Efficacy and safety of a nanoparticle therapeutic vaccine in patients with chronic hepatitis B: A randomized clinical trial.

BACKGROUND AND AIM: HBV DNA can be reduced using antiviral drugs in patients with chronic hepatitis B (CHB); however, the rate of HBeAg seroconversion remains low. A clinical trial was conducted to assess the efficacy and safety of a de novo designed liposome-based nanoparticle lipopeptide vaccine, εPA-44, for CHB. APPROACH AND RESULTS: A two-stage phase 2 trial, which included a 76-week, randomized, double-blind, placebo-controlled trial (stage 1) and a 68-week open-label extension (stage 2), was conducted in 15 centers across China (Clinicaltrials.gov No. NCT00869778). In stage 1, 360 human leukocyte antigen A2 (HLA-A2)-positive and HBeAg-positive patients were randomly and equally distributed to receive six subcutaneous injections of 600 µg or 900 µg εPA-44 or placebo at week 0, 4, 8, 12, 20, and 28. In stage 2, 183 patients received extended 900 µg εPA-44, and 26 patients were observed for relapse without further treatment. The primary endpoint was the percentage of patients with HBeAg seroconversion at week 76. At week 76, patients receiving 900 µg εPA-44 achieved significantly higher HBeAg seroconversion rate (38.8%) versus placebo (20.2%) (95% CI, 6.9-29.6%; p = 0.002). With a combined endpoint of HBeAg seroconversion, alanine aminotransferase normalization and HBV DNA < 2,000 IU/mL, both 900 µg (18.1%) and 600 µg (14.3%), resulted in significantly higher rate versus placebo (5.0%) (p = 0.002 and p = 0.02, respectively) at week 76. In stage 2, none (0 of 20) of 900 µg εPA-44-treated patients experienced serologic relapse. The safety profile of εPA-44 was comparable to that of placebo. CONCLUSIONS: Among HLA-A2-positive patients with progressive CHB, a finite duration of 900 µg εPA-44 monotherapy resulted in significantly higher HBeAg seroconversion rate than placebo and sustained off-treatment effect. A phase 3 trial is ongoing (ChiCTR2100043708).

Patient-shared TCRß-CDR3 clonotypes correlate with favorable prognosis in chronic hepatitis B.

The presence of shared T-cell clonotypes was found in several different diseases, but its relationship with the progression of disease remains unclear. By sequencing the complementary determining region 3 of T-cell receptor (TCR) ß chains from the purified antigen-experienced CD8+ T cells, we characterized the T-cell repertoire in a prospective cohort study among 75 patients with chronic hepatitis B in China, as well as a healthy control and a validation cohort. We found that most T-cell clones from patients harbored the "patient-specific" TCR sequences. However, "patient-shared" TCR clonotypes were also widely found, which correlated with the favorable turnover of disease. Interestingly, the frequency of the "patient-shared" clonotypes can serve as a biomarker for favorable prognosis. Based on the clonotypes in those patients with favorable outcomes, we created a database including several clusters of protective anti-HBV CD8+ T-cell clonotypes that might be a reasonable target for therapeutic vaccine development or adoptive cell transfer therapy. These findings were validated in an additional independent cohort of patients. These results suggest that the "patient-shared" TCR clonotypes may serve as a valuable prognostic tool in the treatment of chronic hepatitis B and possibly other chronic viral diseases.

DNA methylation variant, B-vitamins intake and longitudinal change in body mass index.

BACKGROUND: Growing evidence has implicated DNA methylation (DNAm) in the regulation of body adiposity; a recent epigenome-wide association study (EWAS) identified a genetic variant determining DNAm at the SREBF1 gene that affected body mass index (BMI). OBJECTIVE: In the present study, we tested interactions between DNAm variant rs752579 and methylation metabolism-related B-vitamins (folate, vitamin B2, vitamin B6, and vitamin B12) on longitudinal change in BMI in the Women's Health Initiative Memory Study (WHIMS). DESIGN: A total of 5687 white women aged 65-79 from WHIMS with genotyping data on SNP rs752579 were included in the analysis. B-vitamins intakes were estimated by a self-report semi-quantitative food frequency questionnaire. BMI was measured at baseline and 6-year follow-up. RESULT: We found significant interactions between the SREBF1 rs752579 genotype and intake of food source B-vitamins on 6-year change in BMI (p interaction <0.01 for all). BMI changes (kg/m2) per DNAm-increasing (C) allele were -0.29, 0.06, and 0.11 within subgroups of increasing tertiles of food source folate intake; and the corresponding BMI changes (kg/m2) were -0.25, -0.01, and 0.15 for vitamin B2 intake; -0.17, -0.16, and 0.21 for vitamin B6 intake; and -0.12, -0.23, and 0.26 for vitamin B12 intake, respectively. Similar gene-diet interaction patterns were observed on the change in body weight. CONCLUSIONS: Our data suggest that habitual intake of food source B-vitamins may modify the effect of DNAm-related variant on long-term adiposity change.

A circadian rhythm-related MTNR1B genetic variant modulates the effect of weight-loss diets on changes in adiposity and body composition: the POUNDS Lost trial.

PURPOSE: A common variant of the melatonin receptor 1B (MTNR1B) gene has been related to increased signaling of melatonin, a hormone previously associated with body fatness mainly through effects on energy metabolism. We examined whether the MTNR1B variant affects changes of body fatness and composition in response to a dietary weight loss intervention. METHODS: The MTNR1B rs10830963 variant was genotyped for 722 overweight and obese individuals, who were randomly assigned to one of four diets varying in macronutrient composition. Anthropometric and body composition measurements (DXA scan) were collected at baseline and at 6 and 24 months of follow-up. RESULTS: Statistically significant interactions were observed between the MTNR1B genotype and low-/high-fat diet on changes in weight, body mass index (BMI), waist circumference (WC) and total body fat (p interaction = 0.01, 0.02, 0.002 and 0.04, respectively), at 6 months of dietary intervention. In the low-fat diet group, increasing number of the sleep disruption-related G allele was significantly associated with a decrease in weight (p = 0.004), BMI (p = 0.005) and WC (p = 0.001). In the high-fat diet group, carrying the G allele was positively associated with changes in body fat (p = 0.03). At 2 years, the associations remained statistically significant for changes in body weight (p = 0.02), BMI (p = 0.02) and WC (p = 0.048) in the low-fat diet group, although the gene-diet interaction became less significant. CONCLUSIONS: The results suggest that carriers of the G allele of the MTNR1B rs10830963 may have a greater improvement in body adiposity and fat distribution when eating a low-fat diet.

Macronutrient-specific effect of the MTNR1B genotype on lipid levels in response to 2 year weight-loss diets.

Compelling evidence indicates that lipid metabolism is in partial control of the circadian system. In this context, it has been reported that the melatonin receptor 1B (MTNR1B) genetic variant influences the dynamics of melatonin secretion, which is involved in the circadian system as a chronobiotic. The objective was to analyze whether the MTNR1B rs10830963 genetic variant was related to changes in lipid levels in response to dietary interventions with different macronutrient distribution in 722 overweight/obese subjects from the POUNDS Lost trial. We did not find a significant association between the MTNR1B genotype and changes in lipid metabolism. However, dietary fat intake significantly modified genetic effects on 2 year changes in total and LDL cholesterol (P interaction = 0.006 and 0.001, respectively). In the low-fat diet group, carriers of the sleep disruption G allele (minor allele) showed a greater reduction of total cholesterol (ß ± SE = -5.78 ± 2.88 mg/dl, P = 0.04) and LDL cholesterol (ß ± SE = -7.19 ± 2.37 mg/dl, P = 0.003). Conversely, in the high-fat diet group, subjects carrying the G allele evidenced a smaller decrease in total cholesterol (ß ± SE = 5.81 ± 2.65 mg/dl, P = 0.03) and LDL cholesterol (ß ± SE = 5.23 ± 2.21 mg/dl, P = 0.002). Subjects carrying the G allele of the circadian rhythm-related MTNR1B variant may present a bigger impact on total and LDL cholesterol when undertaking an energy-restricted low-fat diet.

Analysis of T cell receptor repertoire in monozygotic twins concordant and discordant for chronic hepatitis B infection.

Due to their identical inheritance and shared surroundings, identical twins have been the recommended group for studying the susceptibility and prognosis of diseases. Here, CD8+ T cell receptor beta (TCRß) chains were analyzed by high-throughput sequencing in three pairs of healthy identical twins and chronic hepatitis B patients. The data showed a high level of similarity in the TCR repertoire of each pair in terms of average TCR Vß segment expression and frequency of the complementary determining region 3 (CDR3) pattern and skewed or oligoclonal clonotypes. Notably, the level of similarity in TCR Vß expression between the twins appeared to be independent of the consistency or inconsistency of chronic HBV infection, although the detailed CDR3 pattern and frequency were related to disease prognosis. There were more immunodominant clonotypes in patients with HBV antigen seroconversion, which showed an increased abundance. These immunodominant clonotypes may be used as favorable prognostic biomarkers and potential targets for immunotherapy. Thus, delineating the CD8+ T cell repertoire of identical twins with concordant chronic viral infections provides a promising means to screen protective TCR genes for immunotherapy.

Genetic, epigenetic and transcriptional variations at NFATC2IP locus with weight loss in response to diet interventions: The POUNDS Lost Trial.

DNA Methylation of NFATC2IP was recently identified as being causally related to body mass index. The present study aimed to examine the roles of the genetic variation, methylation and gene expression at this locus in adiposity changes in a 2-year weight-loss trial. Participants (n = 692) were genotyped and randomly assigned to 1 of the 4 reduced-calorie diets, DNA methylation was derived from stored blood samples at baseline (n = 48), and adipose tissue gene expression was measured in 96 volunteers. We found significant interactions of fat intake with the genetic (rs11150675) and transcriptional (ILMN_1725441) variations at the NFATC2IP locus on 2-year weight change (Pinteraction < .01). Similarly, cis-DNA methylation at cg26663590 of the NFATC2IP locus showed an opposite impact on weight-loss in response to high-fat vs low-fat diet (effect size, 4.62 vs -1.24 kg). Additionally, baseline methylation at cg26663590 causally mediated 52.8% of the effect of rs11150675 on 2-year weight-loss in the high-fat diet group (P = .01), whereas no such mediation was observed in the low-fat diet group. Our findings suggest potentially causal effects of genetic, epigenetic and transcriptional variations at the NFATC2IP locus on adiposity changes in response to dietary fat intake.

Effects of the interaction between glycated haemoglobin genetic risk score and postpartum weight reduction on glycaemic changes: A gene-weight interaction analysis.

AIM: To investigate the effects of the interaction between glycated haemoglobin (HbA1c) genetic risk score and weight changes during and after pregnancy (postpartum weight reduction and gestational weight gain) on long-term glycaemic changes in the largest cohort of women with a history of gestational diabetes mellitus (GDM). METHODS: This was a retrospective cohort using the baseline data from the Tianjin Gestational Diabetes Mellitus Prevention Programme. A genetic risk score was established by combining 10 HbA1c-related single-nucleotide polymorphisms, which were identified by genome-wide association studies. General linear regression models were applied to evaluate the effect of interaction between HbA1c genetic risk score and weight changes during and after pregnancy (postpartum weight reduction and gestational weight gain) on glycaemic changes. RESULTS: 'A total of 1156 women with a history of GDM were included in this respective cohort study. Statistical differences in pre-pregnancy weight, pre-delivery weight and postpartum weight were evidenced across different groups of postpartum weight reduction. After adjusting for covariates, statistical significance for changes in HbA1c level was only observed in the postpartum weight reduction <5 kg/y group (P = 0.002), and a significant effect of interaction between HbA1c genetic risk score and postpartum weight reduction on long-term changes in HbA1c was evidenced (P interaction = 0.01). In women with postpartum weight reduction ≥8 kg/y, those with a lower HbA1c genetic risk score had a greater decrease in HbA1c level. CONCLUSIONS: HbA1c genetic risk score interacts with postpartum weight reduction to affect long-term changes in HbA1c levels among women with a history of GDM.

Dissection of a circulating and intrahepatic CD4(+)Foxp3(+) T-cell subpopulation in chronic hepatitis B virus (HBV) infection: a highly informative strategy for distinguishing chronic HBV infection states.

BACKGROUND: The definition of CD4(+)Foxp3(+) regulatory T cells (Tregs) is challenging as it relates to chronic hepatitis B virus (HBV) infection. Recently, the heterogeneity of human CD4(+)Foxp3(+) T cells has been confirmed. METHODS: Three circulating CD4(+)Foxp3(+) T-cell subpopulations in chronic HBV patients were identified, and their frequencies associated with clinical parameters were analyzed. Antigen specificity of Tregs was further studied. RESULTS: We found that circulating and intrahepatic CD4(+)CD45RA(-)Foxp3(hi)-activated Tregs (aTregs) were selectively increased in patients with chronic active hepatitis B and acute-on-chronic liver failure (ACLF) but not in asymptomatic carriers. The aTreg frequency was strongly correlated with HBV DNA load but not liver damage. In both peripheral blood mononuclear cells and livers, ACLF patients showed a dramatically elevated frequency of interleukin 17A-secreting CD45RA(-)Foxp3(lo) nonsuppressive T cells (non-Tregs), which were shown to be associated with severe liver damage. Interestingly, an HBV core antigen (HBcAg)-derived peptide could preferentially expand CD4(+)CD25(+)Foxp3(+) T cells and aTregs in HLA-DR9(+) chronic active hepatitis B patients, and these Tregs required ligand-specific reactivation for suppressor function. CONCLUSIONS: The delineation of a CD4(+)Foxp3(+) T-cell subpopulation is a highly informative strategy for distinguishing different chronic HBV infection states. HBcAg-derived peptides may be responsible for activation of Tregs that, in turn, specifically inhibit anti-HBV immune response but not liver inflammation.

Prevalence and Trends in Gestational Diabetes Mellitus Among Women in the United States, 2006-2017: A Population-Based Study.

The prevalence of gestational diabetes mellitus (GDM) has increased with the increasing rate of obesity. However, national data on the prevalence and secular trends of GDM during the past decade in the United States are lacking. This study included 37,357 women aged more than 18 years and who had ever been pregnant from the National Health Interview Survey (NHIS). We examined GDM prevalence in 2006, 2016, and 2017, with age-standardized to the US population in 2000. We found that the prevalence of GDM per 100 people increased from 4.6 (95% CI, 4.1-5.1) in 2006 to 8.2 (95% CI, 7.5-8.9) in 2016 (test for difference; P <0.001), with a relatively increased rate of 78%. Non-Hispanic white women tended to have a lower increase (2.8%) than non-Hispanic black women (3.8%), Hispanic women (4.1%), and women of other race/ethnicity (8.4%). The prevalence of GDM in non-Hispanic white women was higher than that in non-Hispanic black women in 2006 (4.8% vs 3.5%, P = 0.006); such differences became non-significant in 2016 (P = 0.72). Additionally, the increase of GDM from 2006 to 2016 tended to be more evident among women who were overweight (25≤ BMI ≤30 kg/m2), physically inactive, and with family income below the poverty threshold than women in other BMI ranges, with more physical activity, and with higher incomes. The prevalence of GDM per 100 people in 2017 was 8.4 (7.6-9.2), and there was no significant change in the overall and subgroup prevalence compared with 2016. Collectively, in the United States, the prevalence of GDM continuously increased, nearly doubled, from 2006 to 2016, and then leveled off in 2017. The increase appeared more marked among the minority populations and subpopulations with overweight people, insufficient activity, and family incomes below the poverty threshold.

High coercivity Pr2Fe14B magnetic nanoparticles by a mechanochemical method.

Nd2Fe14B nanoparticles are widely used because of their outstanding hard magnetic properties. In fact, Pr2Fe14B has higher magneto-crystalline anisotropy than Nd2Fe14B, which makes Pr-Fe-B a promising magnetic material. However, the chemical synthesis route to Pr2Fe14B nanoparticles is challenging because of the higher reduction potential of Pr3+, as well as the complex annealing conditions. In this work, Pr2Fe14B nanoparticles were successfully synthesized via an efficient and green mechanochemical method consisting of high energy ball milling, annealing, and a washing process. Microstructural investigations revealed that the oxide precursors were uniformly wrapped by CaO and CaH2, which formed an embedded structure after ball milling. Then, Pr2Fe14B powder was synthesized via a time-saving annealing process. The impact of the Pr2O3 content and the preparation conditions was investigated. The coercivity of the as-annealed powder with 100 wt% Pr2O3 excess is 18.9 kOe. After magnetic alignment, the coercivity, remanence, and maximum energy product were: 9.8 kOe, 78.4 emu g-1, and 9.8 MGOe, respectively. The present work provides a promising strategy for preparing anisotropic Pr-Fe-B permanent magnetic materials.

Rational optimization of tumor epitopes using in silico analysis-assisted substitution of TCR contact residues.

Altered peptide ligands with increased affinity of the peptide-MHC complex for the TCR provide an alternative strategy to natural T-cell epitopes for cancer immunotherapy, as they can recruit and stimulate stronger T-cell repertoires. However, it remains unclear how alterations of the TCR contact residues improve the interaction between the peptide-MHC complex and the TCR molecule. In this study, we introduced a molecular simulation strategy to optimize a tumor immunodominant epitope NY-ESO-1(157-165) by the substitution of the potential TCR contact residues. We correlated molecule simulation with T-cell activation capacity assay and detected the effect of modifications of TCR contact residues on T-cell recognition. An agonist peptide W5F with substitution at Trp5 with Phe was identified and it exhibits a stronger ability to induce a cross-reactive CTL response with the WT peptide. Additionally, the W5F-induced CTL could be maintained with the WT peptide and possess higher capacity in lysing native NY-ESO-1-expressing tumor cells. These results provide important insights into the enhanced immunogenicity of epitopes through substitution at the TCR contact sites and revealed a novel molecular simulation approach for rational therapeutic peptide vaccine design.

Fine antigenic variation within H5N1 influenza virus hemagglutinin's antigenic sites defined by yeast cell surface display.

Fifteen strains of mAb specific for HA of the A/Hong Kong/482/97 (H5N1) influenza virus were generated. The HA antigenic sites of the human A/Hong Kong/482/97 (H5N1) influenza virus were defined by using yeast cell surface-displaying system and anti-H5 HA mAb. Evolution analysis of H5 HA identified residues that exhibit diversifying selection in the antigenic sites and demonstrated surprising differences between residue variation of H5 HA and H3 HA. A conserved neutralizing epitope in the H5 HA protein recognized by mAb H5M9 was found using viruses isolated from 1997-2006. Seven single amino acid substitutions were introduced into the HA antigenic sites, respectively, and the alteration of antigenicity was assessed. The structure obtained by homology-modeling and molecular dynamic methods showed that a subtle substitution at residue 124 propagates throughout its nearby loop (152-159). We discuss how the structural changes caused by point mutation might explain the altered antigenicity of the HA protein. The results demonstrate the existence of immunodominant positions in the H5 HA protein, alteration of these residues might improve the immunogenicity of vaccine strains.

Next-generation pathogen diagnosis with CRISPR/Cas-based detection methods.

Ideal methods for detecting pathogens should be sensitive, specific, rapid, cost-effective and instrument-free. Conventional nucleic acid pathogen detection strategies, mostly PCR-based techniques, have various limitations, such as expensive equipment, reagents and skilled performance. Recently, CRISPR/Cas-based methods have burst onto the scene, with the potential to power the pathogen detection field. Here we introduce these unique methods and discuss its hurdles and promises.

Identification and modification of an HLA-A*0201-restricted cytotoxic T lymphocyte epitope from Ran antigen.

Ran is considered to be a promising target for tumor-specific immunotherapy because its protein is exclusively expressed in tumor tissues, though its mRNA can be expressed in most normal tissues. In our study, we obtained four candidate wild-type epitopes designated Ran1, Ran2, Ran3, and Ran4, derived from the Ran antigen with the highest predicted affinity with MHC-I, indicated by affinity prediction plots and molecular dynamics simulation. However, in vitro affinity assays of these epitopes showed only a moderate affinity with MHC-I. Thus, we designed altered peptide ligands (APLs) derived from Ran wild-type epitopes with preferred primary and auxiliary HLA-A*0201 molecule anchor residue replacement. Of the eight tested peptides, the 1Y analog had the strongest binding-affinity and lowest-dissociation rate to HLA-A*0201. Additionally, we investigated the CTLs activities induced by Ran wild-type peptides and the APLs in human PBMCs and in HLA-A*0201/K(b) transgenic mice. Ran1 1Y was superior to other APLs and wild-type peptides in eliciting epitope-specific CTL immune responses both in vitro and in vivo. In summary, a wild-type epitope of the tumor-specific antigen Ran, expressed broadly in many tumors, was identified and designated Ran1. An APL of Ran1, Ran1 1Y, was further designed and verified in vitro and in vivo and found to elicit a stronger Ran-specific CTL response, indicating a potential anti-tumor application in the future.

A novel dominant B-cell epitope of FSHR identified by molecular docking induced specific immune response and suppressed fertility.

The follicle stimulating hormone (FSH) is of great importance in reproduction modulation of both sexes. The extracellular domain (ECD) of its receptor (FSHR) is crucial for FSH binding and subsequent signal transduction; therefore, it is the potential target for fertility control. To avoid unwanted side-effect when used as immunocontraceptive agent, the ECD was analysed by online prediction combined with molecular docking to identify the candidate B-cell epitopes. Four potential B-cell epitopes were identified and synthesised in tandem with Pan DR epitope. Then the epitope-based peptides were used to boost adult male mice following rhFSHR protein priming, thus to determine their immune responses and fertility inhibition capacity. Three of the four peptides showed suppressed fertility accompanied with small testis and lower serum testosterone level, which was consistent with absolutely lower sperm quantity and poor quality. Among the four epitope peptides, Pep2 displayed the lowest fertility rate of 26.67%, which was similar to that of rhFSHR homologously prime/boost mice (23.30 and 25.00%). Thus, we identified a novel immunodominant B-cell epitope by molecular docking and protein prime/peptide boost strategy.

A novel mimovirus vaccine containing survivin epitope with adjuvant IL-15 induces long-lasting cellular immunity and high antitumor efficiency.

Numerous evidences have indicated that CD8+ cytotoxic T lymphocytes (CTLs) played a significant role in protecting host against tumors, thus CTLs have been involved as potentially relevant candidate targets of cancer immunotherapy. Moreover it is crucial to fully elucidate antigen-specific CTL response, especially high-avidity and long-lasting CTL response in vivo. In the present study, we reported a novel tumor vaccine (mimovirus), a viron-size particulate which consisted of a cell-penetrating peptide of Tat(49-57), a CTL epitope peptide survivin(85-93) and a plasmid encoding murine interleukin-15 (IL-15). We demonstrated that this tumor vaccine could effectively mediate the expression of the gene and presentation of the tumor antigen derived peptide ex vivo. Furthermore, the tumor vaccine supported a robust memory CTL-mediated long-term immunity in vivo, which could effectively protect BALB/c mice against fatal CT26 tumor challenge and improve their survival. These findings suggest that the tumor vaccine may provide an alternative therapeutic strategy for cancer patients.

[The relationship between CD4+ CD25+ regulatory T cell in the peripheral blood and poor or nonresponsiveness to hepatitis B vaccine].

OBJECTIVE: To investigate CD4+ CD25+ regulatory T cell frequencies in the peripheral blood of poor or non-responsiveness to Hepatitis B vaccine, and try to understand the relationship between CD4+ CD25+ regulatory T cell and poor or non-responsiveness to Hepatitis B vaccine. METHODS: Flow cytometric analysis was employed for CD4+ CD25+ regulatory T cell frequencies in the peripheral blood of 25 cases of non-responsiveness, 30 cases of poor-responsiveness, and collected 20 cases of responsiveness as control. RESULTS: CD4+ CD25+ regulatory T cell frequencies of responsiveness was (4.32 +/- 1.21)%, poor-responsiveness was (7.01 +/- 1.06)% and non-responsiveness was (12.75 +/- 2.01)%. It was found that non and poor-responsiveness showed a high percentage of CD4+ CD25+ regulatory T cell as compared with responsiveness (t = 8.426, t = 3.289, P<0.01). CONCLUSION: The poor and non-responsiveness should be related with the increase of CD4+ CD25+ regulatory T cell and this might be considered as an important cause of poor and non-responsiveness.

Lifestyle intervention modifies the effect of the MC4R genotype on changes in insulin resistance among women with prior gestational diabetes: Tianjin Gestational Diabetes Mellitus Prevention Program.

BACKGROUND: A history of gestational diabetes mellitus (GDM) has been related to an elevated risk of type 2 diabetes. The melanocortin-4 receptor (MC4R) genotype has been related to glycemic changes in women with prior GDM. OBJECTIVE: The objective of this study was to analyze whether lifestyle intervention modified the association between the MC4R genotype and changes in insulin sensitivity among women with prior GDM. METHODS: We genotyped MC4R rs6567160 and measured glucose and insulin in fasting plasma samples at baseline and during the first 2 follow-up visits in 1128 women with prior GDM. They were randomly assigned to either a 4-y lifestyle intervention involving both diet and physical activity or a control group from a randomized clinical trial, the Tianjin Gestational Diabetes Mellitus Prevention Program. We analyzed the interaction between the MC4R genotype and lifestyle intervention on changes in insulin resistance. RESULTS: From baseline to 1.28 y, the MC4R genotype was related to changes in fasting insulin, HOMA-IR, and homeostasis model assessment of ß cell function (HOMA-B) in the intervention group. Each risk allele (C) of rs6567160 was associated with a 0.08-unit greater decrease in log(insulin), log(HOMA-IR), and log(HOMA-B) (P = 0.02, 0.04, and 0.04, respectively), whereas in the control group, each C allele tended to be associated with a greater increase in HOMA-IR (P = 0.09). We found significant interactions between the MC4R genotype and lifestyle intervention on 1.28-y changes in fasting insulin and HOMA-IR (P = 0.006 and 0.008, respectively), and such interaction remained significant when we analyzed the trajectory of changes in insulin and HOMA-IR from baseline to 2.55 y (both P = 0.03). CONCLUSIONS: The exploratory results from the first 2 follow-up visits indicate that women with prior GDM carrying a diabetes-increasing MC4R genotype (CC or TC) may obtain better improvement than the TT genotype in insulin resistance through lifestyle intervention. This trial was registered at clinicaltrials.gov as NCT01554358.

Genetically determined vitamin D levels and change in bone density during a weight-loss diet intervention: the Preventing Overweight Using Novel Dietary Strategies (POUNDS Lost) Trial.

Background: Obesity is closely associated with bone health. Although diet and weight loss produce many metabolic benefits, studies of weight loss diets on bone health are conflicting. Genetic variations, such as vitamin D levels, may partly account for these conflicting observations by regulating bone metabolism. Objective: We investigated whether the genetic variation associated with vitamin D concentration affected changes in bone mineral density (BMD) in response to a weight-loss diet intervention. Design: In the 2-y Preventing Overweight Using Novel Dietary Strategies (POUNDS Lost) trial, BMD was measured for 424 participants who were randomly assigned to 1 of 4 diets varying in macronutrient intakes. A genetic risk score (GRS) was calculated based on 3 genetic variants [i.e., 7-dehydrocholesterol reductase (DHCR7) rs12785878, cytochrome P450 2R1 (CYP2R1) rs10741657 and group-specific component globulin (GC) rs2282679] related to circulating vitamin D levels. A dual-energy X-ray absorptiometry scan was performed to assess changes in whole-body BMD over 2 y. The final analysis included 370 participants at baseline. Results: We found a significant interaction between dietary fat intake and vitamin D GRS on 2-y changes in whole-body BMD (P-interaction = 0.02). In the high-fat diet group, participants with higher GRS showed significantly less reduction in whole-body BMD than those with lower GRS, whereas the genetic associations were not significant in the low-fat diet group. We also found a significant interaction between dietary fat intake and the GRS on 6-mo change in femur neck BMD (P-interaction = 0.02); however, the interaction became nonsignificant at 2 y. Conclusion: Our data indicate that dietary fat intake may modify the effect of vitamin D-related genetic variation on changes in BMD. Overweight or obese patients predisposed to sufficient vitamin D may benefit more in maintaining BMD along with weight loss by eating a low-fat diet. This trial was registered at clinicaltrials.gov as NCT03258203.