The genetic spectrum of familial hypercholesterolemia in the central south region of China

Xiang, Rong; Fan, Liang‐Liang; Lin, Minjie; Li, Jingjing; Shi, Xiangyu; Jin, Jie‐Yuan; Liu, Yu‐Xing; Chen, Yaqin; Xia, Kun; Zhao, Shui‐Ping

doi:10.1016/j.atherosclerosis.2017.02.007

Cited by 22 publications

(20 citation statements)

References 26 publications

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“…Our observed monogenic carrier rates for severe hypercholesterolemia (2%) are consistent with observations in other population-based cohorts 26 , 27 and health-care-associated biobanks 25 but lower than for patients with clinical criteria for familial hypercholesterolemia (up to 24%) 27 , particularly those clinically referred for familial hypercholesterolemia genetic testing (up to 50%) 28 – 31 . As anticipated, this subgroup is also likely to have a greater monogenic relative to polygenic contribution 32 , 33 .…”

Section: Discussionsupporting

confidence: 90%

Deep-coverage whole genome sequences and blood lipids among 16,324 individuals

et al. 2018

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Large-scale deep-coverage whole-genome sequencing (WGS) is now feasible and offers potential advantages for locus discovery. We perform WGS in 16,324 participants from four ancestries at mean depth >29X and analyze genotypes with four quantitative traits—plasma total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, and triglycerides. Common variant association yields known loci except for few variants previously poorly imputed. Rare coding variant association yields known Mendelian dyslipidemia genes but rare non-coding variant association detects no signals. A high 2M-SNP LDL-C polygenic score (top 5th percentile) confers similar effect size to a monogenic mutation (~30 mg/dl higher for each); however, among those with severe hypercholesterolemia, 23% have a high polygenic score and only 2% carry a monogenic mutation. At these sample sizes and for these phenotypes, the incremental value of WGS for discovery is limited but WGS permits simultaneous assessment of monogenic and polygenic models to severe hypercholesterolemia.

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Section: Discussionsupporting

confidence: 90%

Deep-coverage whole genome sequences and blood lipids among 16,324 individuals

et al. 2018

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“…In some European countries, a founder effect exists with the predomination of a few mutations because of the relatively univocal population [ 27 , 28 ]. While a previous study from central south region of China found only 43 mutations in 219 FH patients [ 19 ], the present study identified a total of 119 FH-associated variants in 285 patients and found that the variant LDLR c.1448G > A (p. W483X) presented the highest frequency but with only 9 carriers. The data suggested a high genetic heterogeneity for FH in Chinese population which may attribute to the boarder geographical regions and nationalities.…”

Section: Discussioncontrasting

confidence: 58%

Genetic basis of index patients with familial hypercholesterolemia in Chinese population: mutation spectrum and genotype-phenotype correlation

Sun

Zhou

et al. 2018

Lipids Health Dis

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BackgroundAlthough there have been many reports in the genetics of familial hypercholesterolemia (FH) worldwide, studies in regard of Chinese population are lacking. In this multi-center study, we aim to characterize the genetic spectrum of FH in Chinese population, and examine the genotype-phenotype correlations in detail.MethodsA total of 285 unrelated index cases from China with clinical FH were consecutively recruited. Next-generation sequencing and bioinformatics tools were used for mutation detection of LDLR, APOB and PCSK9 genes and genetic analysis.ResultsOverall, the detection rate is 51.9% (148/285) in the unrelated index cases with a total of 119 risk variants identified including 84 in the LDLR gene, 31 in APOB and 4 in PCSK9 gene. Twenty-eight variants were found in more than one individual and LDLR c.1448G > A (p. W483X) was most frequent one detected in 9 patients. Besides, we found 8 (7 LDLR and 1 APOB) novel variants referred as “pathogenic (or likely pathogenic) variants” according to in silico analysis. In the phenotype analysis, patients with LDLR null mutation had significantly higher LDL cholesterol level than LDLR defective and APOB/PCSK9 mutation carriers and those with no mutations (p < 0.001). Furthermore, 13 double heterozygotes, 16 compound heterozygotes and 5 true LDLR homozygotes were identified and the true LDLR homozygotes had the most severe phenotypes.ConclusionsThe present study confirmed the heterogeneity of FH genetics in the largest Chinese cohort, which could replenish the knowledge of mutation spectrum and contribute to early screening and disease management.

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“… 1 FH is characterized by elevated low-density lipoprotein cholesterol (LDL; OMIM #606945), leading to lipid accumulation and increased risk of cardiovascular disease (CVD). 2 – 4 Premature coronary artery disease is also often encountered in patients with FH, 5 a well-known genetic disease. Additionally, LDL-C levels are associated with the risk of CVD.…”

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confidence: 99%

Q192R polymorphism in the PON1 gene and familial hypercholesterolemia in a Saudi population

Alharbi

Al-Nbaheen

Alharbi

et al. 2017

Annals of Saudi Medicine

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BACKGROUNDFamilial hypercholesterolemia (FH) is an autosomal dominant condition characterized by abnormal levels of low-density lipoprotein (LDL) in the blood. FH is a risk factor for atherosclerosis and cardiovascular disease. The relationship between the paraoxonase 1 (PON1) gene, atherosclerosis and coronary artery disease has not been studied in Saudi patients.OBJECTIVETo investigate the genetic associations of the Q192R polymorphism in the PON1 gene with FH in Saudi patients.DESIGNCase-control study.SETTINGTertiary care center, Riyadh.METHODSTwo hundred Saudi patients were enrolled in this study, including 100 patients with FH and 100 healthy controls, during the period from January 2012 to March 2013. Serum was separated from coagulated blood (3 mL) and used for analysis of lipid profiles. Genomic DNA was isolated from anticoagulant-treated blood (2 mL). Genotyping for the Q192R polymorphism was performed by polymerase chain reaction-restriction fragment length polymorphism analysis, followed by 3% agarose gel electrophoresis.MAIN OUTCOME MEASUREThe strength of association between the Q192R polymorphism and FH in the Saudi population.RESULTSWe confirmed that QR versus QQ (odds ratio [OR]: 1.55; 95% confidence interval [CI]: 1.05–3.43; P=.03), QR+RR versus QQ (OR: 1.98; 95% CI: 1.13–3.49; P=.01), and R versus Q (OR: 1.68; 95% CI: 1.09–2.59; P=.01) in the Q192R polymorphism were associated with FH in the Saudi population.CONCLUSIONIn conclusion, the Q192R polymorphism in the PON1 gene is associated with FH in the Saudi population. Our results confirmed that the R allele, QR, and dominant model genotypes were associated with FH.LIMITATIONOnly a single variant (Q192R) was analyzed, and the medical and family histories of the patients were not known.

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The genetic spectrum of familial hypercholesterolemia in the central south region of China

Cited by 22 publications

References 26 publications

Deep-coverage whole genome sequences and blood lipids among 16,324 individuals

Deep-coverage whole genome sequences and blood lipids among 16,324 individuals

Genetic basis of index patients with familial hypercholesterolemia in Chinese population: mutation spectrum and genotype-phenotype correlation

Q192R polymorphism in the PON1 gene and familial hypercholesterolemia in a Saudi population

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