| 1. |
- Cuchel, M., et al.
(author)
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Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society
- 2014
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In: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 35:32
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Journal article (peer-reviewed)abstract
- Aims Homozygous familial hypercholesterolaemia (HoFH) is a rare life-threatening condition characterized by markedly elevated circulating levels of low-density lipoprotein cholesterol (LDL-C) and accelerated, premature atherosclerotic cardiovascular disease (ACVD). Given recent insights into the heterogeneity of genetic defects and clinical phenotype of HoFH, and the availability of new therapeutic options, this Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society (EAS) critically reviewed available data with the aim of providing clinical guidance for the recognition and management of HoFH. Methods and results Early diagnosis of HoFH and prompt initiation of diet and lipid-lowering therapy are critical. Genetic testing may provide a definitive diagnosis, but if unavailable, markedly elevated LDL-C levels together with cutaneous or tendon xanthomas before 10 years, or untreated elevated LDL-C levels consistent with heterozygous FH in both parents, are suggestive of HoFH. We recommend that patients with suspected HoFH are promptly referred to specialist centres for a comprehensive ACVD evaluation and clinical management. Lifestyle intervention and maximal statin therapy are the mainstays of treatment, ideally started in the first year of life or at an initial diagnosis, often with ezetimibe and other lipid-modifying therapy. As patients rarely achieve LDL-C targets, adjunctive lipoprotein apheresis is recommended where available, preferably started by age 5 and no later than 8 years. The number of therapeutic approaches has increased following approval of lomitapide and mipomersen for HoFH. Given the severity of ACVD, we recommend regular follow-up, including Doppler echocardiographic evaluation of the heart and aorta annually, stress testing and, if available, computed tomography coronary angiography every 5 years, or less if deemed necessary. Conclusion This EAS Consensus Panel highlights the need for early identification of HoFH patients, prompt referral to specialized centres, and early initiation of appropriate treatment. These recommendations offer guidance for a wide spectrum of clinicians who are often the first to identify patients with suspected HoFH.
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| 2. |
- Hegele, R. A., et al.
(author)
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The polygenic nature of hypertriglyceridaemia: implications for definition, diagnosis, and management
- 2014
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In: Lancet Diabetes & Endocrinology. - : Elsevier BV. - 2213-8587. ; 2:8, s. 655-666
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Journal article (peer-reviewed)abstract
- Plasma triglyceride concentration is a biomarker for circulating triglyceride-rich lipoproteins and their metabolic remnants. Common mild-to-moderate hypertriglyceridaemia is typically multigenic, and results from the cumulative burden of common and rare variants in more than 30 genes, as quantified by genetic risk scores. Rare autosomal recessive monogenic hypertriglyceridaemia can result from large-effect mutations in six different genes. Hypertriglyceridaemia is exacerbated by non-genetic factors. On the basis of recent genetic data, we redefine the disorder into two states: severe (triglyceride concentration >10 mmol/L), which is more likely to have a monogenic cause; and mild-to-moderate (triglyceride concentration 2-10 mmol/L). Because of clustering of susceptibility alleles and secondary factors in families, biochemical screening and counselling for family members is essential, but routine genetic testing is not warranted. Treatment includes management of lifestyle and secondary factors, and pharmacotherapy. In severe hypertriglyceridaemia, intervention is indicated because of pancreatitis risk; in mild-to-moderate hypertriglyceridaemia, intervention can be indicated to prevent cardiovascular disease, dependent on triglyceride concentration, concomitant lipoprotein disturbances, and overall cardiovascular risk.
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| 3. |
- Wootton, P. T., et al.
(author)
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Tagging SNP haplotype analysis of the secretory PLA2-V gene, PLA2G5, shows strong association with LDL and oxLDL levels, suggesting functional distinction from sPLA2-IIA: results from the UDACS study
- 2007
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In: Hum Mol Genet. ; 16:12, s. 1437-44
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Journal article (peer-reviewed)abstract
- Animal and human studies suggest that both secretory PLA2 (sPLA2)-V and sPLA2-IIA (encoded, respectively, by the neighbouring PLA2G5 and PLA2G2A genes) contribute to atherogenesis. Elevated plasma sPLA2-IIA predicts coronary heart disease (CHD) risk, but no mass assay for sPLA2-V is available. We previously reported that tagging single nucleotide polymorphism (tSNP) haplotypes of PLA2G2A are strongly associated with sPLA2-IIA mass, but not lipid levels. Here, we use tSNPs of the sPLA2-V gene to investigate the association of PLA2G5 with CHD risk markers. Seven PLA2G5 tSNPs genotypes, explaining >92% of the locus genetic variability, were determined in 519 patients with Type II diabetes (in whom PLA2G2A tSNP data was available), and defined seven common haplotypes (frequencies >5%). PLA2G5 and PLA2G2A tSNPs showed linkage disequilibrium (LD). Compared to the common PLA2G5 haplotype, H1 (frequency 34.9%), haplotypes H2-7 were associated with overall higher plasma LDL (P < 0.00004) and total cholesterol (P < 0.00003) levels yet lower oxLDL/LDL (P = 0.006) and sPLA2-IIA mass (P = 0.04), probably reflecting LD with PLA2G2A. Intronic tSNP (rs11573248), unlikely itself to be functional, distinguished H1 from LDL-raising haplotypes and may mark a functional site. In conclusion, PLA2G5 tSNP haplotypes demonstrate an association with total and LDL cholesterol and oxLDL/LDL, not seen with PLA2G2A, thus confirming distinct functional roles for these two sPLA2s.
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| 4. |
- Wootton, P. T., et al.
(author)
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Tagging-SNP haplotype analysis of the secretory PLA2IIa gene PLA2G2A shows strong association with serum levels of sPLA2IIa: results from the UDACS study
- 2006
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In: Hum Mol Genet. ; 15:2, s. 355-61
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Journal article (peer-reviewed)abstract
- Recent prospective analysis identified secretory phospholipase A(2)-IIa (sPLA(2)IIa) as a coronary artery disease (CAD) risk predictor. This study aimed to examine the relationship between serum levels of sPLA(2)IIa and variation in the sPLA(2)IIa gene (PLA2G2A) in a cohort of patients with Type II diabetes (T2D) mellitus. Six tagging single nucleotide polymorphisms (tSNPs) accounting for > 92% of the genetic variability in PLA2G2A were identified and distinguished six common haplotypes (frequencies > 5%). In the 523 Caucasian T2D patients, levels of sPLA(2)IIa, independent of CRP, were negatively correlated with total antioxidant status (P = 0.003) and high-density lipoprotein cholesterol (P = 0.006) in men and correlated with CAD status in women (P = 0.002) (Odds ratio of top two tertiles versus bottom = 2.50) [95% CI (1.13-5.53) P = 0.024]. Overall, tSNP haplotypes showed a highly significant association with sPLA(2)IIa levels (P < 0.0001), explaining 6.3% of the variance. The most common haplotype (frequency 14.2%) was associated with 53% higher sPLA(2)IIa levels [3.25 ng/ml (+/- 0.14)] compared with the combined other haplotypes [2.13 ng/ml (+/- 0.09), P < 0.00001]. Five of the six tSNPs were associated with significant effects on sPLA(2)IIa levels but the raising haplotype could not be distinguished by a single tSNP and none are likely to be functional. These data confirm the relationship between elevated sPLA(2)IIa levels and CAD risk reported in both cases: control and prospective analyses. The strong impact of PLA2G2A haplotypic variation on sPLA(2)IIa levels will help clarify the causality of this association.
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