Murielle Bochud

Polymorphisms in Toll-like receptor 9 influence the clinical course of HIV-1 infection

Background:The clinical course of HIV-1 infection is highly variable among individuals, at least in part as a result of genetic polymorphisms in the host. Toll-like receptors (TLRs) have a key role in innate immunity and mutations in the genes encoding these receptors have been associated with increased or decreased susceptibility to infections. Objectives:To determine whether single-nucleotide polymorphisms (SNPs) in TLR2–4 and TLR7–9 influenced the natural course of HIV-1 infection. Methods:Twenty-eight SNPs in TLRs were analysed in HAART-naive HIV-positive patients from the Swiss HIV Cohort Study. The SNPs were detected using Sequenom technology. Haplotypes were inferred using an expectation–maximization algorithm. The CD4 T cell decline was calculated using a least-squares regression. Patients with a rapid CD4 cell decline, less than the 15th percentile, were defined as rapid progressors. The risk of rapid progression associated with SNPs was estimated using a logistic regression model. Other candidate risk factors included age, sex and risk groups (heterosexual, homosexual and intravenous drug use). Results:Two SNPs in TLR9 (1635A/G and +1174G/A) in linkage disequilibrium were associated with the rapid progressor phenotype: for 1635A/G, odds ratio (OR), 3.9 [95% confidence interval (CI),1.7–9.2] for GA versus AA and OR, 4.7 (95% CI,1.9–12.0) for GG versus AA (P = 0.0008). Conclusion:Rapid progression of HIV-1 infection was associated with TLR9 polymorphisms. Because of its potential implications for intervention strategies and vaccine developments, additional epidemiological and experimental studies are needed to confirm this association.

Heritability and intrafamilial aggregation of arterial characteristics.

Background We investigated the heritability and familial aggregation of various indexes of arterial stiffness and wave reflection and we partitioned the phenotypic correlation between these traits into shared genetic and environmental components. Methods Using a family-based population sample, we recruited 204 parents (mean age, 51.7 years) and 290 offspring (29.4 years) from the population in Cracow, Poland (62 families), Hechtel-Eksel, Belgium (36), and Pilsen, the Czech Republic (50). We measured peripheral pulse pressure (PPp) sphygmomanometrically at the brachial artery; central pulse pressure (PPc), the peripheral augmentation indexes (PAIxs) and central augmentation indexes (CAIxs) by applanation tonometry at the radial artery; and aortic pulse wave velocity (PWV) by tonometry or ultrasound. In multivariate-adjusted analyses, we used the ASSOC and PROC GENMOD procedures as implemented in SAGE and SAS, respectively. Results We found significant heritability for PAIx, CAIx, PPc and mean arterial pressure ranging from 0.37 to 0.41; P ≤ 0.0001. The method of intrafamilial concordance confirmed these results; intrafamilial correlation coefficients were significant for all arterial indexes (r ≥ 0.12; P ≤ 0.02) with the exception of PPc (r = −0.007; P = 0.90) in parent–offspring pairs. The sib–sib correlations were also significant for CAIx (r = 0.22; P = 0.001). The genetic correlation between PWV and the other arterial indexes were significant (ρG ≥ 0.29; P < 0.0001). The corresponding environmental correlations were only significantly positive for PPp (ρE = 0.10, P = 0.03). Conclusion The observation of significant intrafamilial concordance and heritability of various indexes of arterial stiffness as well as the genetic correlations among arterial phenotypes strongly support the search for shared genetic determinants underlying these traits.

Salz und kardiovaskuläres Risiko: Evidenz aus epidemiologische Studien

Die drei hauptsachlichen Moglichkeiten, den Salzkonsum in der Allgemeinbevolkerung abzuschatzen, sind Diatfragebogen, Untersuchung des Verhaltnisses Natrium/Kreatinin in einer Urinprobe sowie Sammeln von 24-Stunden-Urin.

Sel et risque cardiovasculaire: évidence des études épidémiologiques

Les trois facons principales d’estimer la consommation de sel dans la population generale sont le questionnaire alimentaire, le sport urinaire (rapport sodium/creatinine) ainsi que la recolte d’urine de 24 heures.

A functional microsatellite in the macrophage migration inhibitory factor gene influences susceptibility to meningococcal sepsis

The cytokine migration inhibitory factor (MIF) has recently emerged as an important effector molecule of innate immune responses and sepsis. Two functional MIF promoter polymorphisms, a 5–8 CATT tetranucleotide repeat at -794 (CATT5–8) and a -173*G/C single nucleotide polymorphism, have been associated with susceptibility to and/or severity of rheumatoid arthritis, atopy and ulcerative colitis. Our objective was to study the impact of MIF gene polymorphisms on susceptibility to Neisseria meningitidis sepsis and to analyze the functional and biological effects of MIF polymorphisms in vitro.