Association of TCN2 rs1801198 c.776G>C polymorphism with markers of one-carbon metabolism and related diseases: a systematic review and meta-analysis of genetic association studies [Gene-nutrient interactions]

Background: Vitamin B-12 (cobalamin) deficiency may produce severe neurologic and hematologic manifestations. Approximately 20–25% of circulating cobalamin binds to transcobalamin 2 (TCN2), which is referred to as active vitamin B-12. The G allele of the TCN2 c.776G>C (rs1801198) polymorphism has been associated with a lower plasma concentration of holotranscobalamin. However, genotype association studies on rs1801198 have led to conflicting results regarding its influence on one-carbon metabolism (OCM) markers or its association with pathologic conditions.

Objective: We assessed the association of rs1801198 genotypes with OCM marker concentrations and primary risks of congenital abnormalities, cancer, and Alzheimer disease.

Design: We conducted a systematic review of the literature that was published from January 1966 to February 2017 and included all studies that assessed the association between rs1801198 and OCM markers or a pathologic condition.

Results: Thirty-four studies met the inclusion criteria. Subjects with the rs1801198 GG genotype had significantly lower concentrations of holotranscobalamin [standardized mean difference (SMD): –0.445 (95% CI: –0.673, –0.217; P < 0.001); I² = 48.16% (95% CI: 0.00%, 78.10%; P = 0.07)] and higher concentrations of homocysteine (European descent only) [SMD: 0.070 (95% CI: 0.020, 0.120; P = 0.01); I² = 0.00% (95% CI: 0.00%, 49.59%; P = 0.73)] than did subjects with the rs1801198 CC genotype. The meta-analysis on the association between rs1801198 and methylmalonic acid (MMA) lacked statistical power. No significant difference was observed regarding cobalamin, folate, and red blood cell folate. No significant association was observed between rs1801198 and primary risks of congenital abnormalities, cancer, or Alzheimer disease.

Conclusions: Meta-analysis results indicate an influence of rs1801198 on holotranscobalamin and homocysteine concentrations in European-descent subjects. In addition, well-designed and -powered studies should be conducted for assessing the association between rs1801198 and MMA and clinical manifestations that are linked to a decreased availability of cobalamin. This review was registered at http://ift.tt/2dOOxo8 as CRD42017058504.

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Dynamics of intrapericardial and extrapericardial fat tissues during long-term, dietary-induced, moderate weight loss [Nutritional status, dietary intake, and body composition]

Background: In view of evidence linking pericardial fat accumulation with increased cardiovascular disease risk, strategies to reduce its burden are needed. Data comparing the effects of specific long-term dietary interventions on pericardial fat tissue mobilization are sparse.

Objective: We sought to evaluate intrapericardial-fat (IPF) and extrapericardial-fat (EPF) changes during weight-loss interventions by different dietary regimens.

Design: During 18 mo of a randomized controlled trial, we compared a Mediterranean/low-carbohydrate (MED/LC) diet plus 28 g walnuts/d with a calorically equal low-fat (LF) diet among randomly assigned participants with moderate abdominal obesity. We performed whole-body MRI and volumetrically quantified IPF and EPF among 80 participants to follow the 18-mo changes.

Results: The participants [mean age: 48.6 y; mean body mass index (BMI; in kg/m²); 31.7; 90% men] had baseline IPF and EPF (mean ± SD) volumes of 172.4 ± 53.3 mL and 194.9 ± 71.5 mL, respectively. The 18-mo moderate weight loss of 3.7 kg was similar in both groups, but the reduction in waist circumference was higher in the MED/LC group (–6.9 ± 6.6 cm) than in the LF diet group (–2.3 ± 6.5 cm; P = 0.01). After 18 mo, the IPF volume had reduced twice as much in the MED/LC group compared with the LF group [–37 ± 26.2 mL (–22% ± 15%) compared with –15.5 ± 26.2 mL (–8% ± 15%), respectively; P < 0.05, after adjustment for changes in weight or visceral adipose tissue]. The EPF volume had reduced similarly in both groups [–41.6 ± 30.2 mL (–23% ± 16%) in the MED/LC group compared with –37.9 ± 28.3 mL (–19% ± 14%) in the LF group; P > 0.1]. After controlling for weight loss, IPF and EPF volume reduction paralleled changes in lipid profile but not with improved glycemic profile variables: the IPF relative reduction was associated with a decrease in triglycerides (TGs) (β = 0.090; 95% CI: 0.026, 0.154; P = 0.007) and the ratio of TGs to high-density lipoprotein (HDL) cholesterol (β = 2.689; 95% CI: 0.373, 5.003; P = 0.024), and the EPF relative reduction was associated with an increase in HDL cholesterol (β = –0.452; 95% CI: –0.880, –0.023; P = 0.039) and a decrease in total cholesterol and HDL cholesterol (β = 3.766; 95% CI: 1.092, 6.440; P = 0.007).

Conclusions: Moderate but persistent dietary-induced weight loss substantially decreased both IPF and EPF volumes. Reduction of pericardial adipose tissues is independently associated with an improved lipid profile. The Mediterranean diet, rich in unsaturated fats and restricted carbohydrates, is superior to an LF diet in terms of the IPF burden reduction. This trial was registered at clinicaltrials.gov as NCT01530724.

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Can changes in the plasma lipidome help explain the cardiovascular benefits of the Mediterranean diet? [Editorials]

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Mediation and modification of genetic susceptibility to obesity by eating behaviors [Nutritional status, dietary intake, and body composition]

Background: Many genetic variants show highly robust associations with body mass index (BMI). However, the mechanisms through which genetic susceptibility to obesity operates are not well understood. Potentially modifiable mechanisms, including eating behaviors, are of particular interest to public health.

Objective: Here we explore whether eating behaviors mediate or modify genetic susceptibility to obesity.

Design: Genetic risk scores for BMI (BMI-GRSs) were calculated for 3515 and 2154 adults in the Fenland and EDEN (Etude des déterminants pré et postnatals de la santé et du développement de l'enfant) population-based cohort studies, respectively. The eating behaviors—emotional eating, uncontrolled eating, and cognitive restraint—were measured through the use of a validated questionnaire. The mediating effect of each eating behavior on the association between the BMI-GRS and measured BMI was assessed by using the Sobel test. In addition, we tested for interactions between each eating behavior and the BMI-GRS on BMI.

Results: The association between the BMI-GRS and BMI was mediated by both emotional eating (EDEN: P-Sobel = 0.01; Fenland: P-Sobel = 0.02) and uncontrolled eating (EDEN: P-Sobel = 0.04; Fenland: P-Sobel = 0.0006) in both sexes combined. Cognitive restraint did not mediate this association (P-Sobel > 0.10), except among EDEN women (P-Sobel = 0.0009). Cognitive restraint modified the relation between the BMI-GRS and BMI among men (EDEN: P-interaction = 0.0001; Fenland: P-interaction = 0.04) and Fenland women (P-interaction = 0.0004). By tertiles of cognitive restraint, the association between the BMI-GRS and BMI was strongest in the lowest tertile of cognitive restraint, and weakest in the highest tertile.

Conclusions: Genetic susceptibility to obesity was partially mediated by the "appetitive" eating behavior traits (uncontrolled and emotional eating) and, in 3 of the 4 population groups studied, was modified by cognitive restraint. High levels of cognitive control over eating appear to attenuate the genetic susceptibility to obesity. Future research into interventions designed to support restraint may help to protect genetically susceptible individuals from weight gain.

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Home- and community-based growth monitoring to reduce early life growth faltering: an open-label, cluster-randomized controlled trial [Growth, development, and pediatrics]

Background: Despite the continued high prevalence of faltering growth, height monitoring remains limited in many low- and middle-income countries.

Objective: The objective of this study was to test whether providing parents with information on their child's height can improve children's height and developmental outcomes.

Design: Villages in Chipata District, Zambia (n = 127), were randomly assigned with equal probability to 1 of 3 groups: home-based growth monitoring (HBGM), community-based growth monitoring including nutritional supplementation for children with stunted growth (CBGM+NS), and control. Primary study outcomes were individual height-for-age z score (HAZ) and overall child development assessed with the International Fetal and Newborn Growth Consortium for the 21st Century Neurodevelopment Assessment tool. Secondary outcomes were weight-for-age z score (WAZ), protein consumption, breastfeeding, and general dietary diversity.

Results: We enrolled a total of 547 children with a median age of 13 mo at baseline. Estimated mean difference (β) in HAZ was 0.127 (95% CI: –0.107, 0.361) for HBGM and –0.152 (95% CI: –0.341, 0.036) for CBGM+NS. HBGM had no impact on child development [β: –0.017 (95% CI: –0.133, 0.098)]; CBGM+NS reduced overall child development scores by –0.118 SD (95% CI: –0.230, –0.006 SD). Both interventions had larger positive effects among children with stunted growth at baseline, with estimated interaction effects of 0.503 (95% CI: 0.160, 0.846) and 0.582 (95% CI: 0.134, 1.030) for CBGM+NS and HBGM, respectively. HBGM increased mean WAZ [β = 0.183 (95% CI: 0.037, 0.328)]. Both interventions improved parental reports of children's protein intake.

Conclusions: The results from this trial suggest that growth monitoring has a limited effect on children's height and development, despite improvements in self-reported feeding practices. HBGM had modest positive effects on children with stunted growth. Given its relatively low cost, this intervention may be a cost-effective tool for increasing parental efforts toward reducing children's physical growth deficits. This trial was registered at clinicaltrials.gov as NCT02242539.

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Quantity and source of dietary protein influence metabolite production by gut microbiota and rectal mucosa gene expression: a randomized, parallel, double-blind trial in overweight humans [Energy and protein metabolism]

Background: Although high-protein diets (HPDs) are frequently consumed for body-weight control, little is known about the consequences for gut microbiota composition and metabolic activity and for large intestine mucosal homeostasis. Moreover, the effects of HPDs according to the source of protein need to be considered in this context.

Objective: The objective of this study was to evaluate the effects of the quantity and source of dietary protein on microbiota composition, bacterial metabolite production, and consequences for the large intestinal mucosa in humans.

Design: A randomized, double-blind, parallel-design trial was conducted in 38 overweight individuals who received a 3-wk isocaloric supplementation with casein, soy protein, or maltodextrin as a control. Fecal and rectal biopsy–associated microbiota composition was analyzed by 16S ribosomal DNA sequencing. Fecal, urinary, and plasma metabolomes were assessed by ¹H-nuclear magnetic resonance. Mucosal transcriptome in rectal biopsies was determined with the use of microarrays.

Results: HPDs did not alter the microbiota composition, but induced a shift in bacterial metabolism toward amino acid degradation with different metabolite profiles according to the protein source. Correlation analysis identified new potential bacterial taxa involved in amino acid degradation. Fecal water cytotoxicity was not modified by HPDs, but was associated with a specific microbiota and bacterial metabolite profile. Casein and soy protein HPDs did not induce inflammation, but differentially modified the expression of genes playing key roles in homeostatic processes in rectal mucosa, such as cell cycle or cell death.

Conclusions: This human intervention study shows that the quantity and source of dietary proteins act as regulators of gut microbiota metabolite production and host gene expression in the rectal mucosa, raising new questions on the impact of HPDs on the large intestine mucosa homeostasis. This trial was registered at clinicaltrials.gov as NCT02351297.

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Vitamin D prenatal programming of childhood metabolomics profiles at age 3 y [Nutritional epidemiology and public health]

Background: Vitamin D deficiency is implicated in a range of common complex diseases that may be prevented by gestational vitamin D repletion. Understanding the metabolic mechanisms related to in utero vitamin D exposure may therefore shed light on complex disease susceptibility.

Objective: The goal was to analyze the programming role of in utero vitamin D exposure on children's metabolomics profiles.

Design: First, unsupervised clustering was done with plasma metabolomics profiles from a case-control subset of 245 children aged 3 y with and without asthma from the Vitamin D Antenatal Asthma Reduction Trial (VDAART), in which pregnant women were randomly assigned to vitamin D supplementation or placebo. Thereafter, we analyzed the influence of maternal pre- and postsupplement vitamin D concentrations on cluster membership. Finally, we used the metabolites driving the clustering of children to identify the dominant metabolic pathways that were influential in each cluster.

Results: We identified 3 clusters of children characterized by 1) high concentrations of fatty acids and amines and low maternal postsupplement vitamin D (mean ± SD; 27.5 ± 11.0 ng/mL), 2) high concentrations of amines, moderate concentrations of fatty acids, and normal maternal postsupplement vitamin D (34.0 ± 14.1 ng/mL), and 3) low concentrations of fatty acids, amines, and normal maternal postsupplement vitamin D (35.2 ± 15.9 ng/mL). Adjusting for sample storage time, maternal age and education, and both child asthma and vitamin D concentration at age 3 y did not modify the association between maternal postsupplement vitamin D and cluster membership (P = 0.0014). Maternal presupplement vitamin D did not influence cluster membership, whereas the combination of pre- and postsupplement concentrations did (P = 0.03).

Conclusions: Young children can be clustered into distinct biologically meaningful groups by their metabolomics profiles. The clusters differed in concentrations of inflammatory mediators, and cluster membership was influenced by in utero vitamin D exposure, suggesting a prenatal programming role of vitamin D on the child's metabolome. This trial was registered at clinicaltrials.gov as NCT00920621.

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