Genetic variation of PLTP modulates lipoprotein profiles in hypoalphalipoproteinemia

Aouizerat, Bradley E.; Engler, Mary B.; Natanzon, Yanina; Kulkarni, Medha V.; Song, James; Eng, Celeste; Huuskonen, Jarkko; Rivera, Christopher R.; Poon, Annie; Bensley, Matt; Sehnert, Amy J.; Zellner, Christian; Malloy, Mary J.; Kane, John P.; Pullinger, Clive R.

doi:10.1194/jlr.m500476-jlr200

Cited by 31 publications

(25 citation statements)

References 29 publications

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“…Our finding is in agreement with those of others using different study populations; bearing these allelic variants has been shown to have obligatory associations with increased triglyceride levels, independent of geographic origin or disease of the population examined. [29][30][31][32] We also compared the serum cholesterol levels in all groups, but we could not detect an association between carrying any allele and cholesterol level, which is consistent with the observations of others; 11,33 however, in some studies, changes in cholesterol levels were observed in carriers of the -1131C allele. 34,35 In the present stroke patients, there was an approximately 2-fold accumulation in the -1131C as well as in the IVS3+ 476A alleles, whereas the distribution of the 1259C allele was almost the same in patients with stroke and in controls.…”

Section: Discussionsupporting

confidence: 79%

Apolipoprotein A5 Gene IVS3+G476A Allelic Variant Confers Susceptibility for Development of Ischemic Stroke

Maász

Kisfali

Járomi

et al. 2008

Circ J

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troke is an acute temporary, or often permanent damage of the brain. In industrialized countries stroke is the third leading cause of death after cardiovascular disorders and malignant tumors. 1 It can affect both sexes at any time of life; however, it is more prevalent in males and people over 50 years of age. Ischemic stroke results in local dysfunction of the brain and comprises 80% of cases. 2 Ischemic stroke can be unequivocally attributed to numerous classic clinical and environmental risk factors, such as diabetes mellitus, hypertension, smoking and excessive alcohol or drug consumption. 3 The role of several factors in the development of the disease is still the subject of investigations, including the possible significance of increased triglyceride levels. In the past decade numerous genetic susceptibility factors have been verified, which alone or in combination with other genes or exogenous factors can have a role in the development of stroke. [4][5][6][7] The apolipoprotein A5 (APOA5) gene is located nearby the APOAI-APOCIII-APOAIV cluster in the 11q23 chroCirculation Journal Vol.72, July 2008 mosome. It includes 3 exons and encodes 366 amino acids. The mature APOA5 protein is synthesized by the liver and secreted into the plasma where it plays a crucial regulatory role in triglyceride metabolism. 8,9 All of the most frequently occurring variants, T-1131C, T1259C, C56G, IVS3+G476A, have been reported as associated with elevated triglyceride levels, and some of them were also found to be independent risk factors for cardio-and cerebrovascular diseases. [10][11][12] Albeit limited data are available about the role of the T1259C and IVS3+G476A variants in triglyceride metabolism, 11,13 their possible significance in stroke has not been examined at all. We have demonstrated that the T-1131C variant confers susceptibility for ischemic stroke, 14 so as a natural extension, the goal of the present study was to investigate the possible pathogenic role of the 1259C and IVS3+476A allelic variants, and the T-1131C variant was also tested in the study population. Methods Study PopulationA total of 378 Caucasian unrelated patients (150 males, 228 females; mean age: 66.1±0.74 years, range: 24-95) with ischemic stroke were enrolled. All of them underwent extended clinical assessment, including general physical and laboratory cardiological and neurological examinations, and past medical and familial histories. After receiving the magnetic resonance imaging (MRI) and clinical neurological results the 378 patients were allocated to 1 of 3 stroke subgroups as previously described. 14 The first group had

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Section: Discussionsupporting

confidence: 79%

Apolipoprotein A5 Gene IVS3+G476A Allelic Variant Confers Susceptibility for Development of Ischemic Stroke

Maász

Kisfali

Járomi

et al. 2008

Circ J

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“…Aouizerat et al recently reported 4 missense mutations in PLTP in 276 low HDL subjects, only 1 of which was associated with decreased transfer activity. 12 Importantly, we demonstrate that one-third of HDLdeficient subjects (41/124 subjects) exhibit cellular cholesterol efflux defects and that the majority of these individuals do not harbor functional mutations in ABCA1 (34/41 subjects). Overall, functional nonsynonymous sequence variants in major candidate genes contribute to the low HDL-C phenotype in a minority (12%) of subjects (Table 1).…”

Section: Discussionmentioning

confidence: 99%

“…[7][8][9] Phospholipid transfer protein (PLTP) also contributes to remodeling of HDL, and low HDL is a feature of PLTP deficiency in the mouse 10,11 ; in a human low HDL population, 4 missense mutations have been reported, 1 of which was associated with decreased lipid transfer. 12 Tangier disease, an autosomal recessive disorder characterized by almost complete HDL deficiency, is characterized by defective cellular lipid efflux to apoA-I, resulting from homozygosity or compound heterozygosity for mutations in the ATP-binding cassette transporter ABCA1. [13][14][15][16][17][18][19] Defective lipid efflux is also a significant factor in familial HDL deficiency, and, in several of these kindreds, affected subjects are heterozygous carriers of ABCA1 mutations.…”

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confidence: 99%

Genetic Etiology of Isolated Low HDL Syndrome

Kiss

Kavaslar

Okuhira

et al. 2007

ATVB

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Objective-We have used a multitiered approach to identify genetic and cellular contributors to high-density lipoprotein (HDL) deficiency in 124 human subjects. Methods and Results-We resequenced 4 candidate genes for HDL regulation and identified several functional nonsynonymous mutations including 2 in apolipoprotein A-I (APOA1), 4 in lecithin:cholesterol acyltransferase (LCAT), 1 in phospholipid transfer protein (PLTP), and 7 in the ATP-binding cassette transporter ABCA1, leaving 88% (110/124) of HDL deficient subjects without a genetic diagnosis. Cholesterol efflux assays performed using cholesterol-loaded monocyte-derived macrophages from the 124 low HDL subjects and 48 control subjects revealed that 33% (41/124) of low HDL subjects had low efflux, despite the fact that the majority of these subjects (34/41) were not carriers of dysfunctional ABCA1 alleles. In contrast, only 2% of control subjects presented with low efflux (1/48). In 3 families without ABCA1 mutations, efflux defects were found to cosegregate with low HDL. Conclusions-Efflux defects are frequent in low HDL syndromes, but the majority of HDL deficient subjects with cellular cholesterol efflux defects do not harbor ABCA1 mutations, suggesting that novel pathways contribute to this phenotype.

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“…This may be partially explained by its pattern of expression, suggesting functions in organs such as brain, lung, and the gonads ( 126 ). The gene was screened for sequence variants in low HDL-C population in two independent studies, in 124 individuals with HDL-C levels below the 10 th percentile for age and sex ( 31 ) and in 276 subjects below the ‫ف‬ 20 th percentile for age and sex, as well as in 364 matched controls ( 127 ). Mutations in PLTP were uncommon in these low HDL-C populations.…”

Section: Linkage and Candidate-gene Studies For Analyzing Polygenic Hmentioning

confidence: 99%

Genetic causes of high and low serum HDL-cholesterol

Weissglas‐Volkov

Pajukanta

2010

Journal of Lipid Research

180

132

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Genetic variation of PLTP modulates lipoprotein profiles in hypoalphalipoproteinemia

Cited by 31 publications

References 29 publications

Apolipoprotein A5 Gene IVS3+G476A Allelic Variant Confers Susceptibility for Development of Ischemic Stroke

Apolipoprotein A5 Gene IVS3+G476A Allelic Variant Confers Susceptibility for Development of Ischemic Stroke

Genetic Etiology of Isolated Low HDL Syndrome

Genetic causes of high and low serum HDL-cholesterol

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