Cardiovascular genetic assessment and treatment in middle age to reduce the risk of heart disease and dementia in old age

Assessment and treatment of cardiovascular disease (CVD) risk factors as a preventable cause of cognitive decline, morbidity and mortality is an important clinical goal. The apolipoprotein E (Apo E) gene provides a genetic link between CVD and the development of Alzheimer's disease (AD). The E4 allele increases the risk of coronary heart disease by more than 40% and contributes to the development of late-onset AD in more than 50% of affected patients. Disease expression in the presence of this allele is triggered by interaction with modifiable risk factors such as smoking, alcohol intake and high-calorie diets. It also displays differential therapeutic responses with use of cholesterol-lowering statins and acetylcholinesterase inhibitors. Apo E genotyping as part of a comprehensive evaluation of multiple CVD risk factors, performed in conjunction with nutrition and cognitive assessments, provides the opportunity to optimise treatment to the needs of the individual.For full text, click here:SA Fam Pract 2006;48(4):53-5

Predominance of a 6 bp deletion in exon 2 of the LDL receptor gene in Africans with familial hypercholesterolaemia

The original publication is available at http://jmg.bmj.com/In South Africa, the high prevalence of familial hypercholesterolaemia (FH) among Afrikaners, Jews, and Indians as a result of founder genes is in striking contrast to its reported virtual absence in the black population in general. In this study, the molecular basis of primary hypercholesterolaemia was studied in 16 Africans diagnosed with FH. DNA analysis using three screening methods resulted in the identification of seven different mutations in the coding region of the low density lipoprotein (LDLR) gene in 10 of the patients analysed. These included a 6 bp deletion (GCGATG) accounting for 28% of defective alleles, and six point mutations (D151H, R232W, R385Q, E387K, P678L, and R793Q) detected in single families. The Sotho patient with missense mutation R232W was also heterozygous for a de novo splicing defect 313+1G→A. Several silent mutations/polymorphisms were detected in the LDLR and apolipoprotein B genes, including a base change (g→t) at nucleotide position −175 in the FP2 LDLR regulatory element. This promoter variant was detected at a significantly higher (p<0.05) frequency in FH patients compared to controls and occurred in cis with mutation E387K in one family. Analysis of four intragenicLDLR gene polymorphisms showed that the same chromosomal background was identified at this locus in the four FH patients with the 6 bp deletion. Detection of the 6 bp deletion in Xhosa, Pedi, and Tswana FH patients suggests that it is an ancient mutation predating tribal separation approximately 3000 years ago.Harry and Doris Crossley FoundationSouth African Medical Research CouncilUniversity of StellenboschBritish Heart Foundation (grant no PG/96013)Publisher's versio

Analysis of sequence variations in low-density lipoprotein receptor gene among Malaysian patients with familial hypercholesterolemia

<p>Abstract</p> <p>Background</p> <p>Familial hypercholesterolemia is a genetic disorder mainly caused by defects in the low-density lipoprotein receptor gene. Few and limited analyses of familial hypercholesterolemia have been performed in Malaysia, and the underlying mutations therefore remain largely unknown.</p> <p>We studied a group of 154 unrelated FH patients from a northern area of Malaysia (Kelantan). The promoter region and exons 2-15 of the LDLR gene were screened by denaturing high-performance liquid chromatography to detect short deletions and nucleotide substitutions, and by multiplex ligation-dependent probe amplification to detect large rearrangements.</p> <p>Results</p> <p>A total of 29 gene sequence variants were reported in 117(76.0%) of the studied subjects. Eight different mutations (1 large rearrangement, 1 short deletion, 5 missense mutations, and 1 splice site mutation), and 21 variants. Eight gene sequence variants were reported for the first time and they were noticed in familial hypercholesterolemic patients, but not in controls (p.Asp100Asp, p.Asp139His, p.Arg471Gly, c.1705+117 T>G, c.1186+41T>A, 1705+112C>G, Dup exon 12 and p.Trp666ProfsX45). The incidence of the p.Arg471Gly variant was 11%. Patients with pathogenic mutations were younger, had significantly higher incidences of cardiovascular disease, xanthomas, and family history of hyperlipidemia, together with significantly higher total cholesterol and low density lipoprotein levels than patients with non-pathogenic variants.</p> <p>Conclusions</p> <p>Twenty-nine gene sequence variants occurred among FH patients; those with predicted pathogenicity were associated with higher incidences of cardiovascular diseases, tendon xanthomas, and higher total and low density lipoprotein levels compared to the rest. These results provide preliminary information on the mutation spectrum of this gene among patients with FH in Malaysia.</p

Post-TB health and wellbeing

TB affects around 10.6 million people each year and there are now around 155 million TB survivors. TB and its treatments can lead to permanently impaired health and wellbeing. In 2019, representatives of TB affected communities attending the ‘1st International Post-Tuberculosis Symposium´ called for the development of clinical guidance on these issues. This clinical statement on post-TB health and wellbeing responds to this call and builds on the work of the symposium, which brought together TB survivors, healthcare professionals and researchers. Our document offers expert opinion and, where possible, evidence-based guidance to aid clinicians in the diagnosis and management of post-TB conditions and research in this field. It covers all aspects of post-TB, including economic, social and psychological wellbeing, post TB lung disease (PTLD), cardiovascular and pericardial disease, neurological disability, effects in adolescents and children, and future research needs

Impact of Intermediate Hyperglycemia and Diabetes on Immune Dysfunction in Tuberculosis

Supplementary Data: Supplementary materials are available at Clinical Infectious Diseases online at https://academic.oup.com/cid/article/72/1/69/5857148#274319223 . Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.Copyright © The Author(s) 2020. Background: People with diabetes have an increased risk of developing active tuberculosis (TB) and are more likely to have poor TB-treatment outcomes, which may impact on control of TB as the prevalence of diabetes is increasing worldwide. Blood transcriptomes are altered in patients with active TB relative to healthy individuals. The effects of diabetes and intermediate hyperglycemia (IH) on this transcriptomic signature were investigated to enhance understanding of immunological susceptibility in diabetes-TB comorbidity. Methods: Whole blood samples were collected from active TB patients with diabetes (glycated hemoglobin [HbA1c] ≥6.5%) or IH (HbA1c = 5.7% to <6.5%), TB-only patients, and healthy controls in 4 countries: South Africa, Romania, Indonesia, and Peru. Differential blood gene expression was determined by RNA-seq (n = 249). Results: Diabetes increased the magnitude of gene expression change in the host transcriptome in TB, notably showing an increase in genes associated with innate inflammatory and decrease in adaptive immune responses. Strikingly, patients with IH and TB exhibited blood transcriptomes much more similar to patients with diabetes-TB than to patients with only TB. Both diabetes-TB and IH-TB patients had a decreased type I interferon response relative to TB-only patients. Conclusions: Comorbidity in individuals with both TB and diabetes is associated with altered transcriptomes, with an expected enhanced inflammation in the presence of both conditions, but also reduced type I interferon responses in comorbid patients, suggesting an unexpected uncoupling of the TB transcriptome phenotype. These immunological dysfunctions are also present in individuals with IH, showing that altered immunity to TB may also be present in this group. The TB disease outcomes in individuals with IH diagnosed with TB should be investigated further.European Union’s Seventh Framework Programme (FP7 2007-2013 - Health) under grant agreement No 305279

Clinical versus molecular diagnosis of heterozygous familial hypercholesterolaemia in the diverse South African population

CITATION: Vergotine, J., Thiart, R. & Kotze, M. J. 2001. Clinical versus molecular diagnosis of heterozygous familial hypercholesterolaemia in the diverse South African population. South African Medical Journal, 91(12):1053-1059.The original publication is available at http://www.samj.org.zaObjective. Familial hypercholesterolaemia (FH) is a common genetic disease characterised by strikingly elevated plasma cholesterol concentration, which can lead to premature coronary death if left untreated. In this study DNA diagnosis of FH, which allows detection before onset of clinical symptoms, was evaluated against biochemical parameters routinely used to identify subjects with FH. Design. A population-based strategy was used to identify low-density lipoprotein receptor (LDLR) gene defects in South Africans with clinical signs of FH, followed by a family-based DNA screening approach for presymptomatic diagnosis of FH. Results. DNA screening of 790 at-risk relatives for the FH-related mutations identified in 379 index cases, allowed accurate disease diagnosis in an additional 338 relatives and exclusion of the relevant mutation in 452 individuals. The sensitivity and specificity of the diagnosis, based on total cholesterol values measured in family members of FH heterozygous index cases with one of the three founder-related mutations, D154N, D206E and V408M, were 89.3% and 81.9%, respectively. Conclusion. The predominance of 10 LDLR gene mutations in the local populations justifies population-directed DNA diagnosis of FH in South Africa on a routine basis, particularly since expression of the defective gene measured in biochemical tests does not allow accurate diagnosis of FH in all cases. DNA testing provides a definitive tool for family tracing aimed at pre-clinical diagnosis and preventive treatment of FH.Publisher’s versio

Die molekulere analise van mutante cf-gene vir mutasie-identifikasie

Proefskrif (M.Sc.(Geneeskundige Wetenskappe)) -- Universiteit van Stellenbosch, 1994.Een kopie mikrofiche.Full text to be digitised and attached to bibliographic record

Lifetime distributions with wave-like bathtub hazard

In this paper, we argue the necessity of dealing with lifetime distributions with wave-like bathtub hazard function. Four classes of wave-like bathtub hazards are investigated. For preparing maximum likelihood estimation of the hazard parameters, the first-order and second-order partial derivatives are derived

Hybrid reliability modelling under general uncertainty

The real world phenomena are often facing the co-existence reality of different formality of uncertainty and thus the probabilistic reliability modeling practices are very doubtful. Under complicated uncertainty environments, hybrid variable modeling is important in reliability and risk analysis, which includes Bayesian distributional theory, random fuzzy distributional theory, as well as fuzzy random distributional theory as special distribution families. In this paper, we define a new hybrid lifetime which is specified by a random lifetime distribution with an uncertain distributed parameter, which is called as random uncertain hybrid lifetime. We furthermore define the average chance distribution as a quality index for quantifying the hybrid lifetime and accordingly the average chance reliability is derived