Genetic Evidence for Causal Relationships Between Maternal Obesity-Related Traits and Birth Weight.

IMPORTANCE: Neonates born to overweight or obese women are larger and at higher risk of birth complications. Many maternal obesity-related traits are observationally associated with birth weight, but the causal nature of these associations is uncertain. OBJECTIVE: To test for genetic evidence of causal associations of maternal body mass index (BMI) and related traits with birth weight. DESIGN, SETTING, AND PARTICIPANTS: Mendelian randomization to test whether maternal BMI and obesity-related traits are potentially causally related to offspring birth weight. Data from 30,487 women in 18 studies were analyzed. Participants were of European ancestry from population- or community-based studies in Europe, North America, or Australia and were part of the Early Growth Genetics Consortium. Live, term, singleton offspring born between 1929 and 2013 were included. EXPOSURES: Genetic scores for BMI, fasting glucose level, type 2 diabetes, systolic blood pressure (SBP), triglyceride level, high-density lipoprotein cholesterol (HDL-C) level, vitamin D status, and adiponectin level. MAIN OUTCOME AND MEASURE: Offspring birth weight from 18 studies. RESULTS: Among the 30,487 newborns the mean birth weight in the various cohorts ranged from 3325 g to 3679 g. The maternal genetic score for BMI was associated with a 2-g (95% CI, 0 to 3 g) higher offspring birth weight per maternal BMI-raising allele (P = .008). The maternal genetic scores for fasting glucose and SBP were also associated with birth weight with effect sizes of 8 g (95% CI, 6 to 10 g) per glucose-raising allele (P = 7 × 10(-14)) and -4 g (95% CI, -6 to -2 g) per SBP-raising allele (P = 1×10(-5)), respectively. A 1-SD ( ≈ 4 points) genetically higher maternal BMI was associated with a 55-g higher offspring birth weight (95% CI, 17 to 93 g). A 1-SD ( ≈ 7.2 mg/dL) genetically higher maternal fasting glucose concentration was associated with 114-g higher offspring birth weight (95% CI, 80 to 147 g). However, a 1-SD ( ≈ 10 mm Hg) genetically higher maternal SBP was associated with a 208-g lower offspring birth weight (95% CI, -394 to -21 g). For BMI and fasting glucose, genetic associations were consistent with the observational associations, but for systolic blood pressure, the genetic and observational associations were in opposite directions. CONCLUSIONS AND RELEVANCE: In this mendelian randomization study, genetically elevated maternal BMI and blood glucose levels were potentially causally associated with higher offspring birth weight, whereas genetically elevated maternal SBP was potentially causally related to lower birth weight. If replicated, these findings may have implications for counseling and managing pregnancies to avoid adverse weight-related birth outcomes.

Recognition of sialylated poly-N-acetyllactosamine chains on N- and O-linked glycans by human and avian influenza A virus hemagglutinins.

Human influenza viruses are proposed to recognize sialic acids (pink diamonds) on glycans extended with poly-LacNAc chains (LacNAc=(yellow circle+blue square)). N- and O-linked glycans were extended with different poly-LacNAc chains with α2-3- and α2-6-linked sialic acids recognized by human and avian influenza viruses, respectively. The specificity of recombinant hemagglutinins (receptors in green) was investigated by using glycan microarray technology.

Parenting Styles of Parents Who Had Children With and Without High Risk at Birth: A Cross-sectional Comparative Study.

Introduction Parenting style plays a major role in child development by influencing cognitive, social-emotional development, academic performance, and behavioral problems. These characteristics are fairly stable right into adulthood. The influence of risk factors in children on the parenting style of mothers and fathers has not been studied in developing countries. Aims and methods The aim of this study is to determine the parenting style of mothers and fathers of children (3-12 years) born with and without high risk and to analyze the influence of this on parenting style. This is an analytical, cross-sectional, comparative study. Sixty-four out of 90 parents of children who have been newborn intensive care unit (NICU) graduates, with moderate to severe risk factors at birth as per the National Neonatology Forum guidelines of India, and 73 parents of children without risk factors at birth were enrolled. A parenting style and dimension questionnaire was used. The commonest parenting style in mothers and fathers and a correlation between parenting style and risk factors in children at birth were identified. Results Baseline characteristics were comparable between the high-risk and non-high-risk groups. Eighty percent of mothers and 70% of fathers followed the authoritative parenting style. There was no significant correlation between risk factors and gender, family type or socioeconomic status and the parenting style. Lack of follow-through was the only factor that was significantly present in fathers of children born without risk factors. Conclusion Authoritative was the most common parenting style, with no significant difference between parenting in the high-risk and non-high-risk groups. Adopting the appropriate parenting style will optimize developmental outcomes. Further studies are required to look at the influence of proactive positive parenting practices.

Disubstituted Sialic Acid Ligands Targeting Siglecs CD33 and CD22 Associated with Myeloid Leukaemias and B Cell Lymphomas.

The siglec family of sialic acid-binding proteins are endocytic immune cell receptors that are recognized as potential targets for cell directed therapies. CD33 and CD22 are prototypical members and are validated candidates for targeting acute myeloid leukaemia and non-Hodgkin's lymphomas due to their restricted expression on myeloid cells and B-cells, respectively. While nanoparticles decorated with high affinity siglec ligands represent an attractive platform for delivery of therapeutic agents to these cells, a lack of ligands with suitable affinity and/or selectivity has hampered progress. Herein we describe selective ligands for both of these siglecs, which when displayed on liposomal nanoparticles, can efficiently target the cells expressing them in peripheral human blood. Key to their identification was the development of a facile method for chemo-enzymatic synthesis of disubstituted sialic acid analogues, combined with iterative rounds of synthesis and rapid functional analysis using glycan microarrays.

Genetic risk score for prediction of newborn adiposity and large-for-gestational-age birth.

CONTEXT: Macrosomic infants are at increased risk for adverse metabolic outcomes. Improving prediction of large-for-gestational-age (LGA) birth may help prevent these outcomes. OBJECTIVE: This study sought to determine whether genes associated with obesity-related traits in adults are associated with newborn size, and whether a genetic risk score (GRS) predicts LGA birth. SETTING AND DESIGN: Single nucleotide polymorphisms (SNPs) in 40 regions associated with adult obesity-related traits were tested for association with newborn size. GRS's for birth weight and sum of skinfolds (SSF) specific to ancestry were calculated using the most highly associated SNP for each ancestry in genomic regions with one or more SNPs associated with birth weight and/or SSF in at least one ancestry group or meta-analyses. PARTICIPANTS: Newborns from the Hyperglycemia Adverse Pregnancy Outcomes Study were studied (942 Afro-Caribbean, 1294 Northern European, 573 Mexican-American, and 1182 Thai). OUTCOME MEASURES: Birth weight >90th percentile (LGA) and newborn SSF >90th percentile were primary outcomes. RESULTS: After adjustment for ancestry, sex, gestational age at delivery, parity, maternal genotype, maternal smoking/alcohol intake, age, body mass index, height, blood pressure and glucose, 25 and 23 SNPs were associated (P < .001) with birth weight and newborn SSF, respectively. The GRS was highly associated with both phenotypes as continuous variables across all ancestries (P ≤ 1.6 × 10(-19)) and improved prediction of birth weight and SSF >90th percentile when added to a baseline model incorporating the covariates listed above. CONCLUSIONS: A GRS comprised of SNPs associated with adult obesity-related traits may provide an approach for predicting LGA birth and newborn adiposity beyond established risk factors.

On-chip synthesis and screening of a sialoside library yields a high affinity ligand for Siglec-7.

The Siglec family of sialic acid-binding proteins are differentially expressed on white blood cells of the immune system and represent an attractive class of targets for cell-directed therapy. Nanoparticles decorated with high-affinity Siglec ligands show promise for delivering cargo to Siglec-bearing cells, but this approach has been limited by a lack of ligands with suitable affinity and selectivity. Building on previous work employing solution-phase sialoside library synthesis and subsequent microarray screening, we herein report a more streamlined 'on-chip' synthetic approach. By printing a small library of alkyne sialosides and subjecting these to 'on-chip' click reactions, the largest sialoside analogue library to date was generated. Siglec-screening identified a selective Siglec-7 ligand, which when displayed on liposomal nanoparticles, allows for targeting of Siglec-7(+) cells in peripheral human blood. In silico docking to the crystal structure of Siglec-7 provides a rationale for the affinity gains observed for this novel sialic acid analogue.