Direct-to-consumer genetic testing for factor V Leiden and prothrombin 20210G>A: the consumer experience.

BACKGROUND: Clinical genetic testing for inherited predisposition to venous thromboembolism (VTE) is common among patients and their families. However, there is incomplete consensus about which individuals should receive testing, and the relative risks and benefits. METHODS: We assessed outcomes of receiving direct-to-consumer (DTC) results for the two most common genetic risk factors for VTE, factor V Leiden in the F5 gene (FVL) and prothrombin 20210G>A in the F2 gene (PT). Two thousand three hundred fifty-four customers (1244 variant-positive and 1110 variant-negative individuals) of the personal genetics company 23andMe, Inc., who had received results online for F5 and F2 variants, participated in an online survey-based study. Participants responded to questions about perception of VTE risk, discussion of results with healthcare providers (HCPs) and recommendations received, actions taken to control risk, emotional responses to receiving risk results, and perceived value of the information. RESULTS: Most participants (90% of variant-positive individuals, 99% of variant-negative individuals) had not previously been tested for F5 and/or F2 variants. The majority of variant-positive individuals correctly perceived that they were at higher than average risk for developing VTE. These individuals reported moderate rates of discussing results with HCPs (41%); receiving prevention advice from HCPs (31%), and making behavioral changes to control risk (e.g., exercising more, 30%). A minority (36%) of variant-positive individuals worried more after receiving VTE results. Nevertheless, most participants reported that knowing their risk had been an advantage (78% variant-positive and 58% variant-negative) and were satisfied knowing their genetic probability for VTE (81% variant-positive and 67% variant-negative). CONCLUSION: Consumers reported moderate rates of behavioral change and perceived personal benefit from receiving DTC genetic results for VTE risk.

Differential Activation of Fetal Hofbauer Cells in Primigravidas Is Associated with Decreased Birth Weight in Symptomatic Placental Malaria.

BACKGROUND: Placental malaria is a leading global cause of low birth weight neonates, especially in first-time mothers. To better understand the role of innate immunity in placental malaria, we investigated the relationships between histopathological markers of placental malaria, fetal and maternal macrophage responses, and perinatal outcomes in a cross-sectional case control study of pregnant women presenting with symptomatic malaria at the time of delivery. RESULTS: Primigravidas showed increased hemozoin deposition in placental villi (p=0.02), syncytiotrophoblasts (p=0.01), and fetal Hofbauer cells (p=0.01). The percentage of hemozoin-positive villi negatively correlated with infant birth weight (regression coefficient [b] = -0.03 kg decrease in birth weight per % increase in hemozoin-positive villi, p=0.035). Malaria-infected placentas showed a twofold increase in Hofbauer cells (p<0.001) and maternal macrophages (p<0.001). Placental malaria was associated with a threefold increase in the percentage of M2 maternal macrophages (19.2% vs 6.4%, p=0.01). Primigravidas showed a significant decrease in the Hofbauer cell M2-percentage in placental malaria (92.7% vs. 97.0%, p=0.04), which was predictive of infant birth weight (b=0.08 kg increase in birth weight per % increase in M2 Hofbauer cells, p=0.001). There was no association between maternal macrophage response and infant birth weights. CONCLUSIONS: Placentas with malarial infection had increased numbers of fetal Hofbauer cells in the villous stroma and maternal macrophages in the intervillous space. In primigravidas, decreased anti-inflammatory M2-type Hofbauer cells were predictive of lower birth weight. M2-type maternal macrophages were increased in placental malaria, but there was no association with gravidity or birth weight. These results suggested a protective role of M2 Hofbauer cells in fetal growth restriction.

Genome-wide association and HLA region fine-mapping studies identify susceptibility loci for multiple common infections.

Infectious diseases have a profound impact on our health and many studies suggest that host genetics play a major role in the pathogenesis of most of them. We perform 23 genome-wide association studies for common infections and infection-associated procedures, including chickenpox, shingles, cold sores, mononucleosis, mumps, hepatitis B, plantar warts, positive tuberculosis test results, strep throat, scarlet fever, pneumonia, bacterial meningitis, yeast infections, urinary tract infections, tonsillectomy, childhood ear infections, myringotomy, measles, hepatitis A, rheumatic fever, common colds, rubella and chronic sinus infection, in over 200,000 individuals of European ancestry. We detect 59 genome-wide significant (P < 5 × 10-8) associations in genes with key roles in immunity and embryonic development. We apply fine-mapping analysis to dissect associations in the human leukocyte antigen region, which suggests important roles of specific amino acid polymorphisms in the antigen-binding clefts. Our findings provide an important step toward dissecting the host genetic architecture of response to common infections.Susceptibility to infectious diseases is, among others, influenced by the genetic landscape of the host. Here, Tian and colleagues perform genome-wide association studies for 23 common infections and find 59 risk loci for 17 of these, both within the HLA region and non-HLA loci.

Genetic variants associated with motion sickness point to roles for inner ear development, neurological processes and glucose homeostasis.

Roughly one in three individuals is highly susceptible to motion sickness and yet the underlying causes of this condition are not well understood. Despite high heritability, no associated genetic factors have been discovered. Here, we conducted the first genome-wide association study on motion sickness in 80 494 individuals from the 23andMe database who were surveyed about car sickness. Thirty-five single-nucleotide polymorphisms (SNPs) were associated with motion sickness at a genome-wide-significant level (P < 5 × 10(-8)). Many of these SNPs are near genes involved in balance, and eye, ear and cranial development (e.g. PVRL3, TSHZ1, MUTED, HOXB3, HOXD3). Other SNPs may affect motion sickness through nearby genes with roles in the nervous system, glucose homeostasis or hypoxia. We show that several of these SNPs display sex-specific effects, with up to three times stronger effects in women. We searched for comorbid phenotypes with motion sickness, confirming associations with known comorbidities including migraines, postoperative nausea and vomiting (PONV), vertigo and morning sickness and observing new associations with altitude sickness and many gastrointestinal conditions. We also show that two of these related phenotypes (PONV and migraines) share underlying genetic factors with motion sickness. These results point to the importance of the nervous system in motion sickness and suggest a role for glucose levels in motion-induced nausea and vomiting, a finding that may provide insight into other nausea-related phenotypes like PONV. They also highlight personal characteristics (e.g. being a poor sleeper) that correlate with motion sickness, findings that could help identify risk factors or treatments.

Histopathologies, immunolocalization, and a glycan binding screen provide insights into Plasmodium falciparum interactions with the human placenta.

During pregnancy, Plasmodium falciparum-infected erythrocytes cytoadhere to the placenta. Infection is likely initiated at two sites where placental trophoblasts contact maternal blood: 1) via syncytiotrophoblast (STB), a multicellular transporting and biosynthetic layer that forms the surface of chorionic villi and lines the intervillous space, and 2) through invasive cytotrophoblasts, which line uterine vessels that divert blood to the placenta. Here, we investigated mechanisms of infected erythrocyte sequestration in relationship to the microanatomy of the maternal-fetal interface. Histological analyses revealed STB denudation in placental malaria, which brought the stromal cores of villi in direct contact with maternal blood. STB denudation was associated with hemozoin deposition (P = 0.01) and leukocyte infiltration (P = 0.001) and appeared to be a feature of chronic placental malaria. Immunolocalization of infected red blood cell receptors (CD36, ICAM1/CD54, and chondroitin sulfate A) in placentas from uncomplicated pregnancies showed that STB did not stain, while the underlying villous stroma was immunopositive. Invasive cytotrophoblasts expressed ICAM1. In malaria, STB denudation exposed CD36 and chondroitin sulfate A in the villous cores to maternal blood, and STB expressed ICAM1. Finally, we investigated infected erythrocyte adherence to novel receptors by screening an array of 377 glycans. Infected erythrocytes bound Lewis antigens that immunolocalized to STB. Our results suggest that P. falciparum interactions with STB-associated Lewis antigens could initiate placental malaria. Subsequent pathologies, which expose CD36, ICAM1, and chondroitin sulfate A, might propagate the infection.

Polysialic acid enhances the migration and invasion of human cytotrophoblasts.

Polysialic acid (polySia) is a large, cell-surface linear homopolymer composed of α2,8-linked sialic acid residues. Most extensively studied in the nervous system, this unique glycan modulates development by enhancing cell migration and regulating differentiation. PolySia also functions in developing and adult immune systems and is a signature of many cancers. In this study, we demonstrated that human placental trophoblasts, an epithelial lineage, also display this glycan. Cytotrophoblasts and syncytiotrophoblasts expressed polySia in the first trimester and downregulated it during the course of pregnancy. PolySia promoted cytotrophoblast migration in an explant model of chorionic villous growth. Removal of this glycan also reduced cytotrophoblast penetration of basement membranes in an in vitro model of invasion. Finally, we showed that polySia was overexpressed in biopsies from patients with gestational trophoblastic diseases, including benign molar pregnancies and malignant choriocarcinomas. These results demonstrated, for the first time, functional roles for polySia during normal human placental development and implicated these unusual oligosaccharides in the unrestrained invasion of trophoblast tumors.

Transcriptional response of Candida albicans to nitric oxide and the role of the YHB1 gene in nitrosative stress and virulence.

Here, we investigate how Candida albicans, the most prevalent human fungal pathogen, protects itself from nitric oxide (*NO), an antimicrobial compound produced by the innate immune system. We show that exposure of C. albicans to *NO elicits a reproducible and specific transcriptional response as determined by genome-wide microarray analysis. Many genes are transiently induced or repressed by *NO, whereas a set of nine genes remain at elevated levels during *NO exposure. The most highly induced gene in this latter category is YHB1, a flavohemoglobin that detoxifies *NO in C. albicans and other microbes. We show that C. albicans strains deleted for YHB1 have two phenotypes in vitro; they are hypersensitive to *NO and they are hyperfilamentous. In a mouse model of disseminated candidiasis, a YHB1 deleted C. albicans strain shows moderately attenuated virulence, but the virulence defect is not suppressed by deletion of the host NOS2 gene. These results suggest that *NO production is not a prime determinant of virulence in the mouse tail vein model of candidiasis and that the attenuated virulence of a yhb1delta/yhb1delta strain is attributable to a defect other than its reduced ability to detoxify *NO.