Low-density lipoprotein receptor genotypes modify the sera metabolome of patients with homozygous familial hypercholesterolemia

Du, Zhiyong; Li, Fan; Li, Linyi; Wang, Yu; Li, Jianping; Yang, Yujuan; Jiang, Long; Wang, Luya; Qin, Yanwen

doi:10.1016/j.isci.2022.105334

Cited by 6 publications

(8 citation statements)

References 48 publications

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“…All patients were enrolled from the Familial Hypercholesterolemia Families Cohort (FHFC) affiliated to Beijing Anzhen Hospital of the Capital University of Medical Sciences between January 2018 and July 2022 [ 9 , 14 ]. This study cohort has been registered with (number: ChiCTR1900022156).…”

Section: Methodsmentioning

confidence: 99%

“…FH diagnosis was established by means of the Dutch Lipid Clinic Network (DLCN) diagnostic criteria [ 20 ]: DLCN score ≥ 6, an untreated LDL-C ≥ 4.7 mmol/L, either corneal arcus or xanthomas, premature ASCVD history in first-degree relatives, and genetically confirmed FH. The diagnostic criteria for HoFH were as follows: untreated LDL-C ≥ 13 mmol/L or treated LDL-C ≥ 8 mmol/L, either cutaneous or tendon xanthomas, and two mutations in the LDLR, APOB, PCSK9, or LDLRAP1 genes [ 14 , 20 ].…”

Section: Methodsmentioning

confidence: 99%

“…All study subjects were genetically confirmed to have mutant alleles at the LDLR gene. Genotyping was obtained from patients if it had been performed or tested according to our previously reported methods [ 14 , 21 ].…”

Section: Methodsmentioning

confidence: 99%

“…Metabolite extraction was followed with our previously established protocol [ 14 , 22 ]: Briefly, a total of 50 μL aliquots of serum was thawed at 4 °C, a volume of 200 μL ice-cold solution (acetonitrile: water = 1:1, v / v ) containing a variety of isotopic internal standards (0.25 mg/L cholic acid-2, 2, 4, 4- d 4 , 0.54 mg/L tauroursodeoxycholic acid- d 4 , 0.35 mg/L glycocholic acid- d 4 , 0.35 mg/L L-leucine-5, 5, 5- d 3 , 0.15 mg/L L-arginine- d 7 , 0.12 mg/L stearic acid-18, 18, 18- d 3 , 0.21 mg/L LysoPC (19:0)- d 5 , 0.16 mg/L PC(18:0/20:4)- d 11 , 0.20 mg/L cholesterol- d 7 , 0.1 mg/L stearoyl-L-carnitine- d 3 ) was added. The mixture was vortexed for 2 min and centrifuged at 15,000 rpm for 12 min, at 4 °C.…”

Section: Methodsmentioning

confidence: 99%

“…Although genetic testing can accurately identify HoFH, it is expensive and is not available in most clinical settings in developing countries. In China, genetic testing is always performed in index HoFH patients and their familial members [ 8 , 14 ]. The diagnosis of an index HoFH is largely based on the clinical phenotype upon the extremely elevated LDL-C concentrations and family history.…”

Section: Introductionmentioning

confidence: 99%

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Metabolomic Approach to Screening Homozygotes in Chinese Patients with Severe Familial Hypercholesterolemia

et al. 2023

JCM

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Homozygous familial hypercholesterolemia (HoFH) is a rare inborn-errors-of-metabolism disorder characterized by devastatingly elevated low-density lipoprotein cholesterol (LDL-C) and premature cardiovascular disease. The gold standard for screening and diagnosing HoFH is genetic testing. In China, it is expensive and is always recommended for the most likely HoFH subjects with aggressive LDL-C phenotype. However, the LDL-C levels of HoFH patients and a substantial proportion of heterozygous FH (HeFH) patients overlapped considerably. Here, we performed a cost-effective metabolomic profiling on genetically diagnosed HoFH (n = 69) and HeFH patients (n = 101) with overlapping LDL-C levels, aiming to discovery a unique metabolic pattern for screening homozygotes in patients with severe FH. We demonstrated a differential serum metabolome profile in HoFH patients compared to HeFH patients. Twenty-one metabolomic alterations showed independent capability in differentiating HoFH from severe HeFH. The combined model based on seven identified metabolites yielded a corrected diagnosis in 91.3% of HoFH cases with an area under the curve value of 0.939. Collectively, this study demonstrated that metabolomic profiling serves as a useful and economical approach to preselecting homozygotes in FH patients with severe hypercholesterolemia and may help clinicians to conduct selective genetic confirmation testing and familial cascade screening.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Metabolomic Approach to Screening Homozygotes in Chinese Patients with Severe Familial Hypercholesterolemia

et al. 2023

JCM

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Metabolomic epidemiology offers insights into disease aetiology

Fuller,

Zhu,

Nicholas

et al. 2023

Nat Metab

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Metabolic systems approaches update molecular insights of clinical phenotypes and cardiovascular risk in patients with homozygous familial hypercholesterolemia

Jiang

et al. 2023

BMC Med

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Background Homozygous familial hypercholesterolemia (HoFH) is an orphan metabolic disease characterized by extremely elevated low-density lipoprotein cholesterol (LDL-C), xanthomas, aortic stenosis, and premature atherosclerotic cardiovascular disease (ASCVD). In addition to LDL-C, studies in experimental models and small clinical populations have suggested that other types of metabolic molecules might also be risk factors responsible for cardiovascular complications in HoFH, but definitive evidence from large-scale human studies is still lacking. Herein, we aimed to comprehensively characterize the metabolic features and risk factors of human HoFH by using metabolic systems strategies. Methods Two independent multi-center cohorts with a total of 868 individuals were included in the cross-sectional study. First, comprehensive serum metabolome/lipidome-wide analyses were employed to identify the metabolomic patterns for differentiating HoFH patients (n = 184) from heterozygous FH (HeFH, n = 376) and non-FH (n = 100) subjects in the discovery cohort. Then, the metabolomic patterns were verified in the validation cohort with 48 HoFH patients, 110 HeFH patients, and 50 non-FH individuals. Subsequently, correlation/regression analyses were performed to investigate the associations of clinical/metabolic alterations with typical phenotypes of HoFH. In the prospective study, a total of 84 HoFH patients with available follow-up were enrolled from the discovery cohort. Targeted metabolomics, deep proteomics, and random forest approaches were performed to investigate the ASCVD-associated biomarkers in HoFH patients. Results Beyond LDL-C, various bioactive metabolites in multiple pathways were discovered and validated for differentiating HoFH from HoFH and non-FH. Our results demonstrated that the inflammation and oxidative stress-related metabolites in the pathways of arachidonic acid and lipoprotein(a) metabolism were independently associated with the prevalence of corneal arcus, xanthomas, and supravalvular/valvular aortic stenosis in HoFH patients. Our results also identified a small marker panel consisting of high-density lipoprotein cholesterol, lipoprotein(a), apolipoprotein A1, and eight proinflammatory and proatherogenic metabolites in the pathways of arachidonic acid, phospholipid, carnitine, and sphingolipid metabolism that exhibited significant performances on predicting first ASCVD events in HoFH patients. Conclusions Our findings demonstrate that human HoFH is associated with a variety of metabolic abnormalities and is more complex than previously known. Furthermore, this study provides additional metabolic alterations that hold promise as residual risk factors in HoFH population.

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Low-density lipoprotein receptor genotypes modify the sera metabolome of patients with homozygous familial hypercholesterolemia

Cited by 6 publications

References 48 publications

Metabolomic Approach to Screening Homozygotes in Chinese Patients with Severe Familial Hypercholesterolemia

Metabolomic Approach to Screening Homozygotes in Chinese Patients with Severe Familial Hypercholesterolemia

Metabolomic epidemiology offers insights into disease aetiology

Metabolic systems approaches update molecular insights of clinical phenotypes and cardiovascular risk in patients with homozygous familial hypercholesterolemia

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