Spectrum of low-density lipoprotein receptor (LDLR) mutations in a cohort of Sri Lankan patients with familial hypercholesterolemia – a preliminary report

Abstract

BackgroundHypercholesterolemia is a major determinant of cardiovascular disease-associated morbidity and mortality. Mutations in the LDL-receptor (LDLR) gene are implicated in the majority of the cases with familial hypercholesterolemia (FH). However, the spectrum of mutations in the LDLR gene in Sri Lankan patients has not been investigated. The objective of this study was to report the frequency and spectrum of variants in LDLR in a cohort of Sri Lankan patients with FH.MethodsA series of consecutive patients with FH, diagnosed according to Modified Simon Broome criteria or Dutch Lipid Clinic Network criteria at the University Medical Unit, Colombo, were recruited. Clinical data was recorded. DNA was extracted from peripheral blood samples. The LDLR gene was screened for genetic variants by Sanger sequencing.ResultsA total of 27 patients [13 (48%) males, 14 (52%) females; age range 24–73 years] were tested. Clinical features found among these 27 patients were: xanthelasma in 5 (18.5%), corneal arcus in 1 (3.7%), coronary artery disease (CAD) in 10 (37%), and a family history of hypercholesterolemia and/or CAD in 24 (88.9%) patients. In the entire cohort, mean total cholesterol was 356.8 mg/dl (±66.4) and mean LDL-cholesterol was 250.3 mg/dl (±67.7). Sanger sequencing of the 27 patients resulted in the identification of known pathogenic missense mutations in 5 (18.5%) patients. Four were heterozygotes for 1 mutation each. They were c.682G > C in 2 patients, c.1720C > A in 1 patient, and c.1855 T > A in 1 patient. One patient with severe FH phenotypes was a compound heterozygote for one known mutation, c.2289G > T, and another missense variant, c.1670C > G (p.Thr557Ser), with unknown functional impact. This latter variant has not been reported in any other population previously.ConclusionsThe frequency of known mutations in the LDLR gene in this cohort of patients was markedly low compared to frequencies reported in other populations. This highlights the likelihood of a complex, polygenic inheritance of FH in Sri Lankan patients, indicating the need for a comprehensive genetic evaluation that includes the screening for mutations in other genes that cause FH, such as APOB, PCSK9, and LDLRAP1.

Genetic Diagnosis of Familial Hypercholesterolemia in Asia

“…One patient was compound heterozygous for LDLR c.2289 G > T (p.E763D) and LDLR c.1670 C > G (p.T557S). The study found that LDLR mutations were markedly low in this population ( Paththinige et al, 2018 ).…”

Alleviation of high-fat-diet induced obesity and cholesterol accumulation in mice by extracts from male zooid of Antheraea pernyi

“…The expressions of CYP7A1and LDLR in the EMZAP-treated groups (the Low Group and the High Group) was increased compared with the Model Group. The increased expressions of these two genes were capable of reducing the cholesterol content in the plasma [26,27]. The increased expression of LXRα has been shown to improve hyperlipidemia and prevent atherosclerosis [28].…”

Generation of hyperlipidemic rabbit models using multiple sgRNAs targeted CRISPR/Cas9 gene editing system

“…Hyperlipidemia is a common genetic disorder inherit by genetic mutations mostly in LDLR, apoB-100, or proprotein convertase subtilisin kexin type 9 (PCSK9) loci which can result in xanthoma, atherosclerosis, coronary atherosclerotic heart disease (CAD), and other cardiovascular diseases [ 12 ]. The majority (60–80%) of the patients with family hyperlipidemia (FH) harbor mutations in the LDLR gene [ 13 ], but apoE serves as a major member of many ligands of LDLR which can transport plasma chylomicrons and VLDL cholesterol to the liver for metabolism by LDL receptor and related receptors. As a result, LDLR and apoE, especially the LDLR, play a critical role for the clearance of lipoprotein remnant.…”