Investigation of parent-of-origin effects induced by fenofibrate treatment on triglycerides levels

Background

Genome-wide association studies performed on triglycerides (TGs) have not accounted for epigenetic mechanisms that may partially explain trait heritability.

Results

Parent-of-origin (POO) effect association analyses using an agnostic approach or a candidate approach were performed for pretreatment TG levels, posttreatment TG levels, and pre- and posttreatment TG-level differences in the real GAW20 family data set. We detected 22 genetic variants with suggestive POO effects with at least 1 phenotype (P ≤ 10^− 5). We evaluated the association of these 22 significant genetic variants showing POO effects with close DNA methylation probes associated with TGs. A total of 18 DNA methylation probes located in the vicinity of the 22 SNPs were associated with at least 1 phenotype and 6 SNP-probe pairs were associated with DNA methylation probes at the nominal level of P < 0.05, among which 1 pair presented evidence of POO effect. Our analyses identified a paternal effect of SNP rs301621 on the difference between pre- and posttreatment TG levels (P = 1.2 × 10^− 5). This same SNP showed evidence for a maternal effect on methylation levels of a nearby probe (cg10206250; P = 0.01). Using a causal inference test we established that the observed POO effect of rs301621 was not mediated by DNA methylation at cg10206250.

Conclusions

We performed POO effect association analyses of SNPs with TGs, as well as association analyses of SNPs with DNA methylation probes. These analyses, which were followed by a causal inference test, established that the paternal effect at the SNP rs301621 is induced by treatment and is not mediated by methylation level at cg10206250.

     

Factor VIIIa A2 Subunit Shows a High Affinity Interaction with Factor IXa: CONTRIBUTION OF A2 SUBUNIT RESIDUES 707-714 TO THE INTERACTION WITH FACTOR IXa*

Factor (F) VIIIa forms a number of contacts with FIXa in assembling the FXase enzyme complex. Surface plasmon resonance was used to examine the interaction between immobilized biotinylated active site-modified FIXa, and FVIII and FVIIIa subunits. The FVIIIa A2 subunit bound FIXa with high affinity (K_d = 3.9 ± 1.6 nm) that was similar to the A3C1C2 subunit (K_d = 3.6 ± 0.6 nm). This approach was used to evaluate a series of baculovirus-expressed, isolated A2 domain (bA2) variants where alanine substitutions were made for individual residues within the sequence 707-714, the C-terminal region of A2 thought to be FIXa interactive. Three of six bA2 variants examined displayed 2- to 4-fold decreased affinity for FIXa as compared with WT bA2. The variant bA2 proteins were also tested in two reconstitution systems to determine activity and affinity parameters in forming FXase and FVIIIa. V_max values for all variants were similar to the WT values, indicating that these residues do not affect cofactor function. All variants showed substantially greater increases in apparent K_d relative to WT in reconstituting the FXase complex (8- to 26-fold) compared with reconstituting FVIIIa (1.3- to 6-fold) suggesting that the mutations altered interaction with FIXa. bA2 domain variants with Ala replacing Lys⁷⁰⁷, Asp⁷¹², and Lys⁷¹³ demonstrated the greatest increases in apparent K_d (17- to 26-fold). These results indicate a high affinity interaction between the FVIIIa A2 subunit and FIXa and show a contribution of several residues within the 707-714 sequence to this binding.     

Antiporter NHX2 differentially induced in Mesembryanthemum crystallinum natural genetic variant under salt stress

Plants exhibit several mechanisms to survive under high salinity conditions. The uptake and compartmentalization of Na⁺ ion by the NHX antiporter is a crucial mechanism in homeostasis maintenance. Therefore, we evaluated McNHX2 gene expression and several physiological responses induced in three natural genetic variants of ice plants under salt stress. Based on morphology and growth behavior of wild type populations from an arid region of northwestern Mexico, we identified three ice plant natural genetic variants and called P0, P9, and P11. Several physiological parameters, such as water potential, relative water content, chlorophyll, and Na⁺ and K⁺ ion contents from all natural genetic variants exhibited a differential response under high salinity conditions. Specifically, the P0 variant showed lower water potential changes and least perturbation of Na⁺/K⁺ ratio than those of the P9 and P11 variants under saline conditions, suggesting that the P0 variant is the most salt tolerant. Unexpectedly, McNHX2 expression was repressed in the P11 variant while it was upregulated in the P0 and P9 variants under saline treatments. The McNHX2 gene was sequenced showing 15 introns and 16 exons; polymorphisms were found among the cDNAs sequences from the three natural genetic variants. All these data suggest that differential responses to high salinity involve different mechanisms operating in each variant for counteracting saline stress effects.

     

Interleukin-8 is the single most up-regulated gene in whole genome profiling of <Emphasis Type="Italic">H. pylori</Emphasis> exposed gastric epithelial cells

Background  

The association between Helicobacter pylori infection and upper gastrointestinal disease is well established. However, only a small fraction of H. pylori carriers develop disease, and there are great geographical differences in disease penetrance. The explanation to this enigma lies in the interaction between the bacterium and the host. H. pylori Outer Membrane Phospholipase A (OMPLA) has been suggested to play a role in the virulence of this bacterium. The aim of this study was to profile the most significant cellular pathways and biological processes affected in gastric epithelial cells during 24 h of H. pylori exposure, and to study the inflammatory response to OMPLA⁺ and OMPLA^- H. pylori variants.     

Preclinical pharmacokinetics,pharmacodynamics, tissue distribution,and tumor penetration of anti-PD-L1 monoclonal antibody,an immune checkpoint inhibitor

MPDL3280A is a human monoclonal antibody that targets programmed cell death-1 ligand 1 (PD-L1), and exerts anti-tumor activity mainly by blocking PD-L1 interaction with programmed cell death-1 (PD-1) and B7.1. It is being investigated as a potential therapy for locally advanced or metastatic malignancies. The purpose of the study reported here was to characterize the pharmacokinetics, pharmacodynamics, tissue distribution and tumor penetration of MPDL3280A and/or a chimeric anti-PD-L1 antibody PRO304397 to help further clinical development.

The pharmacokinetics of MPDL3280A in monkeys at 0.5, 5 and 20 mg·kg^?1 and the pharmacokinetics / pharmacodynamics of PRO304397 in mice at 1, 3 10 mg·kg^?1 were determined after a single intravenous dose. Tissue distribution and tumor penetration for radiolabeled PRO304397 in tumor-bearing mouse models were determined.

The pharmacokinetics of MPDL3280A and PRO304397 were nonlinear in monkeys and mice, respectively. Complete saturation of PD-L1 in blood in mice was achieved at serum concentrations of PRO304397 above ～0.5 µg·mL^?1. Tissue distribution and tumor penetration studies of PRO304397 in tumor-bearing mice indicated that the minimum tumor interstitial to plasma radioactivity ratio was ～0.3; saturation of target-mediated uptake in non–tumor tissues and desirable exposure in tumors were achieved at higher serum concentrations, and the distribution into tumors was dose-and time-dependent.

The biodistribution data indicated that the efficacious dose is mostly likely higher than that estimated based on simple pharmacokinetics/pharmacodynamics in blood. These data also allowed for estimation of the target clinical dose for further development of MPDL3280A.     

The Flexibility of the Nucleic Acids: (III) The Interaction of an Aliphatic Diamine,Putrescine, with Flexible B-DNA

Abstract

A theoretical modelling of the interaction of putrescine (H⁺ ₃N—(CH₂)₄—(-N⁺H₃) with DNA is carried out, introducing two new features which make the simulation of this interaction considerably more realistic. Firstly, the DNA to which putrescine is bound is fully flexible and thus able to respond to the distorting influence of the ligand. Secondly, the effect of changing the ratio of DNA base pairs per bound ligand is explicitly modelled. In this way. we have been able to confirm the experimentally known preference of putrescine binding with AT base pairs in B-DNA, but we also show, through the new features introduced, that the nature of the binding site of the ligand and the resulting impact on DNA conformation is strongly modified by the ligand binding density.     

Functional Coding Variants in SLC6A15, a Possible Risk Gene for Major Depression

SLC6A15 is a neuron-specific neutral amino acid transporter that belongs to the solute carrier 6 gene family. This gene family is responsible for presynaptic re-uptake of the majority of neurotransmitters. Convergent data from human studies, animal models and pharmacological investigations suggest a possible role of SLC6A15 in major depressive disorder. In this work, we explored potential functional variants in this gene that could influence the activity of the amino acid transporter and thus downstream neuronal function and possibly the risk for stress-related psychiatric disorders. DNA from 400 depressed patients and 400 controls was screened for genetic variants using a pooled targeted re-sequencing approach. Results were verified by individual re-genotyping and validated non-synonymous coding variants were tested in an independent sample (N = 1934). Nine variants altering the amino acid sequence were then assessed for their functional effects by measuring SLC6A15 transporter activity in a cellular uptake assay. In total, we identified 405 genetic variants, including twelve non-synonymous variants. While none of the non-synonymous coding variants showed significant differences in case-control associations, two rare non-synonymous variants were associated with a significantly increased maximal ³H proline uptake as compared to the wildtype sequence. Our data suggest that genetic variants in the SLC6A15 locus change the activity of the amino acid transporter and might thus influence its neuronal function and the risk for stress-related psychiatric disorders. As statistically significant association for rare variants might only be achieved in extremely large samples (N >70,000) functional exploration may shed light on putatively disease-relevant variants.     

Interaction 3d-and 4d-Group Metal Ions With GMP

Abstract

The interaction of 3d- and 4d- group metal ions with GMP is studied by the differential UV spectroscopy method. Ni²⁺, Co²⁺, Cu²⁺, Zn²⁺, Cd²⁺ form a chelate structure, interacting innerspherically with N7 and outerspherically with O6, while Ag⁺ binds innerspherically to N7 as well as to O6. The difference in association constants for 3d ions binding to GMP is mainly due to differences in the ion radii.     

Influence of Residue 22 on the Folding, Aggregation Profile, and Toxicity of the Alzheimer's Amyloid β Peptide

Several biophysical techniques have been used to determine differences in the aggregation profile (i.e., the secondary structure, aggregation propensity, dynamics, and morphology of amyloid structures) and the effects on cell viability of three variants of the amyloid β peptide involved in Alzheimer's disease. We focused our study on the Glu²² residue, comparing the effects of freshly prepared samples and samples aged for at least 20 days. In the aged samples, a high propensity for aggregation and β-sheet secondary structure appears when residue 22 is capable of establishing polar (Glu²² in wild-type) or hydrophobic (Val²² in E22V) interactions. The Arctic variant (E22G) presents a mixture of mostly disordered and α-helix structures (with low β-sheet contribution). Analysis of transmission electron micrographs and atomic force microscopy images of the peptide variants after aging showed significant quantitative and qualitative differences in the morphology of the formed aggregates. The effect on human neuroblastoma cells of these Aβ_12-28 variants does not correlate with the amount of β-sheet of the aggregates. In samples allowed to age, the native sequence was found to have an insignificant effect on cell viability, whereas the Arctic variant (E22G), the E22V variant, and the slightly-aggregating control (F19G-F20G) had more prominent effects.     

Genetisch kontrollierte Varianten der NADH-Diaphorase

Zusammenfassung Die NADH-Diaphorase wurde an 725 gesunden Probanden mit Hilfe der Stärkegelelektrophorese untersucht. Zwei verschiedene Varianten wurden beobachtet: eine heterozygot schnelle (DIA 2-1) und eine heterozygot langsame (DIA 3-1). Die Genhäufigkeiten sind: DIA²=0,0021; DIA³=0,0007.

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Genetically determined variants of NADH-diaphorase

Summary By means of starchgel-electrophoresis a screening for variants of NADH-Diaphorase was carried out within a sample of 725 healthy probands. Two kinds of genetically determined variants have been observed: a heterozygous phenotype with greater mobility (DIA 2-1) and a heterozygous phenotype with slower mobility (DIA 3-1). The gene-frequencies are estimated so far as 0.0021 (DIA²) and 0.0007 (DIA³).

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Mit Unterstützung durch die Deutsche Forschungsgemeinschaft.     

Post-translational formation of hypusine in eIF5A: implications in human neurodevelopment

Hypusine [N^ε-(4-amino-2-hydroxybutyl)lysine] is a derivative of lysine that is formed post-translationally in the eukaryotic initiation factor 5A (eIF5A). Its occurrence at a single site in one cellular protein defines hypusine synthesis as one of the most specific post-translational modifications. Synthesis of hypusine involves two enzymatic steps: first, deoxyhypusine synthase (DHPS) cleaves the 4-aminobutyl moiety of spermidine and transfers it to the ε-amino group of a specific lysine residue of the eIF5A precursor protein to form an intermediate, deoxyhypusine [N^ε-(4-aminobutyl)lysine]. This intermediate is subsequently hydroxylated by deoxyhypusine hydroxylase (DOHH) to form hypusine in eIF5A. eIF5A, DHPS, and DOHH are highly conserved in all eukaryotes, and both enzymes exhibit a strict specificity toward eIF5A substrates. eIF5A promotes translation elongation globally by alleviating ribosome stalling and it also facilitates translation termination. Hypusine is required for the activity of eIF5A, mammalian cell proliferation, and animal development. Homozygous knockout of any of the three genes, Eif5a, Dhps, or Dohh, leads to embryonic lethality in mice. eIF5A has been implicated in various human pathological conditions. A recent genetic study reveals that heterozygous germline EIF5A variants cause Faundes–Banka syndrome, a craniofacial–neurodevelopmental malformations in humans. Biallelic variants of DHPS were identified as the genetic basis underlying a rare inherited neurodevelopmental disorder. Furthermore, biallelic DOHH variants also appear to be associated with neurodevelopmental disorder. The clinical phenotypes of these patients include intellectual disability, developmental delay, seizures, microcephaly, growth impairment, and/or facial dysmorphisms. Taken together, these findings underscore the importance of eIF5A and the hypusine modification pathway in neurodevelopment in humans.

     

Phytohormones, Rhizobium mutants, and nodulation in legumes : v. Cytokinin metabolism in effective and ineffective pea root nodules

[³H]Zeatin riboside was supplied to intact pea (Pisum sativum) plants either onto the leaves or onto the root nodules. When applied directly to nodules, approximately 70% of recovered radioactivity remained in the nodules, approximately 15% was detected in the root system, and 15% was in the shoot. However, when supplied to the leaves, little ³H was transported, with approximately 0.05% of recovered radioactivity being found in the root system and nodules. On a fresh weight basis, nodules accumulated more ³H than the parent root. In both types of studies, metabolites with an intact zeatin moiety were detected in root nodules.

In all experiments, two-dimensional thin layer chromatography revealed that little ³H remained as zeatin riboside in root or nodule tissue at the end of the labeling period. Nodules metabolized [³H]zeatin riboside to the following cytokinins/cytokinin metabolites: zeatin, adenosine, adenine, the O-glucosides of zeatin and zeatin riboside, lupinic acid, nucleotides of adenine and zeatin, and the dihydro derivatives of many of these compounds.

Although a few small differences were observed, there were no major differences between root and nodule tissue in their metabolism of [³H] zeatin riboside. Furthermore, any differences between effective and ineffective nodules were generally minor.

     

Ethnic differences in alcohol use,abuse, and sensitivity: A review with genetic interpretation

Abstract

The biomedical literature for the period 1978–84 was surveyed for nine categories of alcohol response (consumption rate, absorption rate from the digestive tract, metabolism rate, alcohol dehydrogenase (ADH) variants, acetaldehyde dehydrogenase (ALDH) variants, “alcohol sensitivity,” cardiovascular changes, psychological changes, alcohol abuse), looking for data on possible ethnic differences. These data were supplemented by selected earlier studies. Excepting psychological changes (on which there were very few studies), evidence for ethnic (or racial) differences was found in each category of response. The most striking differences were between Orientals and non‐Orientals; about half of all Orientals lack a high‐activity form of ALDH which all non‐Orientals have. As a direct consequence, these “deficient” Orientals have markedly increased alcohol sensitivity (flushing, dysphoria, cardiovascular response). These enzyme differences are very probably due to a single gene, as are ethnic differences in ADH variants. For rates of absorption and metabolism, the ethnic differences probably have a polygenic basis.     

Common Human 5′ Dopamine Transporter (SLC6A3) Haplotypes Yield Varying Expression Levels In Vivo

1. Individuals display significant differences in their levels of expression of the dopamine transporter (DAT; SLC6A3). These differences in DAT are strong candidates to contribute to individual differences in motor, mnemonic and reward functions. To identify “cis”-acting genetic mechanisms for these individual differences, we have sought variants in 5′ aspects of the human DAT gene and identified the haplotypes that these variants define.2. We report (i) significant relationships between 5′ DAT haplotypes and human individual differences in ventral striatal DAT expression assessed in vivo using [¹¹C] cocaine PET and (ii) apparent confirmation of these results in studies of DAT expression in postmortem striatum using [³H] carboxyflurotropane binding.3. These observations support the idea that cis-acting variation in 5′ aspects of the human DAT/SLC6A3 locus contributes to individual differences in levels of DAT expression in vivo. 5′ DAT variation is thus a good candidate to contribute to individual differences in a number of human phenotypes.These authors contributed equally to this article     

Nuclear Overhauser Effect and Computational Characterization of the β-Spiral of the Polypentapeptide of Elastin

Abstract

The structure of the elastin polypentapeptide, poly(VPGVG), was studied by nuclear Overhauser effect experiments using perdeuterated Val¹ and Val⁴ samples under the condition where intermolecular interactions are absent. More extensive interaction was found between the Val¹ γCH and Pro² βCH protons than between the Val⁴ γCH and Pro² βCH protons. The Val¹ γCH₃—Pro² βCH interaction does not occur within the same pentamer as previously shown experimentally and as expected from steric considerations. The results are incompatible with the presence of a random chain network in poly(VPGVG) at room temperature but are readily explicable in terms of interturn interactions in a β-spiral structure. More specifically, the results indicate that the β-spiral conformation with 2.9 pentamers/turn is more prevalent than that with 2.7 pentamers/turn. Using conformations developed by molecular mechanics calculations, molecular dynamics simulations were carried out to compare the relative energies of these two variants of this class of β-spiral structures. It was found in vacuo that the structure with 2.9 pentamers/turn is indeed more stable than that of 2.7 pentamers/turn by ~ 1 kcal/mole-pentamer.     

Confirmation of Childhood Acute Lymphoblastic Leukemia Variants,ARID5B and IKZF1, and Interaction with Parental Environmental Exposures

Genome wide association studies (GWAS) have established association of ARID5B and IKZF1 variants with childhood acute lymphoblastic leukemia (ALL). Epidemiological studies suggest that environmental factors alone appear to make a relatively minor contribution to disease risk. The polygenic nature of childhood ALL predisposition together with the timing of environmental triggers may hold vital clues for disease etiology. This study presents results from an Australian GWAS of childhood ALL cases (n = 358) and population controls (n = 1192). Furthermore, we utilised family trio (n = 204) genotypes to extend our investigation to gene-environment interaction of significant loci with parental exposures before conception, and child’s sex and age. Thirteen SNPs achieved genome wide significance in the population based case/control analysis; ten annotated to ARID5B and three to IKZF1. The most significant SNPs in these regions were ARID5B rs4245595 (OR 1.63, CI 1.38–1.93, P = 2.13×10⁻⁹), and IKZF1 rs1110701 (OR 1.69, CI 1.42–2.02, p = 7.26×10⁻⁹). There was evidence of gene-environment interaction for risk genotype at IKZF1, whereby an apparently stronger genetic effect was observed if the mother took folic acid or if the father did not smoke prior to pregnancy (respective interaction P-values: 0.04, 0.05). There were no interactions of risk genotypes with age or sex (P-values >0.2). Our results evidence that interaction of genetic variants and environmental exposures may further alter risk of childhood ALL however, investigation in a larger population is required. If interaction of folic acid supplementation and IKZF1 variants holds, it may be useful to quantify folate levels prior to initiating use of folic acid supplements.     

Genetic Variants in the Bone Morphogenic Protein Gene Family Modify the Association between Residential Exposure to Traffic and Peripheral Arterial Disease

There is a growing literature indicating that genetic variants modify many of the associations between environmental exposures and clinical outcomes, potentially by increasing susceptibility to these exposures. However, genome-scale investigations of these interactions have been rarely performed particularly in the case of air pollution exposures. We performed race-stratified genome-wide gene-environment interaction association studies on European-American (EA, N = 1623) and African-American (AA, N = 554) cohorts to investigate the joint influence of common single nucleotide polymorphisms (SNPs) and residential exposure to traffic (“traffic exposure”)—a recognized vascular disease risk factor—on peripheral arterial disease (PAD). Traffic exposure was estimated via the distance from the primary residence to the nearest major roadway, defined as the nearest limited access highways or major arterial. The rs755249-traffic exposure interaction was associated with PAD at a genome-wide significant level (P = 2.29x10^-8) in European-Americans. Rs755249 is located in the 3’ untranslated region of BMP8A, a member of the bone morphogenic protein (BMP) gene family. Further investigation revealed several variants in BMP genes associated with PAD via an interaction with traffic exposure in both the EA and AA cohorts; this included interactions with non-synonymous variants in BMP2, which is regulated by air pollution exposure. The BMP family of genes is linked to vascular growth and calcification and is a novel gene family for the study of PAD pathophysiology. Further investigation of BMP8A using the Genotype Tissue Expression Database revealed multiple variants with nominally significant (P < 0.05) interaction P-values in our EA cohort were significant BMP8A eQTLs in tissue types highlight relevant for PAD such as rs755249 (tibial nerve, eQTL P = 3.6x10^-6) and rs1180341 (tibial artery, eQTL P = 5.3x10^-6). Together these results reveal a novel gene, and possibly gene family, associated with PAD via an interaction with traffic air pollution exposure. These results also highlight the potential for interactions studies, particularly at the genome scale, to reveal novel biology linking environmental exposures to clinical outcomes.     

Redefining the dose of the entomopathogenic fungus Metarhizium brunneum (Ascomycota,Hypocreales) to increase Fe bioavailability and promote plant growth in calcareous and sandy soils

Background and aims

Plants differ in their ability to use different nitrogen (N) chemical forms, these differences can be related to their ecology and drive community structure. The capacity to uptake intact organic N has been observed in plants of several ecosystems. However, soil organic N uptake by Mediterranean plants is unknown despite organic N being abundant in Mediterranean ecosystems. We compare the uptake of different N forms in two widespread coexisting Mediterranean forest trees with contrasting ecophysiological characteristics: Quercus ilex and Pinus halepensis.

Methods

To estimate root uptake rate of each N form we used equimolar solutions (1 mM N) of ¹⁵NO₃ ^?, ¹⁵NH₄ ⁺ and ¹⁵N-¹³C glycine.

Results

NH₄ ⁺ and glycine were taken up at a similar rate, but faster than NO₃ ^? in both species. Intact dual labeled glycine was found in both species, demonstrating that both species can absorb intact organic N.

Conclusions

Despite their ecological differences, both species had similar preference for N forms suggesting no fundamental niche complementarity for N uptake. The higher preference for NH₄ ⁺ and glycine over NO₃ ^? possibly reflects adaptation to the differing proportions of N forms in Mediterranean soils.

     

Roles for both FtsA and the FtsBLQ subcomplex in FtsN‐stimulated cell constriction in Escherichia coli

Escherichia coli FtsN is a bitopic membrane protein that is essential for triggering active cell constriction. A small periplasmic subdomain (^EFtsN) is required and sufficient for function, but its mechanism of action is unclear. We isolated extragenic ^EFtsN*‐suppressing mutations that restore division in cells producing otherwise non‐functional variants of FtsN. These mapped to the IC domain of FtsA in the cytoplasm and to small subdomains of the FtsB and FtsL proteins in the periplasm. All FtsB and FtsL variants allowed survival without ^EFtsN, but many then imposed a new requirement for interaction between the cytoplasmic domain of FtsN (^NFtsN) and FtsA. Alternatively, variants of FtsA, FtsB or FtsL acted synergistically to allow cell division in the complete absence of FtsN. Strikingly, moreover, substitution of a single residue in FtsB (E56) proved sufficient to rescue ΔftsN cells as well. In FtsN⁺ cells, ^EFtsN*‐suppressing mutations promoted cell fission at an abnormally small cell size, and caused cell shape and integrity defects under certain conditions. This and additional evidence support a model in which FtsN acts on either side of the membrane to induce a conformational switch in both FtsA and the FtsBLQ subcomplex to de‐repress septal peptidoglycan synthesis and membrane invagination.     

Naturally-occurring genetic variants in human DC-SIGN increase HIV-1 capture, cell-transfer and risk of mother-to-child transmission

Background

Mother-to-child transmission (MTCT) is the main cause of HIV-1 infection in children worldwide. Dendritic cell–specific ICAM-3 grabbing-nonintegrin (DC-SIGN, also known as CD209) is an HIV-1 receptor that enhances its transmission to T cells and is expressed on placental macrophages.

Methods and Findings

We have investigated the association between DC-SIGN genetic variants and risk of MTCT of HIV-1 among Zimbabwean infants and characterized the impact of the associated mutations on DC-SIGN expression and interaction with HIV-1. DC-SIGN promoter (p-336C and p-201A) and exon 4 (198Q and 242V) variants were all significantly associated with increased risk of intrauterine (IU) HIV-1 infection. Promoter variants decreased DC-SIGN expression both in vitro and in placental CD163⁺ macrophages (Hofbauer cells) of HIV-1 unexposed infants but not of HIV-1 exposed infants. The exon 4 protein-modifying mutations increased HIV-1 capture and transmission to T cells in vitro.

Conclusion

This study provides compelling evidence to support an important role of DC-SIGN in IU HIV-1 infection.