Genome-wide association studies (GWAS) have laid the foundation for investigations into the biology of complex traits, drug development and clinical guidelines. However, the majority of discovery efforts are based on data from populations of European ancestry 1-3. In light of the differential genetic architecture that is known to exist between populations, bias in representation can exacerbate existing disease and healthcare disparities. Critical variants may be missed if they have a low frequency or are completely absent in European populations, especially as the field shifts its attention towards rare variants, which are more likely to be population-specific 4-10. Additionally, effect sizes and their derived risk prediction scores derived in one population may Reprints and permissions information is available at http://www.nature.com/reprints.

Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age- and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to ~2.8M SNPs with BMI and WHRadjBMI in four strata (men ≤50y, men >50y, women ≤50y, women >50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR<5%) age-specific effects, of which 11 had larger effects in younger (<50y) than in older adults (≥50y). No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel) with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analysis to report convincing evidence of age-dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may provide further insights into the biology that underlies weight change with age or the sexually dimorphism of body shape.

To increase our understanding of the genetic basis of adiposity and its links to cardiometabolic disease risk, we conducted a genome-wide association meta-analysis of body fat percentage (BF%) in up to 100,716 individuals. Twelve loci reached genome-wide significance (P<5 × 10−8), of which eight were previously associated with increased overall adiposity (BMI, BF%) and four (in or near COBLL1/GRB14, IGF2BP1, PLA2G6, CRTC1) were novel associations with BF%. Seven loci showed a larger effect on BF% than on BMI, suggestive of a primary association with adiposity, while five loci showed larger effects on BMI than on BF%, suggesting association with both fat and lean mass. In particular, the loci more strongly associated with BF% showed distinct cross-phenotype association signatures with a range of cardiometabolic traits revealing new insights in the link between adiposity and disease risk.

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 fetal gut prior to birth, meaning that colonization could occur prenatally. Animal studies have shown that prenatal transmission of microbes to the fetus 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.

Our results provide evidence of higher than expected amounts of free fructose in some beverages. Popular beverages made with HFCS have a fructose-to-glucose ratio of approximately 60:40, and thus contain 50% more fructose than glucose. Some pure fruit juices have twice as much fructose as glucose. These findings suggest that beverages made with HFCS and some juices have a sugar profile very different than sucrose, in which amounts of fructose and glucose are equivalent. Current dietary analyses may underestimate actual fructose consumption.

These findings suggest that Hispanic children carrying the GG genotype are susceptible to increased hepatic fat when dietary carbohydrate intake, specifically sugar, is high. Specific dietary interventions based on genetic predisposition in this population may lead to more effective therapeutic outcomes for fatty liver. This trial was registered at clinicaltrials.gov as NCT00697580, 195-1642394A1, and NCT00693511.

The delivery of curcumin, a broad-spectrum anticancer drug, has been explored in the form of liposomal nanoparticles to treat osteosarcoma (OS). Curcumin is water insoluble and an effective delivery route is through encapsulation in cyclodextrins followed by a second encapsulation in liposomes. Liposomal curcumin’s potential was evaluated against cancer models of mesenchymal (OS) and epithelial origin (breast cancer). The resulting 2-Hydroxypropyl-γ-cyclodextrin/curcumin - liposome complex shows promising anticancer potential both in vitro and in vivo against KHOS OS cell line and MCF-7 breast cancer cell line. An interesting aspect is that liposomal curcumin initiates the caspase cascade that leads to apoptotic cell death in vitro in comparison with DMSO-curcumin induced autophagic cell death. In addition, the efficiency of the liposomal curcumin formulation was confirmed in vivo using a xenograft OS model. Curcumin-loaded γ-cyclodextrin liposomes indicate significant potential as delivery vehicles for the treatment of cancers of different tissue origin. From the Clinical Editor Curcumin-loaded γ-cyclodextrin liposomes were demonstrated in vitro to have significant potential as delivery vehicles for the treatment of cancers of mesenchymal and epithelial origin. Differences between mechanisms of cell death were also evaluated.

OBJECTIVEA genome-wide study of adults identified a variant of PNPLA3 (rs738409) associated with ∼twofold higher liver fat. The purpose of this study was to examine the influence of PNPLA3 genotype on liver fat and other related metabolic outcomes in obese Hispanic children and adolescents.RESEARCH DESIGN AND METHODSThree hundred and twenty-seven Hispanics aged 8–18 years were genotyped for rs738409. One hundred and eighty-eight subjects had measures of visceral (VAT) and subcutaneous (SAT) adipose tissue volume and hepatic (HFF) and pancreatic (PFF) fat fraction by magnetic resonance imaging. One hundred and thirty-nine subjects did not have HFF measures but had extensive measures of insulin sensitivity and fasting lipids.RESULTSLiver fat in GG subjects was 1.7 and 2.4 times higher than GC and CC (11.1 ± 0.8% in GG vs. 6.6 ± 0.7% in GC and 4.7 ± 0.9% in CC; P < 0.0001), and this effect was observed even in the youngest children (8–10 years of age). The variant was not associated with VAT, SAT, PFF, or insulin sensitivity or other glucose/insulin indexes. However, Hispanic children carrying the GG genotype had significantly lower HDL cholesterol (40.9 ± 10.9 in CC vs. 37.0 ± 8.3 in CG vs. 35.7 ± 7.4 in GG; P = 0.03) and a tendency toward lower free fatty acid levels (P = 0.06).CONCLUSIONSThese results provide new evidence that the effect of the PNPLA3 variant is apparent in Hispanic children and adolescents, is unique to fat deposition in liver as compared with other ectopic depots examined, and is associated with lower HDL cholesterol.