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De Villiers C.P.,Medical Research Council Center for Molecular and Cellular Biology | Van Der Merwe L.,Medical Research Council Center for Molecular and Cellular Biology | Van Der Merwe L.,University of the Western Cape | Crotti L.,IRCCS Instituto Auxologico Italiano | And 8 more authors.
Circulation: Cardiovascular Genetics | Year: 2014

Background: Long-QT syndrome (LQTS), a cardiac arrhythmia disorder with variable phenotype, often results in devastating outcomes, including sudden cardiac death. Variable expression, independently from the primary diseasecausing mutation, can partly be explained by genetic modifiers. This study investigates variants in a known LQTScausative gene, AKAP9, for potential LQTS-type 1-modifying effects.Methods and Results: Members of a South African LQTS-type 1 founder population (181 noncarriers and 168 mutation carriers) carrying the identical-by-descent KCNQ1 p.Ala341Val (A341V) mutation were evaluated for modifying effects of AKAP9 variants on heart rate-corrected QT interval (QTc), cardiac events, and disease severity. Tag single nucleotide polymorphisms in AKAP9 rs11772585, rs7808587, rs2282972, and rs2961024 (order, 5'-3'positive strand) were genotyped. Associations between phenotypic traits and alleles, genotypes, and haplotypes were statistically assessed, adjusting for the degree of relatedness and confounding variables. The rs2961024 GG genotype, always represented by CGCG haplotype homozygotes, revealed an age-dependent heart rate-corrected QT interval increase (1% per additional 10 years) irrespective of A341V mutation status (P=0.006). The rs11772585 T allele, found uniquely in the TACT haplotype, more than doubled (218%) the risk of cardiac events (P=0.002) in the presence of A341V; additionally, it increased disease severity (P=0.025). The rs7808587 GG genotype was associated with a 74% increase in cardiac event risk (P=0.046), whereas the rs2282972 T allele, predominantly represented by the CATT haplotype, decreased risk by 53% (P=0.001).Conclusions: AKAP9 has been identified as an LQTS-type 1-modifying gene. Variants investigated altered heart rate-corrected QT interval irrespective of mutation status, as well as cardiac event risk, and disease severity, in mutation carriers. © 2014 American Heart Association, Inc.

Trollip A.P.,Medical Research Council Center for Molecular and Cellular Biology | Moore D.,London School of Hygiene and Tropical Medicine | Moore D.,Cayetano Heredia Peruvian University | Coronel J.,Cayetano Heredia Peruvian University | And 16 more authors.
International Journal of Tuberculosis and Lung Disease | Year: 2014

OBJECTIVE: To establish breakpoint concentrations for the fluoroquinolones (moxifloxacin [MFX] and ofloxacin [OFX]) and injectable second-line drugs (amikacin [AMK], kanamycin [KM] and capreomycin [CPM]) u sing the microscopic observation drug susceptibility (MODS) assay. SETTING: A multinational study conducted between February 2011 and August 2012 in Peru, India, Moldova and South Africa. DESIGN: In the first phase, breakpoints for the fluoroquinolones and injectable second-line drugs (n = 58) were determined. In the second phase, MODS secondline drug susceptibility testing (DST) as an indirect test was compared to MGITTMDST (n = 89). In the third (n = 30) and fourth (n = 156) phases, we determined the reproducibility and concordance of MODS secondline DST directly from sputum. RESULTS: Breakpoints for MFX (0.5 μg/ml), OFX (1 μg/ml), AMK (2 μg/ml), KM (5 μg/ml) and CPM (2.5 μg/ml) were determined. In all phases, MODS results were highly concordant with MGIT DST. The few discrepancies suggest that the MODS breakpoint concentrations for some drugs may be too low. CONCLUSION: MODS second-line DST yielded comparable results to MGIT second-line DST, and is thus a promising alternative. Further studies are needed to confirm the accuracy of the drug breakpoints and the reliability of MODS second-line DST as a direct test. © 2014 The Union.

Quintana-Murci L.,Institute Pasteur Paris | Quintana-Murci L.,French National Center for Scientific Research | Harmant C.,Institute Pasteur Paris | Harmant C.,French National Center for Scientific Research | And 9 more authors.
American Journal of Human Genetics | Year: 2010

The study of recently admixed populations provides unique tools for understanding recent population dynamics, socio-cultural factors associated with the founding of emerging populations, and the genetic basis of disease by means of admixture mapping. Historical records and recent autosomal data indicate that the South African Coloured population forms a unique highly admixed population, resulting from the encounter of different peoples from Africa, Europe, and Asia. However, little is known about the mode by which this admixed population was recently founded. Here we show, through detailed phylogeographic analyses of mitochondrial DNA and Y-chromosome variation in a large sample of South African Coloured individuals, that this population derives from at least five different parental populations (Khoisan, Bantus, Europeans, Indians, and Southeast Asians), who have differently contributed to the foundation of the South African Coloured. In addition, our analyses reveal extraordinarily unbalanced gender-specific contributions of the various population genetic components, the most striking being the massive maternal contribution of Khoisan peoples (more than 60%) and the almost negligible maternal contribution of Europeans with respect to their paternal counterparts. The overall picture of gender-biased admixture depicted in this study indicates that the modern South African Coloured population results mainly from the early encounter of European and African males with autochthonous Khoisan females of the Cape of Good Hope around 350 years ago. © 2010 The American Society of Human Genetics.

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