Mutation spectrum and polygenic score in German patients with familial hypercholesterolemia

Rieck, Lorenz; Bardey, Frieda; Grenkowitz, Thomas; Bertram, Lars; Helmuth, Johannes; Mischung, Claudia; Spranger, Joachim; Steinhagen‐Thiessen, Elisabeth; Bobbert, Thomas; Kassner, Ursula; Demuth, Ilja

doi:10.1111/cge.13826

Cited by 13 publications

(13 citation statements)

References 52 publications

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“…However, the difference in the polygenic score among FH/M− and FH/M+ individuals is modest both in our analysis and in other studies. 13 , 24 Moreover, the comparison between LIPIGEN subjects who were H/M− and the healthy subjects from the Whitehall II study showed that the LDL‐C level in the former is about 30% higher than in the latter group, despite comparable polygenic score values. These observations suggest that, in subjects with the FH phenotype but lacking a causative mutation (FH/M−), lipid levels may be determined by the interplay between genetic factors, including the polymorphisms evaluated in our study but also other unknown genetic determinants, and environmental factors.…”

Section: Discussionmentioning

confidence: 99%

Twelve Variants Polygenic Score for Low‐Density Lipoprotein Cholesterol Distribution in a Large Cohort of Patients With Clinically Diagnosed Familial Hypercholesterolemia With or Without Causative Mutations

Olmastroni

Gazzotti

Arca

et al. 2022

JAHA

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Background A significant proportion of individuals clinically diagnosed with familial hypercholesterolemia (FH), but without any disease‐causing mutation, are likely to have polygenic hypercholesterolemia. We evaluated the distribution of a polygenic risk score, consisting of 12 low‐density lipoprotein cholesterol (LDL‐C)‐raising variants (polygenic LDL‐C risk score), in subjects with a clinical diagnosis of FH. Methods and Results Within the Lipid Transport Disorders Italian Genetic Network (LIPIGEN) study, 875 patients who were FH‐mutation positive (women, 54.75%; mean age, 42.47±15.00 years) and 644 patients who were FH‐mutation negative (women, 54.21%; mean age, 49.73±13.54 years) were evaluated. Patients who were FH‐mutation negative had lower mean levels of pretreatment LDL‐C than patients who were FH‐mutation positive (217.14±55.49 versus 270.52±68.59 mg/dL, P <0.0001). The mean value (±SD) of the polygenic LDL‐C risk score was 1.00 (±0.18) in patients who were FH‐mutation negative and 0.94 (±0.20) in patients who were FH‐mutation positive ( P <0.0001). In the receiver operating characteristic analysis, the area under the curve for recognizing subjects characterized by polygenic hypercholesterolemia was 0.59 (95% CI, 0.56–0.62), with sensitivity and specificity being 78% and 36%, respectively, at 0.905 as a cutoff value. Higher mean polygenic LDL‐C risk score levels were observed among patients who were FH‐mutation negative having pretreatment LDL‐C levels in the range of 150 to 350 mg/dL (150–249 mg/dL: 1.01 versus 0.91, P <0.0001; 250–349 mg/dL: 1.02 versus 0.95, P =0.0001). A positive correlation between polygenic LDL‐C risk score and pretreatment LDL‐C levels was observed among patients with FH independently of the presence of causative mutations. Conclusions This analysis confirms the role of polymorphisms in modulating LDL‐C levels, even in patients with genetically confirmed FH. More data are needed to support the use of the polygenic score in routine clinical practice.

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Section: Discussionmentioning

confidence: 99%

Twelve Variants Polygenic Score for Low‐Density Lipoprotein Cholesterol Distribution in a Large Cohort of Patients With Clinically Diagnosed Familial Hypercholesterolemia With or Without Causative Mutations

Olmastroni

Gazzotti

Arca

et al. 2022

JAHA

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“…2 is so small that it is impractical to classify hypercholesterolemic patients only by the score. [36] In addition, based on such continuous variables, it is not realistic to create a threshold to classify the patients as having so-called "polygenic FH". On the other hand, the effect sizes of rare genetic variations of the FH-gene are large enough to allow for classification of monogenic FH in clinical settings.…”

Section: Discussionmentioning

confidence: 99%

Polygenic risk scores for low-density lipoprotein cholesterol and familial hypercholesterolemia

et al. 2021

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Familial hypercholesterolemia (FH) is an autosomal dominant monogenic disorder characterized by elevated levels of lowdensity lipoprotein cholesterol (LDL-C) and an increased risk of premature coronary artery disease (CAD). Recently, it has been shown that a high polygenic risk score (PRS) could be an independent risk factor for CAD in FH patients of European ancestry. However, it is uncertain whether PRS is also useful for risk stratification of FH patients in East Asia. We recruited and genotyped clinically diagnosed FH (CDFH) patients from the Kanazawa University Mendelian Disease FH registry and controls from the Shikamachi Health Improvement Practice genome cohort in Japan. We calculated PRS from 3.6 million variants of each participant (imputed from the 1000 Genome phase 3 Asian dataset) for LDL-C (PRS LDLC ) using a genomewide association study summary statistic from the BioBank Japan Project. We assessed the association of PRS LDLC with LDL-C and CAD among and within monogenic FH, mutation negative CDFH, and controls. We tested a total of 1223 participants (376 FH patients, including 173 with monogenic FH and 203 with mutation negative CDFH, and 847 controls) for the analyses. PRS LDLC was significantly higher in mutation negative CDFH patients than in controls (p = 3.1 × 10 −13 ). PRS LDLC was also significantly linked to LDL-C in controls (p trend = 3.6 × 10 −4 ) but not in FH patients. Moreover, we could not detect any association between PRS LDLC and CAD in any of the groups. In conclusion, mutation negative CDFH patients demonstrated significantly higher PRS LDLC than controls. However, PRS LDLC may have little additional effect on LDL-C and CAD among FH patients.

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“…Common types of PVs in our study were missense, CNV, and frameshift variants (in this order of frequency). On the other hand, missense, frameshift, and nonsense variants were common in a recent German study 22) . Of note, herein, CNVs were detected in a considerable proportion (11.5%) of PV carriers, similar to Japanese data 9) .…”

Section: Clinical Predictors Of Pvsmentioning

confidence: 93%

Phenotypic and Genetic Analyses of Korean Patients with Familial Hypercholesterolemia: Results from the KFH Registry 2020

Kim

Park

Kim

et al. 2022

JAT

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The official journal of the Japan Atherosclerosis Society and the Asian Pacific Society of Atherosclerosis and Vascular Diseases Original Article Aims: Familial hypercholesterolemia (FH) is currently a worldwide health issue. Understanding the characteristics of patients is important for proper diagnosis and treatment. This study aimed to analyze the phenotypic and genetic features, including threshold cholesterol levels, of Korean patients with FH. Methods: A total of 296 patients enrolled in the Korean FH registry were included, according to the following criteria: low-density lipoprotein-cholesterol (LDL-C) 190 mg/dL with tendon xanthoma or family history compatible with FH, or LDL-C 225 mg/dL. DNA sequences of three FH-associated genes were obtained using whole-exome or target exome sequencing. Threshold cholesterol levels for differentiating patients with FH/ pathogenic variant (PV) carriers and predictors of PVs were identified.Results: Of the 296 patients, 104 had PVs and showed more obvious clinical findings, including higher cholesterol levels. PV rates ranged from 30% to 64% when patients were categorized by possible or definite type according to the Simon Broome criteria. Frequent PV types included missense variants and copy number variations (CNVs), while the most frequent location of PVs was p.P685L in LDLR. The threshold LDL-C levels for patient differentiation and PV prediction were 177 and 225 mg/dL, respectively. Younger age, tendon xanthoma, and higher LDL-C levels were identified as independent predictors of PVs, while traditional cardiovascular risk factors were predictors of coronary artery disease.Conclusions: Korean patients with FH had variable PV rates depending on diagnostic criteria and distinctive PV locations. The reported threshold LDL-C levels pave the way for efficient patient care in this population.

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Mutation spectrum and polygenic score in German patients with familial hypercholesterolemia

Cited by 13 publications

References 52 publications

Twelve Variants Polygenic Score for Low‐Density Lipoprotein Cholesterol Distribution in a Large Cohort of Patients With Clinically Diagnosed Familial Hypercholesterolemia With or Without Causative Mutations

Twelve Variants Polygenic Score for Low‐Density Lipoprotein Cholesterol Distribution in a Large Cohort of Patients With Clinically Diagnosed Familial Hypercholesterolemia With or Without Causative Mutations

Polygenic risk scores for low-density lipoprotein cholesterol and familial hypercholesterolemia

Phenotypic and Genetic Analyses of Korean Patients with Familial Hypercholesterolemia: Results from the KFH Registry 2020

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