Summary
The colonization of the gut with microbes in early life is critical to the developing newborn immune system, metabolic function and potentially future health. Maternal microbes are ...transmitted to offspring during childbirth, representing a key step in the colonization of the infant gut. Studies of infant meconium suggest that bacteria are present in the foetal gut prior to birth, meaning that colonization could occur prenatally. Animal studies have shown that prenatal transmission of microbes to the foetus is possible, and physiological changes observed in pregnant mothers indicate that in utero transfer is likely in humans as well. However, direct evidence of in utero transfer of bacteria in humans is lacking. Understanding the timing and mechanisms involved in the first colonization of the human gut is critical to a comprehensive understanding of the early life gut microbiome. This review will discuss the evidence supporting in utero transmission of microbes from mother to infants. We also review sources of transferred bacteria, physiological mechanisms of transfer and modifiers of maternal microbiomes and their potential role in early life infant health. Well‐designed longitudinal birth studies that account for established modifiers of the gut microbiome are challenging, but will be necessary to confirm in utero transfer and further our knowledge of the prenatal microbiome.
Except in rare cases, obesity tends to be a consequence of both an unhealthy lifestyle and a genetic susceptibility to gain weight. With more than 200 common genetic variants identified, there is a ...growing interest in developing personalized preventive and treatment strategies to predict an individual’s obesity risk. We review the literature on the prediction of obesity and show that models based on the established genetic variants have poorer predictive ability than traditional predictors, such as family history of obesity and childhood obesity. Current findings suggest that opportunities for precision medicine in common obesity may be limited.
There is a growing interest in using genetic information to predict people’s risk of obesity. In this review, Loos and Janssens show that prediction of polygenic obesity based on genetic variants is poor, whereas family history of obesity, childhood obesity, and other traditional risk factors are better predictors.
Abstract
More than one in three adults worldwide is either overweight or obese. Epidemiological studies indicate that the location and distribution of excess fat, rather than general adiposity, are ...more informative for predicting risk of obesity sequelae, including cardiometabolic disease and cancer. We performed a genome-wide association study meta-analysis of body fat distribution, measured by waist-to-hip ratio (WHR) adjusted for body mass index (WHRadjBMI), and identified 463 signals in 346 loci. Heritability and variant effects were generally stronger in women than men, and we found approximately one-third of all signals to be sexually dimorphic. The 5% of individuals carrying the most WHRadjBMI-increasing alleles were 1.62 times more likely than the bottom 5% to have a WHR above the thresholds used for metabolic syndrome. These data, made publicly available, will inform the biology of body fat distribution and its relationship with disease.
In a systematic review, we identified 21 separate studies with data on the association between rapid infancy weight gain, up to age 2 y, and subsequent obesity risk. Uniformly all studies reported ...significant positive associations. We transformed the reported effect sizes to a standard infancy weight gain exposure, and found that further differences in study design accounted for much of the variation in risk. An accompanying paper by Melinda Yeung reminds us that there are benefits of postnatal catch‐up growth in certain populations, and suggests that genetic and nutritional factors could moderate the unhealthy translation of rapid infancy weight gain to visceral fat and insulin resistance. Further evidence is needed, and we will need to rigorously test the benefits and risks of any interventions. However, the concept of “healthy” rapid catch‐up infancy growth is an attractive prospect.
Conclusion: Rapid infancy weight gain is consistently associated with increased subsequent obesity risk, but the predictive ability of different weight gain cut‐offs needs to be tested.
BACKGROUND: Large-scale genome-wide association studies have identified 12 genetic loci that are robustly associated with body mass index (BMI). OBJECTIVES: We examined associations and compared ...effect sizes of these newly identified obesity susceptibility loci with various anthropometric traits and assessed their cumulative effects and predictive value for obesity risk. DESIGN: We genotyped 12 single nucleotide polymorphisms (SNPs) from each locus in 20,431 individuals (age: 39-79 y) from the population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk cohort. General linear model and logistic regression were used to examine associations, and the area under the receiver operating characteristic curve (AUC) was used to assess the predictive value of these variants for obesity risk. RESULTS: Effect sizes of the risk alleles ranged between 0.058 and 0.329 for BMI (in kg/m²), between 0.094 and 0.866 kg for weight, and between 0.085 and 0.819 cm for waist circumference, with rs1121980 (FTO locus) showing the largest effect. Risk alleles of rs7132908 (FAIM2 locus) and rs17782313 (MC4R locus) were also associated with taller height. On average, each additional risk allele was associated with increases of 0.149 in BMI (P = 1.54 x 10⁻²²), 0.444 kg in body weight (P = 9.88 x 10⁻²²), and 0.357 cm in waist circumference (P = 1.10 x 10⁻¹⁸) and 10.8% (P = 9.83 x 10⁻¹⁶) and 5.5% (P = 3.38 x 10⁻¹⁰) increased risks of obesity and overweight, respectively. All SNPs combined explained 0.9% of BMI variation, with an AUC of 0.574 (95% CI: 0.559, 0.590) for prediction of obesity. CONCLUSIONS: Common variants for BMI have small effects on obesity measures and show different association patterns with anthropometric traits, with the largest effect shown for the FTO locus. These variants have cumulative effects, yet their predictive value for obesity risk is limited.
Objective
Precision medicine utilizes genomic and other data to optimize and personalize treatment. Although more than 2,500 genetic tests are currently available, largely for extreme and/or rare ...phenotypes, the question remains whether this approach can be used for the treatment of common, complex conditions like obesity, inflammation, and insulin resistance, which underlie a host of metabolic diseases.
Methods
This review, developed from a Trans‐NIH Conference titled “Genes, Behaviors, and Response to Weight Loss Interventions,” provides an overview of the state of genetic and genomic research in the area of weight change and identifies key areas for future research.
Results
Although many loci have been identified that are associated with cross‐sectional measures of obesity/body size, relatively little is known regarding the genes/loci that influence dynamic measures of weight change over time. Although successful short‐term weight loss has been achieved using many different strategies, sustainable weight loss has proven elusive for many, and there are important gaps in our understanding of energy balance regulation.
Conclusions
Elucidating the molecular basis of variability in weight change has the potential to improve treatment outcomes and inform innovative approaches that can simultaneously take into account information from genomic and other sources in devising individualized treatment plans.
Abstract
Studies based on self-reported alcohol consumption and telomere length show inconsistent results. Therefore, we studied the association between gamma-glutamyl transferase (GGT), a widely ...used biomarker of alcohol intake, and telomere length. The possible health relevance in young adulthood was explored by investigating cardiometabolic risk factors. Mixed modelling was performed to examine GGT and alcohol consumption in association with telomere length in buccal cells of 211 adults between 18 and 30 years old of the East Flanders Prospective Twin Survey. In addition, we investigated the association between GGT and cardiometabolic risk factors; waist circumference, systolic blood pressure, fasting glucose, HDL cholesterol, and triglycerides. Although we did not observe an association between self-reported alcohol consumption and telomere length, our results show that a doubling in serum GGT is associated with 7.80% (95% CI − 13.9 to − 1.2%; p = 0.02) shorter buccal telomeres, independently from sex, chronological age, educational level, zygosity and chorionicity, waist-to-hip ratio and smoking. The association between GGT was significant for all five cardiometabolic risk factors, while adjusting for age. We show that GGT, a widely used biomarker of alcohol consumption, is associated with telomere length and with risk factors of cardiometabolic syndrome, despite the young age of this study population.
Substantial progress has been made in identification of type 2 diabetes (T2D) risk loci in the past few years, but our understanding of the genetic basis of T2D in ethnically diverse populations ...remains limited. We performed a genome-wide association study and a replication study in Chinese Hans comprising 8,569 T2D case subjects and 8,923 control subjects in total, from which 10 single nucleotide polymorphisms were selected for further follow-up in a de novo replication sample of 3,410 T2D case and 3,412 control subjects and an in silico replication sample of 6,952 T2D case and 11,865 control subjects. Besides confirming seven established T2D loci (CDKAL1, CDKN2A/B, KCNQ1, CDC123, GLIS3, HNF1B, and DUSP9) at genome-wide significance, we identified two novel T2D loci, including G-protein-coupled receptor kinase 5 (GRK5) (rs10886471: P = 7.1 × 10(-9)) and RASGRP1 (rs7403531: P = 3.9 × 10(-9)), of which the association signal at GRK5 seems to be specific to East Asians. In nondiabetic individuals, the T2D risk-increasing allele of RASGRP1-rs7403531 was also associated with higher HbA(1c) and lower homeostasis model assessment of β-cell function (P = 0.03 and 0.0209, respectively), whereas the T2D risk-increasing allele of GRK5-rs10886471 was also associated with higher fasting insulin (P = 0.0169) but not with fasting glucose. Our findings not only provide new insights into the pathophysiology of T2D, but may also shed light on the ethnic differences in T2D susceptibility.
The obesity paradox in which overweight/obesity is associated with mortality benefits is believed to be explained by confounding and reverse causality rather than by a genuine clinical benefit of ...excess body weight. We aimed to gain deeper insights into the paradox through analyzing mortality relationships with several adiposity measures; assessing subgroups with type 2 diabetes, with coronary heart disease (CHD), with cancer, and by smoking status; and adjusting for several confounders.
We studied the general UK Biobank population (
= 502,631) along with three subgroups of people with type 2 diabetes (
= 23,842), CHD (
= 24,268), and cancer (
= 45,790) at baseline. A range of adiposity exposures were considered, including BMI (continuous and categorical), waist circumference, body fat percentage, and waist-to-hip ratio, and the outcome was all-cause mortality. We used Cox regression models adjusted for age, smoking status, deprivation index, education, and disease history.
For BMI, the obesity paradox was observed among people with type 2 diabetes (adjusted hazard ratio for obese vs. normal BMI 0.78 95% CI 0.65, 0.95) but not among those with CHD (1.00 0.86, 1.17). The obesity paradox was pronounced in current smokers, absent in never smokers, and more pronounced in men than in women. For other adiposity measures, there was less evidence for an obesity paradox, yet smoking status consistently modified the adiposity-mortality relationship.
The obesity paradox was observed in people with type 2 diabetes and is heavily modified by smoking status. The results of subgroup analyses and statistical adjustments are consistent with reverse causality and confounding.
To investigate whether associations of common genetic variants recently identified for fasting glucose or insulin levels in nondiabetic adults are detectable in healthy children and adolescents.
A ...total of 16 single nucleotide polymorphisms (SNPs) associated with fasting glucose were genotyped in six studies of children and adolescents of European origin, including over 6,000 boys and girls aged 9-16 years. We performed meta-analyses to test associations of individual SNPs and a weighted risk score of the 16 loci with fasting glucose.
Nine loci were associated with glucose levels in healthy children and adolescents, with four of these associations reported in previous studies and five reported here for the first time (GLIS3, PROX1, SLC2A2, ADCY5, and CRY2). Effect sizes were similar to those in adults, suggesting age-independent effects of these fasting glucose loci. Children and adolescents carrying glucose-raising alleles of G6PC2, MTNR1B, GCK, and GLIS3 also showed reduced β-cell function, as indicated by homeostasis model assessment of β-cell function. Analysis using a weighted risk score showed an increase β (95% CI) in fasting glucose level of 0.026 mmol/L (0.021-0.031) for each unit increase in the score.
Novel fasting glucose loci identified in genome-wide association studies of adults are associated with altered fasting glucose levels in healthy children and adolescents with effect sizes comparable to adults. In nondiabetic adults, fasting glucose changes little over time, and our results suggest that age-independent effects of fasting glucose loci contribute to long-term interindividual differences in glucose levels from childhood onwards.
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