Phenotypic Differences Between Polygenic and Monogenic Hypobetalipoproteinemia

Vanhoye, Xavier; Coulibaly, Dramane; Marrec, Marie; Pichelin, Matthieu; Charrière, Sybil; Peretti, Noël; Valéro, René; Wargny, Matthieu; Carrié, Alain; Livet, Pierre; Deleuze, Jean‐François; Génin, Emmanuelle; Redon, Richard; Rollat‐Farnier, Pierre Antoine; Goxe, Didier; Degraef, G.; Marmontel, Oriane; Divry, Eléonore; Bigot‐Corbel, Edith; Moulin, Philippe; Cariou, Bertrand; Filippo, Mathilde Di

doi:10.1161/atvbaha.120.315491

Cited by 17 publications

(19 citation statements)

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“…In a familial case of hypobetalipoproteinemia from the HYPOCHOL clinical trial, 27 in which mutations in canonical lipid genes were excluded, one proband was found to be heterozygous for the GPR146 -p.Pro62Leu variant (Figure 4). This 24 year-old woman presented with low levels of total cholesterol (124 mg/dL), LDL-C (59 mg/dL), apoB (60 mg/dL), and triglycerides (50 mg/dL), but normal HDL-C (55 mg/dL).…”

Section: Resultsmentioning

confidence: 99%

Variants in the GPR146 Gene Are Associated With a Favorable Cardiometabolic Risk Profile

Yeung

Dalila

Thio

et al. 2022

ATVB

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BACKGROUND: In mice, GPR146 (G-protein–coupled receptor 146) deficiency reduces plasma lipids and protects against atherosclerosis. Whether these findings translate to humans is unknown. METHODS: Common and rare genetic variants in the GPR146 gene locus were used as research instruments in the UK-Biobank. The Lifelines, and The Copenhagen-City Heart Study, and a cohort of individuals with familial hypobetalipoproteinemia were used to find and study rare GPR146 variants. RESULTS: In the UK-Biobank, carriers of the common rs2362529-C allele present with lower low-density lipoprotein cholesterol, apo (apolipoprotein) B, high-density lipoprotein cholesterol, apoAI, CRP (C-reactive protein), and plasma liver enzymes compared with noncarriers. Carriers of the common rs1997243-G allele, associated with higher GPR146 expression, present with the exact opposite phenotype. The associations with plasma lipids of the above alleles are allele dose-dependent. Heterozygote carriers of a rare coding variant (p.Pro62Leu; n=2615), predicted to be damaging, show a stronger reductions in the above parameters compared with carriers of the common rs2362529-C allele. The p.Pro62Leu variant is furthermore shown to segregate with low low-density lipoprotein cholesterol in a family with familial hypobetalipoproteinemia. Compared with controls, carriers of the common rs2362529-C allele show a marginally reduced risk of coronary artery disease ( P =0.03) concomitant with a small effect size on low-density lipoprotein cholesterol (average decrease of 2.24 mg/dL in homozygotes) of this variant. Finally, mendelian randomization analyses suggest a causal relationship between GPR146 gene expression and plasma lipid and liver enzyme levels. CONCLUSIONS: This study shows that carriers of new genetic GPR146 variants have a beneficial cardiometabolic risk profile, but it remains to be shown whether genetic or pharmaceutical inhibition of GPR146 protects against atherosclerosis in humans.

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Section: Resultsmentioning

confidence: 99%

Variants in the GPR146 Gene Are Associated With a Favorable Cardiometabolic Risk Profile

Yeung

Dalila

Thio

et al. 2022

ATVB

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“…The prediction algorithms classify it as VUS/Likely Pathogenic. Downstream to this variant, other pathogenic truncating alterations have been described, which also suggests that this variant is a pathogenic one [ 28 ]. Table 1 presents the APOB variants in details.…”

Section: Resultsmentioning

confidence: 99%

Establishing the Mutational Spectrum of Hungarian Patients with Familial Hypercholesterolemia

Madar

Juhász

Szücs

et al. 2022

Genes

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Familial hypercholesterolemia (FH) is one of the most common autosomal, dominantly inherited diseases affecting cholesterol metabolism, which, in the absence of treatment, leads to the development of cardiovascular complications. The disease is still underdiagnosed, even though an early diagnosis would be of great importance for the patient to receive proper treatment and to prevent further complications. No studies are available describing the genetic background of Hungarian FH patients. In this work, we present the clinical and molecular data of 44 unrelated individuals with suspected FH. Sequencing of five FH-causing genes (LDLR, APOB, PCSK9, LDLRAP1 and STAP1) has been performed by next-generation sequencing (NGS). In cases where a copy number variation (CNV) has been detected by NGS, confirmation by multiplex ligation-dependent probe amplification (MLPA) has also been performed. We identified 47 causal or potentially causal (including variants of uncertain significance) LDLR and APOB variants in 44 index patients. The most common variant in the APOB gene was the c.10580G>A p.(Arg3527Gln) missense alteration, this being in accordance with literature data. Several missense variants in the LDLR gene were detected in more than one index patient. LDLR variants in the Hungarian population largely overlap with variants detected in neighboring countries.

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“…To study the polygenic cause of primary HBL, we used a compilation of 12 SNPs for patients from the family and controls (n = 856 subjects) developed by Talmud et al [50]. Briefly, the genotypes of 12 SNPs were extracted from whole-genome sequencing data and the polygenic risk score (PRS) was calculated as previously described [3,50]. Patients with a PRS under the 10th percentile of controls were considered to have polygenic HBL.…”

Section: Polygenic Risk Scorementioning

confidence: 99%

“…Hypobetalipoproteinemia (HBL) is characterized by low plasma levels of apolipoprotein B (apoB) and low-density lipoprotein cholesterol (LDL-C), less than the fifth percentile for age and sex [1]. In total, 30 to 50% of patients with primary HBL present a polygenic origin of HBL [2,3], whereas a monogenic origin is identified in 20 to 50% of patients [4]. The most common etiology of monogenic HBL is familial HBL1 (FHBL1 (MIM: 615,558)), a semi-dominant variant in the APOB gene (MIM: 107,730), leading to apoB secretion defects.…”

Section: Introductionmentioning

confidence: 99%

“…Carrying a heterozygous APOB (He-APOB) PTC was associated with a significantly lower risk for coronary heart disease [19]. However, unlike other causes of primary HBL, this condition is associated with an increased risk of NAFLD (non-alcoholic fatty liver disease) when compared to the general population [3,20,21]. NASH (non-alcoholic steatohepatitis) [19], cirrhosis and hepatocellular carcinoma have been described in He-APOB [14,[22][23][24].…”

Section: Introductionmentioning

confidence: 99%

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APOB CRISPR-Cas9 Engineering in Hypobetalipoproteinemia: A Promising Tool for Functional Studies of Novel Variants

Vanhoye

Janin

Caillaud

et al. 2022

IJMS

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Hypobetalipoproteinemia is characterized by LDL-cholesterol and apolipoprotein B (apoB) plasma levels below the fifth percentile for age and sex. Familial hypobetalipoproteinemia (FHBL) is mostly caused by premature termination codons in the APOB gene, a condition associated with fatty liver and steatohepatitis. Nevertheless, many families with a FHBL phenotype carry APOB missense variants of uncertain significance (VUS). We here aimed to develop a proof-of-principle experiment to assess the pathogenicity of VUS using the genome editing of human liver cells. We identified a novel heterozygous APOB-VUS (p.Leu351Arg), in a FHBL family. We generated APOB knock-out (KO) and APOB-p.Leu351Arg knock-in Huh7 cells using CRISPR-Cas9 technology and studied the APOB expression, synthesis and secretion by digital droplet PCR and ELISA quantification. The APOB expression was decreased by 70% in the heterozygous APOB-KO cells and almost abolished in the homozygous-KO cells, with a consistent decrease in apoB production and secretion. The APOB-p.Leu351Arg homozygous cells presented with a 40% decreased APOB expression and undetectable apoB levels in cellular extracts and supernatant. Thus, the p.Leu351Arg affected the apoB secretion, which led us to classify this new variant as likely pathogenic and to set up a hepatic follow-up in this family. Therefore, the functional assessment of APOB-missense variants, using gene-editing technologies, will lead to improvements in the molecular diagnosis of FHBL and the personalized follow-up of these patients.

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Phenotypic Differences Between Polygenic and Monogenic Hypobetalipoproteinemia

Cited by 17 publications

References 44 publications

Variants in the GPR146 Gene Are Associated With a Favorable Cardiometabolic Risk Profile

Variants in the GPR146 Gene Are Associated With a Favorable Cardiometabolic Risk Profile

Establishing the Mutational Spectrum of Hungarian Patients with Familial Hypercholesterolemia

APOB CRISPR-Cas9 Engineering in Hypobetalipoproteinemia: A Promising Tool for Functional Studies of Novel Variants

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