Genetic causes of high and low serum HDL-cholesterol

Weissglas‐Volkov, Daphna; Pajukanta, Päivi

doi:10.1194/jlr.r004739

Cited by 180 publications

(140 citation statements)

References 244 publications

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“…Indeed, high-density lipoprotein cholesterol has an estimated heritability ranging from 40 to 60%. [21][22][23] In addition, the heritability of low-density lipoprotein peak particle diameter is 52% when considering age, body mass index (BMI), and plasma triglyceride concentrations. 24 Thus, this may suggest a potential link between strong DNA methylation heritability of some CpG sites within genes involved in cholesterol metabolism and the reported heritability of cholesterol levels.…”

Section: Discussionmentioning

confidence: 99%

Familial resemblances in blood leukocyte DNA methylation levels

et al. 2016

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Section: Discussionmentioning

confidence: 99%

Familial resemblances in blood leukocyte DNA methylation levels

et al. 2016

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“…To date, candidate genes, genome-wide linkage and GWASs have identified several genetic variations that may account for plasma HDL-C levels (8). GWASs independently identified numerous genetic loci for HDL-C (33)(34)(35).…”

Section: Discussionmentioning

confidence: 99%

“…While loss-of-function mutations in apolipoprotein A-I (APOA1), LCAT or ATP cassette transporter A1 (ABCA1) cause monogenic HDL-C deficiencies, single gene defects in hepatic lipase (LIPC) or cholesteryl ester transfer protein (CETP) are associated with high HDL-C levels in humans (7,8). LCAT, first described in 1962 (9), is a soluble enzyme that has a central role in the formation and maturation of HDL-C.…”

Section: Introductionmentioning

confidence: 99%

Identification of genetic variants of lecithin cholesterol acyltransferase in individuals with high HDL-C levels

Naseri

Hedayati

Daneshpour

et al. 2014

Molecular Medicine Reports

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Abstract. Among the most common lipid abnormalities, a low level of high-density lipoprotein-cholesterol (HDL-C) is one of the first risk factors identified for coronary heart disease. Lecithin cholesterol acyltransferase (LCAT) has a pivotal role in the formation and maturation of HDL-C and in reverse cholesterol transport. To identify genetic loci associated with low HDL-C in a population-based cohort in Tehran, the promoter, coding regions and exon/intron boundaries of LCAT were amplified and sequenced in consecutive individuals (n=150) who had extremely low or high HDL-C levels but no other major lipid abnormalities. A total of 14 single-nucleotide polymorphisms (SNPs) were identified, of which 10 were found to be novel; the L393L, S232T and 16:67977696 C>A polymorphisms have been previously reported in the SNP Database (as rs5923, rs4986970 and rs11860115, respectively) and the non-synonymous R47M mutation has been reported in the Catalogue of Somatic Mutations in Cancer (COSM972635). Three of the SNPs identified in the present study (position 6,531 in exon 5, position 6,696 in exon 5 and position 5,151 in exon 1) led to an amino acid substitution. The most common variants were L393L (4886C/T) in exon 6 and Q177E, a novel mutation, in exon 5, and the prevalence of the heterozygous genotype of these two SNPs was significantly higher in the low HDL-C groups. Univariate conditional logistic regression odds ratios (ORs) were nominally significant for Q177E (OR, 5.64; P=0.02; 95% confidence interval, 1.2-26.2). However, this finding was attenuated following adjustment for confounders. Further studies using a larger sample size may enhance the determination of the role of these SNPs.

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“…Whether these patients, particularly those with normal plasma LDL-C levels, should receive long-term treatment to reduce the plasma sterol levels at an early age remains uncertain, although it has been reported that patients with sitosterolaemia have developed coronary heart disease after the plasma LDL-C, but not sterol, level was treated and controlled 21) . It is worth noting that the mother of the proband and the two affected sisters each exhibited elevated HDL-C levels, particularly the mother, who had a markedly elevated HDL-C level of 3.0 mmol/L, a value compatible with the complete loss of the (cholesteryl ester transfer protein) CETP activity 22) . Large-scale prospective studies have demonstrated a strong inverse relationship between the plasma HDL-C level and risk of coronary artery disease 23) .…”

Section: Discussionmentioning

confidence: 99%

Potential Effects of NPC1L1 Polymorphisms in Protecting against Clinical Disease in a Chinese Family with Sitosterolaemia

Yuen

Kwok

et al. 2014

JAT

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increased absorption and decreased biliary excretion of cholesterol (similar to plant sterols), usually have normal to moderately elevated plasma cholesterol levels, despite the downregulation of endogenous cholesterol synthesis in hepatocytes 4) . Intestinal sterol/cholesterol absorption is governed by three key transporter molecules, including the two ATP-binding cassette (ABC) half transporters, ABCG5 and ABCG8 (previously known as sterolin-1 and -2, respectively), which heterodimerise to form a sterol efflux transporter in the liver and intestine to transport sterols (cholesterol and plant sterols) and the Niemann-Pick C1-like 1 (NPC1L1) transporter, a polytopic transmembrane protein that mediates intestinal absorption of cholesterol and sterols 5) . Sitosterolaemia is caused by mutations in either ABCG5 or ABCG8 6) . It has been estimated that sitosterolaemia occurs in 1 in 5 million people, although the true Introduction Sitosterolaemia (MIM #210250) is a very rare autosomal recessive disease characterized by excessive absorption and high plasma levels (＞30-fold) of plant sterols, particularly sitosterol and campesterol, the two major plant-derived sterols 1,2) . The clinical manifestations include tendon and tuberous xanthomas and premature atherosclerotic disease as a result of sterol deposition in the skin, tendons and coronary arteries [1][2][3] . Patients with sitosterolaemia, in whom there is Sitosterolaemia is caused by mutations in either ABCG5 or ABCG8. Chinese and Japanese individuals usually have mutations in ABCG5. We herein report a known and a novel mutation in ABCG8 and their potential interaction with NPC1L1 polymorphisms in a Chinese family with sitosterolaemia. We sequenced ABCG5 and ABCG8 and measured the levels of plasma plant sterols in a 15-yearold Chinese girl with clinical sitosterolaemia (xanthomas with elevated low-density lipoprotein cholesterol (LDL-C) and plant sterols) and her apparently healthy family members. NPC1L1 was sequenced in the genetically affected sibling and other family members. A known mutation, c.490C＞T (p. Arg164 ＊ ), in exon 4 and a novel mutation, c.1949T＞G (p.Leu650Arg), in exon 13 of ABCG8 were detected in the proband and her sister, who had elevated sterols but low LDL-C levels and no xanthomas. The genetically affected sister, but not the proband, carried two additional heterozygous changes in NPC1L1 (rs2072183 C＞G, rs2301935 A＞C), which were inherited from the mother, who also had a low LDL-C level. In this study, we detected a known and a novel mutation in ABCG8 in a Chinese patient with sitosterolaemia. The same mutations were found in her clinically normal sister, suggesting that the contrasting features with the proband may be related to different variants in NPC1L1 and/or some other undetermined lipid-related genetic factors. J Atheroscler Thromb, 2014; 21:989-995.

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Genetic causes of high and low serum HDL-cholesterol

Cited by 180 publications

References 244 publications

Familial resemblances in blood leukocyte DNA methylation levels

Familial resemblances in blood leukocyte DNA methylation levels

Identification of genetic variants of lecithin cholesterol acyltransferase in individuals with high HDL-C levels

Potential Effects of NPC1L1 Polymorphisms in Protecting against Clinical Disease in a Chinese Family with Sitosterolaemia

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