Host erythrocyte polymorphisms and exposure to Plasmodium falciparum in Papua New Guinea

Contains fulltext : 69991.pdf (publisher's version ) (Open Access)BACKGROUND: The protection afforded by human erythrocyte polymorphisms against the malaria parasite, Plasmodium falciparum, has been proposed to be due to reduced ability of the parasite to invade or develop in erythrocytes. If this were the case, variable levels of parasitaemia and rates of seroconversion to infected-erythrocyte variant surface antigens (VSA) should be seen in different host genotypes. METHODS: To test this hypothesis, P. falciparum parasitaemia and anti-VSA antibody levels were measured in a cohort of 555 asymptomatic children from an area of intense malaria transmission in Papua New Guinea. Linear mixed models were used to investigate the effect of alpha+-thalassaemia, complement receptor-1 and south-east Asian ovalocytosis, as well as glucose-6-phosphate dehydrogenase deficiency and ABO blood group on parasitaemia and age-specific seroconversion to VSA. RESULTS: No host polymorphism showed a significant association with both parasite prevalence/density and age-specific seroconversion to VSA. CONCLUSION: Host erythrocyte polymorphisms commonly found in Papua New Guinea do not effect exposure to blood stage P. falciparum infection. This contrasts with data for sickle cell trait and highlights that the above-mentioned polymorphisms may confer protection against malaria via distinct mechanisms

Population Genomics of the Immune Evasion (var) Genes of Plasmodium falciparum

Var genes encode the major surface antigen (PfEMP1) of the blood stages of the human malaria parasite Plasmodium falciparum. Differential expression of up to 60 diverse var genes in each parasite genome underlies immune evasion. We compared the diversity of the DBLα domain of var genes sampled from 30 parasite isolates from a malaria endemic area of Papua New Guinea (PNG) and 59 from widespread geographic origins (global). Overall, we obtained over 8,000 quality-controlled DBLα sequences. Within our sampling frame, the global population had a total of 895 distinct DBLα “types” and negligible overlap among repertoires. This indicated that var gene diversity on a global scale is so immense that many genomes would need to be sequenced to capture its true extent. In contrast, we found a much lower diversity in PNG of 185 DBLα types, with an average of approximately 7% overlap among repertoires. While we identify marked geographic structuring, nearly 40% of types identified in PNG were also found in samples from different countries showing a cosmopolitan distribution for much of the diversity. We also present evidence to suggest that recombination plays a key role in maintaining the unprecedented levels of polymorphism found in these immune evasion genes. This population genomic framework provides a cost effective molecular epidemiological tool to rapidly explore the geographic diversity of var genes

Individual variation in levels of haptoglobin-related protein in children from Gabon

Background: Haptoglobin related protein (Hpr) is a key component of trypanosome lytic factors (TLF), a subset of highdensity lipoproteins (HDL) that form the first line of human defence against African trypanosomes. Hpr, like haptoglobin (Hp) can bind to hemoglobin (Hb) and it is the Hpr-Hb complexes which bind to these parasites allowing uptake of TLF. This unique form of innate immunity is primate-specific. To date, there have been no population studies of plasma levels of Hpr, particularly in relation to hemolysis and a high prevalence of ahaptoglobinemia as found in malaria endemic areas. Methods and Principal Findings: We developed a specific enzyme-linked immunosorbent assay to measure levels of plasma Hpr in Gabonese children sampled during a period of seasonal malaria transmission when acute phase responses (APR), malaria infection and associated hemolysis were prevalent. Median Hpr concentration was 0.28 mg/ml (range 0.03-1.1). This was 5-fold higher than that found in Caucasian children (0.049 mg/ml, range 0.002-0.26) with no evidence of an APR. A general linear model was used to investigate associations between Hpr levels, host polymorphisms, parasitological factors and the acute phase proteins, Hp, C-reactive protein (CRP) and albumin. Levels of Hpr were associated with Hp genotype, decreased with age and were higher in females. Hpr concentration was strongly correlated with that of Hp, but not CRP

Stimulation of bovine monocyte-derived macrophages with lipopolysaccharide, interferon-ɣ, Interleukin-4 or Interleukin-13 does not induce detectable changes in nitric oxide or arginase activity

Background: Bacterial lipopolysaccharide and interferon-γ stimulation of rodent macrophages in vitro induces up-regulation of inducible nitric oxide synthase, whereas interleukin-4 stimulation results in increased activity of arginase-1. Thus different stimulants result in differing macrophage phenotypes, appropriate for responses to a range of pathogens. The current study was conducted in order to determine whether bovine macrophages derived from monocytes and spleen respond similarly. Results: Lipopolysaccharide and interferon-γ did not induce detectable increases in nitric oxide production by bovine monocyte-derived or splenic macrophages in vitro. Similarly, interleukin-4 and interleukin-13 did not affect arginase activity. However, changes in transcription of genes coding for these products were detected. Conclusion: Differences between macrophage activation patterns exist between cattle and other species and these differences may occur during the post-transcription phase

Home and Online Management and Evaluation of Blood Pressure (HOME BP) using a digital intervention in poorly controlled hypertension: randomised controlled trial

Objective: The HOME BP (Home and Online Management and Evaluation of Blood Pressure) trial aimed to test a digital intervention for hypertension management in primary care by combining self-monitoring of blood pressure with guided self-management. Design: Unmasked randomised controlled trial with automated ascertainment of primary endpoint. Setting: 76 general practices in the United Kingdom. Participants: 622 people with treated but poorly controlled hypertension (>140/90 mm Hg) and access to the internet. Interventions: Participants were randomised by using a minimisation algorithm to self-monitoring of blood pressure with a digital intervention (305 participants) or usual care (routine hypertension care, with appointments and drug changes made at the discretion of the general practitioner; 317 participants). The digital intervention provided feedback of blood pressure results to patients and professionals with optional lifestyle advice and motivational support. Target blood pressure for hypertension, diabetes, and people aged 80 or older followed UK national guidelines. Main outcome measures: The primary outcome was the difference in systolic blood pressure (mean of second and third readings) after one year, adjusted for baseline blood pressure, blood pressure target, age, and practice, with multiple imputation for missing values. Results: After one year, data were available from 552 participants (88.6%) with imputation for the remaining 70 participants (11.4%). Mean blood pressure dropped from 151.7/86.4 to 138.4/80.2 mm Hg in the intervention group and from 151.6/85.3 to 141.8/79.8 mm Hg in the usual care group, giving a mean difference in systolic blood pressure of −3.4 mm Hg (95% confidence interval −6.1 to −0.8 mm Hg) and a mean difference in diastolic blood pressure of −0.5 mm Hg (−1.9 to 0.9 mm Hg). Results were comparable in the complete case analysis and adverse effects were similar between groups. Within trial costs showed an incremental cost effectiveness ratio of £11 ($15, €12; 95% confidence interval £6 to £29) per mm Hg reduction. Conclusions: The HOME BP digital intervention for the management of hypertension by using self-monitored blood pressure led to better control of systolic blood pressure after one year than usual care, with low incremental costs. Implementation in primary care will require integration into clinical workflows and consideration of people who are digitally excluded. Trial registration: ISRCTN13790648

Acute phase protein levels, parasitaemia and frequency of haptoglobin polymorphisms in Gabonese children.

<p>Continuous data are shown as median value [inter-quartile range] or mean (standard deviation) and categorical data are n (%). Note for C-reactive protein, albumin and plasmodium prevalence n = 550.</p>1<p>C-reactive protein >10 µg/mL was the cut-off used to define an acute phase response <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0049816#pone.0049816-Gabay1" target="_blank">[17]</a>.</p>2<p>The cut off value for hypohaptoglobinaemia is <0.18 mg/mL <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0049816#pone.0049816-Kunitake1" target="_blank">[29]</a>.</p>3<p>The cut off value for low albumin is <35 mg/mL <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0049816#pone.0049816-McGuire1" target="_blank">[30]</a>.</p>4<p>The frequency of species in this population has been published previously <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0049816#pone.0049816-Fowkes1" target="_blank">[21]</a>.</p

Univariate assessments of the influence of variables of interest on Hpr levels in Gabonese children.

<p>Coefficients are from univariate general linear models investigating the association between variables of interest and log(Haptoglobin-related protein) values.</p

Haptoglobin related protein levels are correlated with haptoglobin levels in A) Gabonese and B) Caucasian children.

<p>Scatterplot of raw Hpr values (mg/ml) plotted against raw Hp values (mg/ml). Associations were assessed by Spearmans rho. Hpr was positively correlated with Hp in A) Gabonese children (r_s = 0.29, <i>P</i><0.001), and B) Caucasian children (r_s = 0.51, <i>P</i><0.001).</p

Hpr levels in Gabonese and Caucasian children.

<p>Values represent median [interquartile range]. P-values represent comparisons between Caucasians and Gabonese children.</p

Association between aldosterone production and variation in the 11 beta-hydroxylase (CYP11B1) gene

&lt;b&gt;Context:&lt;/b&gt; Variation in the region of chromosome 8 including the genes steroid 11β-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2) influences mineralocorticoid and glucocorticoid metabolism. However, the relative importance of polymorphisms in CYP11B1 and CYP11B2 in determining these phenotypes is unknown.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Objective:&lt;/b&gt; Our objective was to investigate genetic influences of the CYP11B1 and CYP11B2 genes on mineralocorticoid metabolism.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Design:&lt;/b&gt; We measured 24-h urinary excretion of the key metabolites of the principal mineralocorticoids, glucocorticoids and androgens secreted by the adrenal cortex. We genotyped polymorphisms spanning the CYP11B1 and CYP11B2 genes, which together capture all common variations at the locus.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Participants:&lt;/b&gt; Participants included 573 members of 105 British Caucasian families ascertained on a hypertensive proband.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Main Outcome Measures:&lt;/b&gt; We assessed heritability of urinary tetrahydroaldosterone (THAldo) excretion and association of THAldo excretion with genotype.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Results:&lt;/b&gt; The heritability of THAldo excretion was 52% (P &lt; 10&lt;sup&gt;−6&lt;/sup&gt;). There was significant association between THAldo and genotype at several of the CYP11B1/B2 polymorphisms. The strongest association was observed at the rs6387 (2803A/G) polymorphism in intron 3 of CYP11B1 (P = 0.0004). Association followed a codominant model with a 21% higher THAldo excretion per G allele. Genotype at rs6387 accounted for 2.1% of the total population variability of THAldo. We found significant association between THAldo excretion and urinary total androgen excretion, urinary tetrahydrodeoxycortisol level, and urinary cortisol metabolites (all P &lt; 0.001).&lt;p&gt;&lt;/p&gt; &lt;b&gt;Conclusions:&lt;/b&gt; Aldosterone synthesis is highly heritable and is affected by genotype at CYP11B1. Our findings support the hypothesis that genetically determined differences in 11-hydroxylation efficiency can have downstream effects on mineralocorticoid synthesis. Such effects may be of relevance to the development of low-renin essential hypertension.&lt;p&gt;&lt;/p&gt