, genetic backgrounds need to be considered during risk assessment in patients with FH [45].…”