Entry of human immunodeficiency virus type 1 (HIV-1) into target cells requires both CD4 (ref. 1, 2) and one of a growing number of G-protein-coupled seven-transmembrane receptors. Viruses predominantly use one, or occasionally both, of the major co-receptors CCR5 or CXCR4, although other receptors, including CCR2B and CCR3, function as minor co-receptors. CCR3 appears critical in central nervous system infection. A 32-base pair inactivating deletion in CCR5 (delta 32) common to Northern European populations has been associated with reduced, but not absolute, HIV-1 transmission risk and delayed disease progression. A more commonly distributed transition causing a valine to isoleucine switch in transmembrane domain I of CCR2B (64I) with unknown functional consequences was recently shown to delay disease progression but not reduce infection risk. Although we confirm the lack of association of CCR2B 64I with transmission, we cannot confirm the association with delayed progression. Although subjects with CCR5 delta 32 defects had significantly reduced median viral load at study entry, providing a plausible explanation for the association with delayed progression, this association was not seen with CCR2B 64I. Further studies are needed to define the role of CCR2B64I in HIV pathogenesis.

Congenital heart disease (CHD) has a complex genetic etiology, and recent studies suggest that high penetrance de novo mutations may account for only a small fraction of disease. In a multi-institutional cohort surveyed by exome sequencing, combining analysis of 987 individuals (discovery cohort of 59 affected trios and 59 control trios, and a replication cohort of 100 affected singletons and 533 unaffected singletons) we observe variation at novel and known loci related to a specific cardiac malformation the atrioventricular septal defect (AVSD). In a primary analysis, by combining developmental coexpression networks with inheritance modeling, we identify a de novo mutation in the DNA binding domain of NR1D2 (p.R175W). We show that p.R175W changes the transcriptional activity of Nr1d2 using an in vitro transactivation model in HUVEC cells. Finally, we demonstrate previously unrecognized cardiovascular malformations in the Nr1d2tm1-Dgen knockout mouse. In secondary analyses we map genetic variation to protein-interaction networks suggesting a role for two collagen genes in AVSD, which we corroborate by burden testing in a second replication cohort of 100 AVSDs and 533 controls (p = 8.37e-08). Finally, we apply a rare-disease inheritance model to identify variation in genes previously associated with CHD (ZFPM2, NSD1, NOTCH1, VCAN, and MYH6), cardiac malformations in mouse models (ADAM17, CHRD, IFT140, PTPRJ, RYR1 and ATE1), and hypomorphic alleles of genes causing syndromic CHD (EHMT1, SRCAP, BBS2, NOTCH2, and KMT2D) in 14 of 59 trios, greatly exceeding variation in control trios without CHD (p = 9.60e-06). In total, 32% of trios carried at least one putatively disease-associated variant across 19 loci,suggesting that inherited and de novo variation across a heterogeneous group of loci may contribute to disease risk.

BACKGROUND-Conotruncal heart defects comprise 25%-30% of non-syndromic congenital heart defects. This study describes the frequency of chromosome abnormalities and microdeletion 22q11 associated with conotruncal heart malformations.

Congenital heart defects are common malformations, affecting 4–8 per 1,000 total births. Conotruncal defects are an important pathogenetic subset of congenital heart defects, comprising nearly 20 percent of the total. Although both environmental and genetic factors are known to contribute to the occurrence of conotruncal defects, the causes remain unknown for most. To identify novel candidate genes/loci, we used array comparative genomic hybridization to detect chromosomal microdeletions/duplications. From a population base of 974,579 total births born during 1999–2004, we screened 389 California infants born with tetralogy of Fallot or d-transposition of the great arteries. We found that 1.7% (5/288) of males with a conotruncal defect had sex chromosome aneuploidy, a seven-fold increased frequency (relative risk = 7.0; 95% confidence interval 2.9–16.9). We identified eight chromosomal microdeletions/duplications for conotruncal defects. From these duplications and deletions, we found five high priority candidate genes (GATA4, CRKL, BMPR1A, SNAI2 and ZFHX4). This is the initial report that sex chromosome aneuploidy is associated with conotruncal defects among boys. These chromosomal microduplications/deletions provide evidence that GATA4, SNAI2 and CRKL are highly dosage sensitive genes involved in outflow tract development. Genome wide screening for copy number variation can be productive for identifying novel genes/loci contributing to nonsyndromic common malformations.

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Genetic variation influences immune responses and may contribute to differential development of tuberculosis (TB), particularly in immunosuppressed individuals. To examine the risk of Mycobacterium tuberculosis infection progressing to disease in the context of M. tuberculosis/human immunodeficiency virus (HIV) type 1 coinfection, HIV-1 RNA load and human leukocyte antigen (HLA) genotypes were determined among subjects from Harare, Zimbabwe, an area where both TB and HIV-1 are endemic. Patients with TB were compared with control subjects, stratified by HIV-1 infection status and progression of TB disease. Alleles of class I HLA-A and -C were associated with risk of developing active TB, depending on HIV-1 status. Among HIV-positive subjects, HIV-1 load was independently associated with increased risk of developing pulmonary TB. HLA DRB1 homozygosity among HIV-positive subjects was associated with reduced risk of developing pulmonary TB but increased risk of rapid progression to pleural effusion TB. These observations suggest that HLA plays a role in risk of developing symptomatic TB at various stages of disease and that these effects are modified by HIV-1 coinfection.

A large proportion of transiting planetary systems appear to possess only a single planet as opposed to multiple transiting planets. This excess of singles is indicative of significant mutual inclinations existing within a large number of planetary systems, but the origin of these misalignments is unclear. Moreover, recent observational characterization reveals that mutual inclinations tend to increase with proximity to the host star. These trends are both consistent with the dynamical influence of a strong quadrupolar potential arising from the host star during its early phase of rapid rotation, coupled with a non-zero stellar obliquity. Here, we simulate a population of planetary systems subject to the secular perturbation arising from a tilted, oblate host star as it contracts and spins down subsequent to planet formation. We demonstrate that this mechanism can reproduce the general increase in planet-planet mutual inclinations with proximity to the host star, and delineate a parameter space wherein the host star can drive dynamical instabilities. We suggest that approximately 5-10% of low-mass Kepler systems are susceptible to this instability mechanism, suggesting that a significant number of single-transiting planets may truly be intrinsically single. We also report a novel connection between instability and stellar obliquity reduction and make predictions that can be tested within upcoming TESS observations.

In a population‐based case‐control study in California of 228 infants, we investigated 75 genetic variants in 20 genes and risk of gastroschisis with regard to maternal age, race/ethnicity, vitamin use, and smoking exposure. We hypothesized that genes related to vascular compromise may interact with environmental factors to affect the risk of gastroschisis. Haplotypes were constructed for 75 gene variants using the HaploView program. Risk for gastroschisis associated with each gene variant was calculated for both the homozygotes and the heterozygotes, with the homozygous wildtypes as the referent. Risks were estimated as odds ratios (ORs) with 95% confidence intervals (CIs) by logistic regression. We found 11 gene variants with increased risk and four variants with decreased risk of gastroschisis for heterozygous (ORh) or homozygous variants (ORv) genotypes. These included NOS3 (rs1036145) ORh = 0.4 (95% CI: 0.2–0.7); NOS3 (rs10277237) ORv = 2.7 (95% CI: 1.3–6.0); ADD1 (rs12503220) ORh = 2.9 (95% CI: 1.6–5.4), GNB3 (rs5443) ORh = 0.2 (95% CI: 0.1–0.5), ORv = 0.4 (95% CI: 0.2–0.9); ICAM1 (rs281428) ORv = 6.9 (95% CI: 2.1–22.9), ICAM1 (rs3093030) ORv = 2.6 (95% CI: 1.2–5.6); ICAM4 (rs281438) ORv = 4.9 (95% CI: 1.4–16.6), ICAM5 (rs281417) ORh = 2.1 (95% CI: 1.1–4.1), ORv = 4.8 (95% CI: 1.7–13.6); ICAM5 (rs281440) ORh = 23.7 (95% CI: 5.5–102.5), ORv = 20.6 (95% CI: 3.4–124.3); ICAM5 (rs2075741) ORv = 2.2 (95% CI: 1.1–4.4); NAT1 ORv = 0.3 (95% CI: 0.1–0.9). There were additional associations between several gene variants and gastroschisis among women aged 20–24 and among mothers with and without vitamin use. NOS3, ADD1, ICAM1, ICAM4, and ICAM5 warrant further investigation in additional populations and with the interaction of additional environmental exposures. © 2016 Wiley Periodicals, Inc.