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Dilated cardiomyopathy (DCM) is a disease of the heart muscle that affects both humans and dogs. Certain canine diets have been associated with DCM, but the diet-disease link is unexplained, and novel methods are needed to elucidate mechanisms. We conducted metabolomic profiling of 9 diets associated with canine DCM, containing ≥ 3 pulses, potatoes, or sweet potatoes as main ingredients, and in the top 16 dog diet brands most frequently associated with canine DCM cases reported to the FDA (3P/FDA diets), and 9 non-3P/FDA diets. We identified 88 named biochemical compounds that were higher in 3P/FDA diets and 23 named compounds that were lower in 3P/FDA diets. Amino acids, amino acid-derived compounds, and xenobiotics/plant compounds were the largest categories of biochemicals that were higher in 3P/FDA diets. Random forest analyses identified the top 30 compounds that distinguished the two diet groups with 100% predictive accuracy. Four diet ingredients distinguished the two diet groups (peas, lentils, chicken/turkey, and rice). Of these ingredients, peas showed the greatest association with higher concentrations of compounds in 3P/FDA diets. Moreover, the current foodomics analyses highlight relationships between diet and DCM in dogs that can identify possible etiologies for understanding diet-disease relationships in dogs and humans.

Royal jelly (RJ) from honeybee has been widely used as a health promotion supplement. The major royal jelly proteins (MRJPs) have been identified as the functional component of RJ. However, the question of whether MRJPs have anti-senescence activity for human cells remains. Human embryonic lung fibroblast (HFL-I) cells were cultured in media containing no MRJPs (A), MRJPs at 0.1 mg/ml (B), 0.2 mg/ml (C), or 0.3 mg/ml (D), or bovine serum albumin (BSA) at 0.2 mg/ml (E). The mean population doubling levels of cells in media B, C, D, and E were increased by 12.4%, 31.2%, 24.0%, and 10.4%, respectively, compared with that in medium A. The cells in medium C also exhibited the highest relative proliferation activity, the lowest senescence, and the longest telomeres. Moreover, MRJPs up-regulated the expression of superoxide dismutase-1 (SOD1) and down-regulated the expression of mammalian target of rapamycin (MTOR), catenin beta like-1 (CTNNB1), and tumor protein p53 (TP53). Raman spectra analysis showed that there were two unique bands related to DNA synthesis materials, amide carbonyl group vibrations and aromatic hydrogens. These results suggest that MRJPs possess anti-senescence activity for the HFL-I cell line, and provide new knowledge illustrating the molecular mechanism of MRJPs as anti-senescence factors.

Harsh climate induces physiological stress thus compromising organismal survival. Our previous studies demonstrated that curcumin (CUR) supplementation increased survival of turtle under heat stress (HS). Here, we span this work to investigate the survival and lifespan of HS Drosophila fed a diet supplemented with CUR. For this purpose, female and male flies were fed basal diet (N) and CUR diet (0.2 mg/g), and exposed to three conditions: 25°C and 29°C continuously, and 34 °C for 2 h at days 1, 4, and 7, then kept at 25 °C. Lifespan analysis showed that, compared to N-25 °C flies, the mean lifespans of N-29 °C and N-34 °C flies were decreased significantly by 8.5-15.7% in males, and 3.7-7.9% in females. Conversely, in the CUR-supplemented diet, mean lifespans of C-29 °C and C-34 °C flies were significantly extended by 8.7-16.4% in males, and by 8.9-12.8% in females, compared to that of temperature-matched flies fed basal diets. The MDA levels of C-34 °C flies were significantly lower than those of N-34 °C flies, indicating CUR reduced oxidative stress caused by HS. Furthermore, CUR palliated the increased oxidative stress caused by HS, by increasing the expression of SOD1, CAT, and PHGPx and decreasing the expression of Hsp70 and Hsp83. Our results indicated that CUR supplementation increases the survival rate of Drosophila by enhancing thermal tolerance. © 2018 BioFactors, 44(6):577-587, 2018.

Background Copy number variation (CNV) in the salivary amylase gene (AMY1) modulates salivary α-amylase levels and is associated with postprandial glycemic traits. Whether AMY1-CNV plays a role in age-mediated change in insulin resistance (IR) is uncertain. Methods We measured AMY1-CNV using duplex quantitative real-time polymerase chain reaction in two studies, the Boston Puerto Rican Health Study (BPRHS, n = 749) and the Genetics of Lipid-Lowering Drug and Diet Network study (GOLDN, n = 980), and plasma metabolomic profiles in the BPRHS. We examined the interaction between AMY1-CNV and age by assessing the relationship between age with glycemic traits and type 2 diabetes (T2D) according to high or low copy numbers of the AMY1 gene. Furthermore, we investigated associations between metabolites and interacting effects of AMY1-CNV and age on T2D risk. Results We found positive associations of IR with age among subjects with low AMY1-copy-numbers in both studies. T2D was marginally correlated with age in participants with low AMY1-copy-numbers but not with high AMY1-copy-numbers in the BPRHS. Metabolic pathway enrichment analysis identified the pentose metabolic pathway based on metabolites that were associated with both IR and the interactions between AMY1-CNV and age. Moreover, in older participants, high AMY1-copy-numbers tended to be associated with lower levels of ribonic acid, erythronic acid, and arabinonic acid, all of which were positively associated with IR. Conclusions We found evidence supporting a role of AMY1-CNV in modifying the relationship between age and IR. Individuals with low AMY1-copy-numbers tend to have increased IR with advancing age.

Cycadales is an extant group of seed plants occurring in subtropical and tropical regions comprising putatively three families and 10 genera. At least one complete plastid genome sequence has been reported for all of the 10 genera except Microcycas, making it an ideal plant group to conduct comprehensive plastome comparisons at the genus level. This article reports for the first time the plastid genome of Microcycas calocoma. The plastid genome has a length of 165,688 bp with 134 annotated genes including 86 protein-coding genes, 47 non-coding RNA genes (39 tRNA and eight rRNA) and one pseudogene. Using global sequence variation analysis, the results showed that all cycad genomes share highly similar genomic profiles indicating significant slow evolution and little variation. However, identity matrices coinciding with the inverted repeat regions showed fewer similarities indicating that higher polymorphic events occur at those sites. Conserved non-coding regions also appear to be more divergent whereas variations in the exons were less discernible indicating that the latter comprises more conserved sequences. Phylogenetic analysis using 81 concatenated protein-coding genes of chloroplast (cp) genomes, obtained using maximum likelihood and Bayesian inference with high support values (>70% ML and = 1.0 BPP), confirms that Microcycas is closest to Zamia and forms a monophyletic clade with Ceratozamia and Stangeria. While Stangeria joined the Neotropical cycads Ceratozamia, Zamia and Microcyas, Bowenia grouped with the Southern Hemisphere cycads Encephalartos, Lepidozamia and Macrozamia. All Cycas species formed a distinct clade separated from the other genera. Dioon, on the other hand, was outlying from the rest of Zamiaceae encompassing two major clades—the Southern Hemisphere cycads and the Neotropical cycads. Analysis of the whole cp genomes in phylogeny also supports that the previously recognized family—Stangeriaceae—which contained Bowenia and Stangeria, is not monophyletic. Thus, the cp genome topology obtained in our study is congruent with other molecular phylogenies recognizing only a two-family classification (Cycadaceae and Zamiaceae) within extant Cycadales.

We recently reported that epicatechin, a bioactive compound that occurs naturally in various common foods, promoted general health and survival of obese diabetic mice. It remains to be determined whether epicatechin extends health span and delays the process of aging. In the present study, epicatechin or its analogue epigallocatechin gallate (EGCG) (0.25% w/v in drinking water) was administered to 20-mo-old male C57BL mice fed a standard chow. The goal was to determine the antiaging effect. The results showed that supplementation with epicatechin for 37 wk strikingly increased the survival rate from 39 to 69%, whereas EGCG had no significant effect. Consistently, epicatechin improved physical activity, delayed degeneration of skeletal muscle (quadriceps), and shifted the profiles of the serum metabolites and skeletal muscle general mRNA expressions in aging mice toward the profiles observed in young mice. In particular, we found that dietary epicatechin significantly reversed age-altered mRNA and protein expressions of extracellular matrix and peroxisome proliferator-activated receptor pathways in skeletal muscle, and reversed the age-induced declines of the nicotinate and nicotinamide pathway both in serum and skeletal muscle. The present study provides evidence that epicatechin supplementation can exert an antiaging effect, including an increase in survival, an attenuation of the aging-related deterioration of skeletal muscles, and a protection against the aging-related decline in nicotinate and nicotinamide metabolism.-Si, H., Wang, X., Zhang, L., Parnell, L. D., Admed, B., LeRoith, T., Ansah, T.-A., Zhang, L., Li, J., Ordovás, J. M., Si, H., Liu, D., Lai, C.-Q. Dietary epicatechin improves survival and delays skeletal muscle degeneration in aged mice.

The present paper reports for the first time the characteristics of the complete plastid genome of Surianaceae (Suriana maritima L.) in the order Fabales. The circular complete plastid genome is 163,747 bp in length with a typical quadripartite organization containing 115 unique genes, of which 80 are protein-coding genes, 31 tRNA genes and four rRNA genes. The plastid genome of S. maritima is characterized by absence of intron in the atpF gene, which has never been reported for any other species of the Fabales. The gene content and their orders in the plastid genome of Surianaceae are similar to the basal lineages of the legume family (Cercidoideae, Detarioideae) and Quillajaceae, supporting a likely common ancestor for the three families. Phylogenetic analysis supported the sister relationship between Surianaceae and Leguminosae, with strongly supported by Bayesian method and moderately supported by likelihood method. The complete plastid genome of Surianaceae could provide potential benefit in resolving the long-standing unresolved interfamily relationships of Fabales when a more comprehensive sampling from Polygalaceae and Leguminosae is available for future studies.

BACKGROUND: The putative functional variant −265T>C (rs5082) within the APOA2 promoter has shown consistent interactions with saturated fatty acid (SFA) intake to influence the risk of obesity. OBJECTIVE: The aim of this study was to implement an integrative approach to characterize the molecular basis of this interaction. DESIGN: We conducted an epigenome-wide scan on 80 participants carrying either the rs5082 CC or TT genotypes and consuming either a low-SFA (C genotype, promoting an APOA2 expression difference between APOA2 genotypes on a high-SFA diet, and modulating BCAA and tryptophan metabolic pathways. These findings identify potential mechanisms by which this highly reproducible gene-diet interaction influences obesity risk, and contribute new insights to ongoing investigations of the relation between SFA and human health. This study was registered at clinicaltrials.gov as NCT03452787.

Background: Modulation of genetic variants on the effect of omega-3 fatty acid supplements on blood lipids is still unclear. Methods: In a double-blind randomized controlled trial, 150 patients with type 2 diabetes (T2D) were randomized into omega-3 fatty acid group (n = 56 for fish oil and 44 for flaxseed oil) and control group (n = 50) for 180 days. All patients were genotyped for genetic variants at CD36 (rs1527483), NOS3 (rs1799983) and PPARG (rs1801282). Linear regression was used to examine the interaction between omega-3 fatty acid intervention and CD36, NOS3 or PPARG variants for blood lipids. Findings: Significant interaction with omega-3 fatty acid supplements was observed for CD36 on triglycerides (p-interaction = 0.042) and PPAGR on low-density lipoprotein-cholesterol (p-interaction = 0.02). We also found a significant interaction between change in erythrocyte phospholipid omega-3 fatty acid composition and NOS3 genotype on triglycerides (p-interaction = 0.042), total cholesterol (p-interaction = 0.013) and ratio of total cholesterol to high-density lipoprotein cholesterol (p-interaction = 0.015). The T2D patients of CD36-G allele, PPARG-G allele and NOS3-A allele tended to respond better to omega-3 fatty acids in improving lipid profiles. The interaction results of the omega-3 fatty acid group were mainly attributed to the fish oil supplements. Interpretation: This study suggests that T2D patients with different genotypes at CD36, NOS3 and PPARG respond differentially to intervention of omega-3 supplements in blood lipid profiles. Keywords: Diabetes, Genetic variants, Interaction, Omega-3 fatty acids, Randomized controlled trial

Delonix regia, a plant species of the legume family native to Madagascar, has been widely cultivated in the tropical and subtropical regions as an ornamental tree due to its remarkable showy orange-red flowers over summer. Here we report for the first time the complete plastid genome of this species, which has a typical circular structure with a total length of 162,756 bp and contains two inverted repeat regions (IRs, 25,544 bp), a large single copy region (LSC, 92,490 bp), and a small single copy region (SSC, 19,178 bp). The phylogenetic analysis based on the complete plastome sequences of this species and those of the related species from GenBank strongly suggested that D. regia is nested in the subfamily Caesalpinioideae and is sister to a clade consisting of Erythrophlium fordii and the old-sense Mimosoideae.

Postprandial lipemia (PPL), the increased plasma TG concentration after consuming a high-fat meal, is an independent risk factor for CVD. Individual responses to a meal high in fat vary greatly, depending on genetic and lifestyle factors. However, only a few loci have been associated with TG-PPL response. Heritable epigenomic changes may be significant contributors to the unexplained inter-individual PPL variability. We conducted an epigenome-wide association study on 979 subjects with DNA methylation measured from CD4+ T cells, who were challenged with a high-fat meal as a part of the Genetics of Lipid Lowering Drugs and Diet Network study. Eight methylation sites encompassing five genes, LPP, CPT1A, APOA5, SREBF1, and ABCG1, were significantly associated with PPL response at an epigenome-wide level (P < 1.1 × 10−7), but no methylation site reached epigenome-wide significance after adjusting for baseline TG levels. Higher methylation at LPP, APOA5, SREBF1, and ABCG1, and lower methylation at CPT1A methylation were correlated with an increased TG-PPL response. These PPL-associated methylation sites, also correlated with fasting TG, account for a substantially greater amount of phenotypic variance (14.9%) in PPL and fasting TG (16.3%) when compared with the genetic contribution of loci identified by our previous genome-wide association study (4.5%). In summary, the epigenome is a large contributor to the variation in PPL, and this has the potential to be used to modulate PPL and reduce CVD.

The impact of nutrition on the metabolic profile of osteoporosis is incompletely characterized. The objective of this cross-sectional study was to detangle the association of fruit and vegetable (FV) intakes with osteoporosis prevalence. Dietary, anthropometric and blood plasma metabolite data were examined from the Boston Puerto Rican Osteoporosis Study, a cohort of 600 individuals (age 46-79yr). High FV intake was protective against osteoporosis prevalence. Associations of 525 plasma metabolites were assessed with fruit and vegetable intake, and separately with osteoporosis status. Several biological processes affiliated with the FV-associating metabolites, including caffeine metabolism, carnitines and fatty acids, and glycerophospholipids. For osteoporosis-associated metabolites, important processes were steroid hormone biosynthesis in women, and branched-chain amino acid metabolism in men. In all instances, the metabolite patterns differed greatly between sexes, arguing for a stratified nutrition approach in recommending FV intakes to improve bone health. Factors derived from principal components analysis of the FV intakes were correlated with the osteoporosis-associated metabolites, with high intake of dark leafy greens and berries/melons appearing protective in both sexes. These data warrant investigation into whether increasing intakes of dark leafy greens, berries and melons causally affect bone turnover and BMD among adults at risk for osteoporosis via sex-specific metabolic pathways, and how gene-diet interactions alter these sex-specific metabolomic-osteoporosis links.

Epicatechin (EC), a flavonoid present in various foods including cocoa, dark chocolate, berries, and tea, has recently been reported to promote general health and survival of old mice fed a standard chow diet. This is considered a novel discovery in the field of identifying natural compounds to extend lifespan, given that presumably popular anti-aging natural agents including resveratrol, green tea extract, and curcumin had failed in extending the lifespan of standard chow-diet-fed mice. However, the anti-aging mechanism of EC is not fully understood, thus impeding the potential application of this natural compound in improving a healthy lifespan in humans. In this review, we first summarized the main dietary sources that contain a significant amount of EC and recent research regarding the absorption, metabolism and distribution of EC in humans and rodents. The review is then focused on the anti-aging effects of EC in cultured cells, animals and humans with the possible physiological, cellular and molecular mechanisms underlying its lifespan-extending effects.

Background The impact of nutrition on the metabolic profile of osteoporosis (OS) is unknown. Objective Identify biochemical factors driving the association of fruit and vegetable (FV) intakes with OS prevalence using an untargeted metabolomics approach. Design Cross-sectional dietary, anthropometric and plasma metabolite data were examined from the Boston Puerto Rican Osteoporosis Study, n = 600 (46–79 yr). Methods Bone mineral density was assessed by DXA. OS was defined by clinical standards. A culturally adapted FFQ assessed usual dietary intake. Principal components analysis (PCA) of 42 FV items created 6 factors. Metabolomic profiles derived from plasma samples were assessed on a commercial platform. Differences in levels of 525 plasma metabolites between disease groups (OS vs no-OS) were compared using logistic regression; and associations with FV intakes by multivariable linear regression, adjusted for covariates. Metabolites significantly associated with OS status or with total FV intake were analyzed for enrichment in various biological pathways using Mbrole 2.0, MetaboAnalyst, and Reactome, using FDR correction of P-values. Correlation coefficients were calculated as Spearman's rho rank correlations, followed by hierarchical clustering of the resulting correlation coefficients using PCA FV factors and sex-specific sets of OS-associated metabolites. Results High FV intake was inversely related to OS prevalence (Odds Ratio = 0.73; 95% CI = 0.57, 0.94; P = 0.01). Several biological processes affiliated with the FV-associating metabolites, including caffeine metabolism, carnitines and fatty acids, and glycerophospholipids. Important processes identified with OS-associated metabolites were steroid hormone biosynthesis in women and branched-chain amino acid metabolism in men. Factors derived from PCA were correlated with the OS-associated metabolites, with high intake of dark leafy greens and berries/melons appearing protective in both sexes. Conclusions These data warrant investigation into whether increasing intakes of dark leafy greens, berries and melons causally affect bone turnover and BMD among middle-aged and older adults at risk for osteoporosis via sex-specific metabolic pathways, and how gene-diet interactions alter these sex-specific metabolomic-osteoporosis links. ClinicalTrials.gov Identifier: NCT01231958 .

BACKGROUND S100 calcium-binding protein A9 (S100A9) has previously been identified as a type 2 diabetes (T2D) gene. However, this finding requires independent validation and more in-depth analyses in other populations and ancestries. OBJECTIVES We aimed to replicate the associations between an S100A9 variant and insulin resistance and T2D and to initiate an investigation of potential interactions with the habitual diet in several independent populations. DESIGN We investigated the association of the S100A9 variant rs3014866 with insulin resistance and T2D risk and its interactions with diet in 3 diverse populations as follows: the CORDIOPREV (Coronary Diet Intervention with Olive Oil and Cardiovascular Prevention; n = 711), which consisted of Spanish white adults; the GOLDN (Genetics of Lipids Lowering Drugs and Diet Network; n = 818), which involved North American non-Hispanic white adults; and Hispanic adults who participated in the BPRHS (Boston Puerto Rican Health Study; n = 1155). RESULTS Meta-analysis indicated that T carriers presented a lower risk of T2D than CC carriers (pooled OR: 0.714; 95% CI: 0.584, 0.845; P = 0.002). In all 3 populations (CORDIOPREV, GOLDN, and BPRHS), we showed a significant interaction between the rs3014866 single nucleotide polymorphism and dietary SFA:carbohydrate ratio intake for the homeostasis model assessment of insulin resistance (HOMA-IR) (P = 0.028, P = 0.017, and P = 0.026, respectively). CC carriers had a significantly higher HOMA-IR only when SFA:carbohydrate intake was high (P = 0.045 for the CORDIOPREV, P = 0.033 for the GOLDN, and P = 0.046 for the BPRHS) but not when SFA:carbohydrate ratio intake was low. CONCLUSIONS The minor allele (T) of the S100A9 variant rs3014866 is associated with lower T2D risk in 3 populations of different ancestries. Note that individuals with the high-risk CC genotype may be more likely to benefit from a low SFA:carbohydrate ratio intake to improve insulin resistance as evaluated with the use of the HOMA-IR. These trials were registered at clinicaltrials.gov as NCT00924937 (CORDIOPREV), NCT00083369 (GOLDN), and NCT01231958 (BPRHS).

The major royal-jelly proteins (MRJPs) are the main constituents responsible for the specific physiological role of royal jelly (RJ) in honeybees. Male and female Drosophila flies were fed diets containing either no MRJPs (A) or casein (B) at 1.25% (w/w) of diet or MRJPs at 1.25% (C), 2.50% (D), or 5.00% (E). Diets B, C, D, and E increased mean lifespan by 4.3%, 9.0%, 12.4%, and 13.9% in males and by 5.8%, 9.7%, 20.0%, and 11.8% in females in comparison to results from diet A, respectively. The diet supplemented with 2.50% MRJPs seems to have the optimal dose to improve both physiological and biochemical measures related to aging in both sexes. Interestingly, lifespan extension by MRJPs in Drosophila was positively associated with feeding and fecundity and up-regulation of copper and zinc-superoxide dismutase (CuZn-SOD) and the Egfr-mediated signaling pathway. This study provides strong evidence that MRJPs are important components of RJ for prolonging lifespan in Drosophila.

Background: Folate status has been positively associated with cognitive function in many studies; however, some studies have observed associations of poor cognitive outcomes with high folate. In search of an explanation, we hypothesized that the association of folate with cognition would be modified by the interaction of high-folate status with a common 19-bp deletion polymorphism in the dihydrofolate reductase (DHFR) gene. To our knowledge, the cognitive effects of this gene have not been studied previously. Objective: We examined the association between cognitive outcomes with the 19-bp deletion DHFR polymorphism, folate status, and their interaction with high or normal plasma folate. Design: This was a pooled cross-sectional study of the following 2 Boston-based cohorts of community living adults: the Boston Puerto Rican Health Study and the Nutrition, Aging, and Memory in Elders study. Individuals were genotyped for the DHFR 19-bp deletion genotype, and plasma folate status was determined. Cognitive outcomes included the Mini-Mental State Examination, Center for Epidemiologic Studies Depression Scale, and factor scores for the domains of memory, executive function, and attention from a set of cognitive tests. Results: The prevalence of the homozygous deletion (del/del) genotype was 23%. In a multivariable analysis, high folate status (>17.8 ng/mL) was associated with better memory scores than was normal-folate status (fourth–fifth quintiles compared with first–third quintiles: β ± SE = −0.22 ± 0.06, P < 0.01). Carriers of the DHFR del/del genotype had worse memory scores (β ± SE = −0.24 ± 0.10, P < 0.05) and worse executive scores (β = −0.19, P < 0.05) than did those with the del/ins and ins/ins genotypes. Finally, we observed an interaction such that carriers of the del/del genotype with high folate had significantly worse memory scores than those of both noncarriers with high-folate and del/del carriers with normal-folate (β-interaction = 0.26 ± 0.13, P < 0.05). Conclusions: This study identifies a putative gene-nutrient interaction that, if confirmed, would predict that a sizable minority carrying the del/del genotype might not benefit from high-folate status and could see a worsening of memory. An understanding of how genetic variation affects responses to high-folate exposure will help weigh risks and benefits of folate supplementation for individuals and public health.

Turmeric residue (TR), containing residual levels of curcumin, is a solid by-product waste generated after the extraction and separation of curcumin from turmeric root. A feeding trial was conducted to evaluate the effects of TR on the survival of Chinese soft-shelled turtles (SSTs), Pelodiscus sinensis, under a high ambient temperature. A total of 320 female SSTs were assigned randomly to two diets: basal diet (the control group, n=160) and an interventional diet supplemented with 10% TR (the TR group, n=160). Our results demonstrated that supplementation of TR increased the SST survival rate by 135.5%, and superoxide dismutase (SOD) activity of SST liver by 112.8%, and decreased the malondialdehyde (MDA) content of SST liver by 36.4%, compared to the control group. The skin of the SST fed TR showed a golden color. High-performance liquid chromatography (HPLC) analysis indicated that the concentrations of curcumin in TR and the skin of the SST fed TR were (1.69±0.30) and (0.14±0.03) μg/g, respectively. Our observation suggests that supplementation of TR increased the survival rate of SST under high ambient temperatures. We speculated that the increased survival rate and tolerance at the high ambient temperature were associated with the anti-oxidation activity of curcumin from TR. Moreover, curcumin in TR could be deposited in SST skin, which made it more favored in the market of China. Our findings provide new knowledge and evidence to effectively reuse TR as a feed additive in animal and aquatic farming.

Context Vitamin D inadequacy is common in the adult population of the United States. Although the genetic determinants underlying vitamin D inadequacy have been studied in people of European ancestry, less is known about populations with Hispanic or African ancestry. Objective The Trans-Ethnic Evaluation of Vitamin D (TRANSCEN-D) genomewide association study (GWAS) consortium was assembled to replicate genetic associations with 25-hydroxyvitamin D [25(OH)D] concentrations from the Study of Underlying Genetic Determinants of Vitamin D and Highly Related Traits (SUNLIGHT) meta-analyses of European ancestry and to identify genetic variants related to vitamin D concentrations in African and Hispanic ancestries. Design Ancestry-specific (Hispanic and African) and transethnic (Hispanic, African, and European) meta-analyses were performed with Meta-Analysis Helper software (METAL). Patients or Other Participants In total, 8541 African American and 3485 Hispanic American (from North America) participants from 12 cohorts and 16,124 European participants from SUNLIGHT were included in the study. Main Outcome Measures Blood concentrations of 25(OH)D were measured for all participants. Results Ancestry-specific analyses in African and Hispanic Americans replicated single nucleotide polymorphisms (SNPs) in GC (2 and 4 SNPs, respectively). An SNP (rs79666294) near the KIF4B gene was identified in the African American cohort. Transethnic evaluation replicated GC and DHCR7 region SNPs. Additionally, the transethnic analyses revealed SNPs rs719700 and rs1410656 near the ANO6/ARID2 and HTR2A genes, respectively. Conclusions Ancestry-specific and transethnic GWASs of 25(OH)D confirmed findings in GC and DHCR7 for African and Hispanic American samples and revealed findings near KIF4B, ANO6/ARID2, and HTR2A. The biological mechanisms that link these regions with 25(OH)D metabolism warrant further investigation.

Bauhinia × blakeana Dunn, or the Hong Kong Orchid Tree, is a popular ornamental plant in the tropical and subtropical regions. In this study, we report and characterise the complete plastid genome of B. × blakeana in an effort to provide genomic resources for genetic utilization. The complete plastome is 156,100 bp in length and contains the typical quadripartite structure, including two inverted repeat (IR) regions of 25,847 bp, a large single-copy (LSC) region of 86,484 bp and a small single-copy (SSC) region of 17,922 bp. 126 genes are annotated, including 81 protein-coding genes, 37 transfer RNA genes, and eight ribosomal RNA genes. The phylogenetic analysis based on the plastomes from B. × blakeana and 11 previously reported species of Cercidoideae suggested a sister-relationship between B. × blakeana and B. acuminata L. with strong bootstrap support.

Zenia insignis Chun is a rare and threatened species of the monotypic genus Zenia Chun in the subfamily Dialioideae of Leguminosae. The complete plastid genome of Zenia insignis was sequenc...

Blood lipids are associated with cardiovascular disease (CVD) risk. Moreover, circulating lipid and fatty acid levels vary between men and women, and evidence demonstrates these traits may be influenced by single nucleotide polymorphisms (SNP). Sex-genotype interactions related to blood lipids and fatty acids have been poorly investigated and may help elucidate sex differences in CVD risk. The goal of this study was to investigate if the influence of SNPs previously associated with blood lipids and fatty acids varies in a sex-specific manner. Lipids and fatty acids were measured in serum and red blood cells (RBC), respectively, in 94 adults (18–30 years) from the GONE FISHIN’ cohort and 118 age-matched individuals from the GOLDN cohort. HDL-c levels were higher and the total cholesterol/HDL-c (TC/HDL-c) ratio was lower in women versus men (p

Aim To compare the efficacy and safety between rabbit anti-thymocyte globulin (Thymoglobulin) and anti-T lymphocyte globulin (ATG-Fresenius, ATG-F) in donation after cardiac death (DCD) kidney transplantation. Methods We retrospectively analyzed 255 cases of DCD kidney transplantation performed at our hospital from February 2007 to October 2013. The patients were divided into two groups based on their induction therapies with Thymoglobulin (n = 188) or ATG-F (n = 67). Clinical data were collected and compared between the two groups. Results Delayed graft function (DGF) occurred in 36 (19.1%) patients in the Thymoglobulin group versus 17 (25.4%) patients in the ATG-F group (P = 0.281). However, if we subgroup the patients with increased risk factors for DGF, the DGF rate was 9/40 (22.5%) in the Thymoglobulin group versus 9/16 (56.3%) in the ATG-F group (P = 0.015). Duration of DGF was significantly shorter in the Thymoglobulin group (11.7 days vs. 16.1 days). The acute rejection rate was significantly lower in the Thymoglobulin group (9.6% vs. 19.4%, P = 0.035). One-year graft and patient survival were both comparable between the Thymoglobulin and ATG-F groups. The adjusted odds ratio of DGF was 4.283 (1.137–16.13) between the ATG-F and Thymoglobulin groups in patients with increased risk factors for DGF. Conclusion Compared with ATG-F, Thymoglobulin may reduce duration of DGF and acute rejection rate after DCD kidney transplantation. Moreover, Thymoglobulin significantly reduced DGF in patients with increased risk factors for DGF.

Lipoprotein lipase (LPL) is a candidate gene for obesity based on its role in triglyceride hydrolysis and the partitioning of fatty acids towards storage or oxidation. Whether dietary fatty acids modify LPL associated obesity risk is unknown.We examined five single nucleotide polymorphisms (SNPs) (rs320, rs2083637, rs17411031, rs13702, rs2197089) for potential interaction with dietary fatty acids for obesity traits in 1171 participants (333 men and 838 women, aged 45-75 y) of the Boston Puerto Rican Health Study (BPRHS). In women, SNP rs320 interacted with dietary polyunsaturated fatty acids (PUFA) for body mass index (BMI) (P = 0.002) and waist circumference (WC) (P = 0.001) respectively. Higher intake of PUFA was associated with lower BMI and WC in homozygotes of the major allele (TT) (P = 0.01 and 0.005) but not in minor allele carriers (TG and GG). These interactions were replicated in an independent population, African American women of the Atherosclerosis Risk in Communities (ARIC) study (n = 1334).Dietary PUFA modulated the association of LPL rs320 with obesity traits in two independent populations. These interactions may be relevant to the dietary management of obesity, particularly in women.

Royal jelly (RJ) produced by worker honeybees is the sole food for the queen bee throughout her life as well as the larvae of worker bees for the first 3 days after hatching. Supplementation of RJ in the diet has been shown to increase spatial memory in rodents. However, the key constituents in RJ responsible for improvement of cognitive function are unknown. Our objective was to determine if the major royal jelly proteins (MRJPs) extracted from RJ can improve the spatial memory of aged rats. The spatial memory assay using the Morris water maze test was administered once to rats after a 14-week feeding. Metabolomics analysis based on quadrupole time-of-flight mass spectrometry was conducted to examine the differences in compounds from urine. Aged male rats fed MRJPs showed improved spatial memory up to 48.5% when compared to the control male aged rats fed distilled water. The metabolite pattern of the MRJPs-fed aged rats was regressed to that of the young rats. Compounds altered by MRJPs were mapped to nicotinate and nicotinamide metabolism, cysteine taurine metabolism, and energy metabolism pathways. In summary, MRJPs may improve spatial memory and possess the potential for prevention of cognitive impairment via the cysteine and taurine metabolism and energy metabolism pathways in aged rats.

In murine schistosomiasis, immunopathology and cytokine production in response to parasite eggs are uneven and strain dependent. CBA/J (CBA) mice develop severe hepatic granulomatous inflammation associated with prominent Th17 cell responses driven by dendritic cell (DC)-derived IL-1β and IL-23. Such Th17 cells fail to develop in low-pathology C57BL/6 (BL/6) mice, and the reasons for these strain-specific differences in APC reactivity to eggs remain unclear. We show by gene profiling that CBA DCs display an 18-fold higher expression of the C-type lectin receptor CD209a, a murine homolog of human DC-specific ICAM-3–grabbing nonintegrin, compared with BL/6 DCs. Higher CD209a expression was observed in CBA splenic and granuloma APC subpopulations, but only DCs induced Th17 cell differentiation in response to schistosome eggs. Gene silencing in CBA DCs and overexpression in BL/6 DCs demonstrated that CD209a is essential for egg-elicited IL-1β and IL-23 production and subsequent Th17 cell development, which is associated with SRC, RAF-1, and ERK1/2 activation. These findings reveal a novel mechanism controlling the development of Th17 cell–mediated severe immunopathology in helminthic disease.

Non-high-density lipoprotein cholesterol (NHDL) is an independent and superior predictor of CVD risk as compared to LDL alone. It represents a spectrum of atherogenic lipid fractions with possibly a distinct genomic signature. We performed genome-wide association studies (GWAS) to identify loci influencing baseline NHDL and its postprandial lipemic (PPL) response. We carried out GWAS in 4,241 participants of European descent. Our discovery cohort included 928 subjects from the Genetics of Lipid-Lowering Drugs and Diet Network (GOLDN) Study. Our replication cohorts included 3,313 subjects from the Heredity and Phenotype Intervention (HAPI) Heart Study and Family Heart Study (FamHS). A linear mixed model using the kinship matrix was used for association tests. The best association signal was found in a tri-genic region at RHOQ-PIGF-CRIPT for baseline NHDL (lead SNP rs6544903, discovery p = 7e-7, MAF = 2%; validation p = 6e-4 at 0.1 kb upstream neighboring SNP rs3768725, and 5e-4 at 0.7 kb downstream neighboring SNP rs6733143, MAF = 10%). The lead and neighboring SNPs were not perfect surrogate proxies to each other (D′ = 1, r2 = 0.003) but they seemed to be partially dependent (likelihood ration test p = 0.04). Other suggestive loci (discovery p < 1e-6) included LOC100419812 and LOC100288337 for baseline NHDL, and LOC100420502 and CDH13 for NHDL PPL response that were not replicated (p > 0.01). The current and first GWAS of NHDL yielded an interesting common variant in RHOQ-PIGF-CRIPT influencing baseline NHDL levels. Another common variant in CDH13 for NHDL response to dietary high fat intake challenge was also suggested. Further validations for both loci from large independent studies, especially interventional studies, are warranted.

Dysregulation in the circadian system induced by variants of clock genes has been associated with type 2 diabetes. Evidence for the role of cryptochromes, core components of the system, in regulating glucose homeostasis is not supported by CRY1 candidate gene association studies for diabetes and insulin resistance in human, suggesting possible dietary influences. The purpose of this study was to test for interactions between a CRY1 polymorphism, rs2287161, and carbohydrate intake on insulin resistance in two independent populations: a Mediterranean (n = 728) and an European origin North American population (n = 820). Linear regression interaction models were performed in two populations to test for gene-diet interactions on fasting insulin and glucose and two insulin-related traits, homeostasis model assessment of insulin resistance (HOMA-IR) and quantitative insulin sensitivity check index (QUICKI). In addition, fixed effects meta-analyses for these interactions were performed. Cohort-specific interaction analyses showed significant interactions between the CRY1 variant and dietary carbohydrates for insulin resistance in both populations (p

BACKGROUND Associations of either insulin receptor substrate 1 (IRS1) variants or circulating 25-hydroxyvitamin D [25(OH)D] with type 2 diabetes (T2D) and insulin resistance (IR) are inconsistent. This study sought to determine whether circulating 25(OH)D modulates the association of a potentially functional variant at IRS1 (rs2943641) with insulin resistance. METHOD Interaction between IRS1 rs2943641 and circulating 25(OH)D on homeostasis model assessment for IR (HOMA-IR) was examined in the Boston Puerto Rican Health Study (BPRHS) (n = 1144). Replication was performed in the African-American (n = 1126), non-Hispanic white (n = 1967), and Hispanic (n = 1241) populations of the Multi-Ethnic Study of Atherosclerosis (MESA) with genotypes of 3 IRS1 variants, rs2972144, rs1515104, and rs2673142, which are tag single nucleotide polymorphisms (SNPs) and in strong linkage disequilibrium with rs2943641. RESULTS Higher circulating 25(OH)D was associated with lower risk of T2D and IR in BPRHS women homozygous for minor allele rs2943641T. Consistently, in each of 3 MESA populations, HOMA-IR and insulin decreased more evidently with higher circulating 25(OH)D in women of the rs2943641TT genotype than in carriers of the major allele (rs2943641C). Metaanalysis indicated significant and consistent interactions between circulating 25(OH)D and IRS1 variants on HOMA-IR (log transformed) [pooled β = −0.008, 95% CI: −0.016 to −0.001, P interaction = 0.004] and insulin (log transformed) (pooled β = −0.006, 95% CI: −0.011 to −0.002, P interaction = 0.023) in 3065 women of the 4 populations. CONCLUSIONS Participants with different genotypes of IRS1 rs2943641 exhibit differential benefit from high circulating 25(OH)D for the reduction of insulin resistance and T2D risk. This gene–nutrient interaction, which appears to be limited to women, warrants further examination in randomized controlled trials of vitamin D supplementation.

OBJECTIVES: To identify genetic and dietary factors, and their interactions that contribute to type 2 diabetes (T2D) and predict an individual's risk to design more precise prevention and treatment strategies. METHODS: A genome-wide scan for up to three-way interactions between 717,275 single nucleotide polymorphisms (SNPs), and 139 dietary and lifestyle factors was conducted on 1380 participants of the Boston Puerto Rican Health Study using the Generalized Multifactor Dimensionality Reduction (GMDR) method. Based on identified genetic and dietary factors, we then used machine learning (ML) to predict T2D risk, and the accuracy of prediction was assessed using area under the Receiver Operating Characteristic curve (ROC-AUC). RESULTS: A genome-wide scan for main effects and up to three-way interactions between SNPs and dietary factors using GMDR identified a set of 818 SNPs and 12 dietary factors that were selected for the prediction of T2D incidence. Comparing several ML algorithms, we found that stochastic gradient boosting provided the best prediction accuracy of T2D incidence with ROC-AUC of 0.93 in the training set, and overall accuracy of 85% based on test set validation. This approach identified that 52 SNPs in 37 genes, three food groups of high sugar content, and age were key predictors of the best-fit model. CONCLUSIONS: This study illustrates a powerful methodology that can predict incidence of T2D based on gene-gene and gene-environment interactions in combination with machine learning. This genome-wide approach allows identification of those diet and lifestyle factors that interact with genotype and can inform personalized nutrition strategies for the prevention and treatment of T2D. FUNDING SOURCES: This work was funded by the US Department of Agriculture, under agreement no. 8050-51000-098-00D, and NIH grants P01 AG023394, P50 HL105185, and R01 AG027087.

OBJECTIVES: Sweetened beverage (SB) consumption is highly associated with obesity, but the mechanism underlying this correlation is not understood. Our objective was to examine metabolomic links between SB intake and obesity to understand metabolic mechanisms. METHODS: We examined the association of plasma metabolomic profiles with SB intake and obesity risk in 782 participants, aged 45–75y, in the Boston Puerto Rican Health Study (BPRHS) using linear regression models, controlling for potential confounding factors. Based on identified metabolites, we conducted pathway enrichment analysis to identify potential metabolic pathways that link SB intake and obesity risk. Genetic variants in identified metabolic pathways were examined for their interaction with SB intake on metabolites of interest and obesity. Interactions between SB and genotypes on obesity were evaluated for replication in the Framingham Heart Study (FHS). RESULTS: In BPRHS, SB intake was highly correlated with BMI (β = 0.455, P

Background Although dietary treatments can successfully reduce blood lipids in hypercholesterolemic subjects, individual variation in that response has on occasion been linked to allelic differences. SNP rs12449157 has shown association with HDL-C concentrations in GWAS and falls in the glucose-fructose oxidoreductase domain containing 2 (GFOD2) locus. Of interest, previous data suggest that this SNP may be under environmentally driven selection. Thus, the aim of this study was to assess if rs12449157 may mediate the response of lipid traits to a dietary supplementation (DS) with soy protein and soluble fiber in a Mexican population with hypercholesterolemia. Methods Forty-one subjects with hypercholesterolemia were given a low saturated fat diet (LSFD) for 1 month, followed by a LSFD + DS that included 25 g of soy protein and 15 g of soluble fiber (S/SF) daily for 2 months. Anthropometric, clinical, biochemical and dietary variables were determined. We analyzed the gene–diet interaction between the GFOD2 genotype, with the minor allele frequency of 0.24, and the DS on total cholesterol (TC) and LDL-C concentrations. Results Hypercholesterolemic subjects with GFOD2 rs12449157 G allele had higher serum TC and LDL-C at the baseline and showed a greater response to the LSCD + S/SF (− 83.9 and − 57.5 mg/dl, respectively) than those with GFOD2 AA genotype (− 40.1 and − 21.8 mg/dl, respectively) (P = 0.006 for TC, 0.025 for LDL-C, respectively). Conclusion The observed differences in allele-driven, diet-induced changes in blood lipids may be the result of a recent environmentally driven selection on the rs12449157 minor allele. Variation in the GFOD2 gene contributes to the genetic basis for a differential response to a cholesterol- or lipid-lowering diet.

The interaction between a functional apolipoprotein A2 gene (APOA2) variant and saturated fatty acids (SFAs) for the outcome of body mass index (BMI) is among the most widely replicated gene-nutrient interactions. Whether this interaction can be extrapolated to food-based sources of SFAs, specifically dairy foods, is unexplored. Cross-sectional analyses were performed in 2 U.S. population–based samples. We evaluated interactions between dairy foods and APOA2 −265T > C (rs5082) for BMI in the Boston Puerto Rican Health Study (n = 955) and tested for replication in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study (n = 1116). Dairy products were evaluated as total dairy, higher-fat dairy (>1%), and low-fat dairy (≤1%) in servings per day, dichotomized into high and low based on each population median and also as continuous variables. We identified a statistically significant interaction between the APOA2 −265T > C variant and higher-fat dairy food intake in the Boston Puerto Ricans (P-interaction = 0.028) and replicated this relation in the GOLDN study (P-interaction = 0.001). In both groups, individuals with the previously demonstrated SFA-sensitive genotype (CC) who consumed a greater amount of higher-fat dairy foods had greater BMI (P = 0.013 in Boston Puerto Ricans; P = 0.0007 in GOLDN women) compared with those consuming less of the higher-fat dairy foods. The results expand the understanding of the metabolic influence of dairy products, an important food group for which variable relations to body weight may be in part genetically based. Moreover, these findings suggest that other strongly demonstrated gene-nutrient relations might be investigated through appropriate food-based, translatable avenues and may be relevant to dietary management of obesity.

A functional variant in the apolipoprotein AII (APOA2) gene (rs5082) predisposes homozygous carriers to age-related obesity when habitual saturated fat (SFA) intake is high. We used epigenomics, transcription and metabolomics analyses to identify currently unknown mechanisms underlying this well-replicated gene x diet interaction. We conducted an epigenome-wide scan to compare genetically at-risk to low-risk individuals with low (

We recently reported that epicatechin, a bioactive compound, which naturally occurs in various common foods including cocoa, beans, berries, apples, and tea, promoted general health and survival of obese diabetic mice. It remains to be determined whether epicatechin extends health span and delays the process of aging. In the present study, epicatechin or its analog EGCG (0.25% w/v in drinking water) was administrated to 20-month old male C57BL mice fed a standard chow for determining the effects of epicatechin on aging. Results show that supplementation of epicatechin for 37 weeks strikingly increased the survival rate from 39% to 69%, whereas EGCG was inactive. Consistently, epicatechin improved physical activity, delayed skeletal muscle degeneration and shifted the profiles of the serum metabolites in aging mice toward the metabolite profiles observed in young mice. Our analysis found that dietary epicatechin significantly reversed aging-altered mRNA and protein expressions of extracellular matrix (ECM) and peroxisome proliferator-activated receptor (PPAR) pathways in skeletal muscle tissue, and reversed the aging-induced declines of the nicotinate and nicotinamide (NAD) pathway as both serum metabolites and skeletal muscle gene expression. The present study provides novel information on natural compounds and anti-aging research in the manner that epicatechin supplementation was demonstrated to exert anti-aging and anti-sarcopenia effects in normal aging mice by mimicking exercise, as deduced by comparison to exercise intervention data. Results from this study provide direct evidence for one strategy to promote healthy aging and extend lifespan in humans simply by consuming more natural foods having high content of epicatechin.

The field of nutrigenomics shows tremendous promise for improved understanding of the effects of dietary intake on health. The knowledge that metabolic pathways may be altered in individuals with genetic variants in the presence of certain dietary exposures offers great potential for personalized nutrition advice. However, although considerable resources have gone into improving technology for measurement of the genome and biological systems, dietary intake assessment remains inadequate. Each of the methods currently used has limitations that may be exaggerated in the context of gene × nutrient interaction in large multiethnic studies. Because of the specificity of most gene × nutrient interactions, valid data are needed for nutrient intakes at the individual level. Most statistical adjustment efforts are designed to improve estimates of nutrient intake distributions in populations and are unlikely to solve this problem. An improved method of direct measurement of individual usual dietary intake that is unbiased across populations is urgently needed.

PSMD3 encodes subunit 3 of the 26S proteasome, which is involved in regulating insulin signal transduction, and dietary factors could potentially regulate the function of this gene. We aimed to investigate the associations of PSMD3 variants with glucose-related traits and the interactions of those variants with dietary fat and carbohydrate for glucose-related traits in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study and to replicate the findings in the Boston Puerto Rican Health Study (BPRHS). Ten single nucleotide polymorphisms (SNPs) were selected, covering 90% the genetic variations in or near PSMD3. Minor allele (C) carriers of rs4065321 had higher homeostasis model assessment of insulin resistance (HOMA-IR) than noncarriers in males of both the GOLDN (P = 0.022) and BPRHS (P = 0.036). Minor allele (T) carriers of rs709592 had significantly higher HOMA-IR (P = 0.032) than C homozygotes in the GOLDN, whereas the T allele carriers of rs709592 tended to have higher HOMA-IR (P = 0.08) than C homozygotes in the BPRHS. In the GOLDN, there was an interaction between rs709592 and dietary carbohydrate on HOMA-IR (P = 0.049). Subjects carrying the T allele of rs709592 had higher HOMA-IR compared only with noncarriers with low carbohydrate intake (≤49.1% energy; P = 0.004). SNPs rs4065321 and rs709592 both significantly interacted with dietary MUFAs and carbohydrate on glucose concentrations in the GOLDN. Our study suggests that PSMD3 variants are associated with insulin resistance in populations of different ancestries and that these relationships may also be modified by dietary factors.

Sixteen nuclear magnetic resonance (NMR) spectroscopy lipoprotein measurements of more than 1,000 subjects of GOLDN study, at fasting and at 3.5 and 6 h after a postprandial fat (PPL) challenge at visits 2 and 4, before and after a 3 weeks Fenofibrate (FF) treatment, were included in 6 time-independent multivariate factor analyses. Their top 1,541 unique SNPs were assessed for association with GOLDN NMR-particles and classical lipids. Several SNPs with −log10 p > 7.3 and MAF ≥ 0.10, mostly intergenic associated with NMR-single traits near genes FAM84B (8q24.21), CRIPT (2p21), ACOXL (2q13), BCL2L11 (2q13), PCDH10 (4q28.3), NXPH1 (7p22), and SLC24A4 (14q32.12) in association with NMR-LDLs; HOMER1 (5q14.2), KIT (4q11–q12), VSNL1 (2p24.3), QPRT (16p11.2), SYNPR (3p14.2), NXPH1 (7p22), NELL1 (11p15.1), and RUNX3 (1p36) with NMR-HDLs; and DOK5-CBLN4-MC3R (20q13), NELL1 (11p15.1), STXBP6 (14q12), APOB (2p24-p23), GPR133 (12q24.33), FAM84B (8q24.21) and NR5A2 (1q32.1) in association with NMR-VLDLs particles. NMR single traits associations produced 75 % of 114 significant candidates, 7 % belonged to classical lipids and 18 % overlapped, and 16 % matched for time of discovery between NMR- and classical traits. Five proxy genes, (ACOXL, FAM84B, NXPH1, STK40 and VAPA) showed pleiotropic effects. While tagged for significant associations in our study and with some extra evidence from the literature, candidates as CBNL4, FAM84B, NXPH1, SLC24A4 remain unclear for their functional relation to lipid metabolism. Although GOLDN study is one of the largest in studying PPL and FF treatment effects, the relatively small samples (over 700–1,000 subjects) in association tests appeals for a replication of such a study. Thus, further investigation is needed.

The Para rubber tree (Hevea brasiliensis) is an economically important tropical tree species that produces natural rubber, an essential industrial raw material. Here we present a high-quality genome assembly of this species (1.37 Gb, scaffold N50 = 1.28 Mb) that covers 93.8% of the genome (1.47 Gb) and harbours 43,792 predicted protein-coding genes. A striking expansion of the REF/SRPP (rubber elongation factor/small rubber particle protein) gene family and its divergence into several laticifer-specific isoforms seem crucial for rubber biosynthesis. The REF/SRPP family has isoforms with sizes similar to or larger than SRPP1 (204 amino acids) in 17 other plants examined, but no isoforms with similar sizes to REF1 (138 amino acids), the predominant molecular variant. A pivotal point in Hevea evolution was the emergence of REF1, which is located on the surface of large rubber particles that account for 93% of rubber in the latex (despite constituting only 6% of total rubber particles, large and small). The stringent control of ethylene synthesis under active ethylene signalling and response in laticifers resolves a longstanding mystery of ethylene stimulation in rubber production. Our study, which includes the re-sequencing of five other Hevea cultivars and extensive RNA-seq data, provides a valuable resource for functional genomics and tools for breeding elite Hevea cultivars. The rubber tree (Hevea brasiliensis, hereafter referred to as Hevea) is a member of the spurge family (Euphorbiaceae), along with several other economically important species such as cassava (Manihot esculenta) and the castor oil plant (Ricinus communis). Natural rubber (cis-1, 4-polyisoprene) makes up about one-third of the volume of latex that is essentially cytoplasm of the articulated laticifers in Hevea. The latex is extracted by tapping the bark, a non-destructive method of harvesting that facilitates continual production. As an industrial commodity, natural rubber is an elastomer with physical and chemical properties that cannot be fully matched by synthetic rubber1. In contrast to synthetics, the production of natural rubber is sustainable and environment friendly2. The commercial cultivation of Hevea, a native to the Amazon Basin, began in 1896 on a plantation scale in Malaya (now Malaysia) and expanded to other Southeast Asian countries that lead in world natural rubber production today3. Decades of selective breeding have resulted in a gradual improvement in rubber productivity, from 650 kg ha–1 derived from unselected seedlings during the 1920s to 2,500 kg ha–1 yielded by elite cultivars by the 1990s4. Nevertheless, the field production achieved so far is still well below the theoretical yield of 7,000–12,000 kg ha–1, as has been suggested for the rubber tree5. Meanwhile, conventional rubber breeding has been stagnating in the introduction of high-yield cultivars. The reasons include a narrow genetic basis for exploiting breeding potential and difficulty in introducing wild germplasms because of the genetic burden in removing unfavourable alleles6. The incorporation of marker-assisted selection and transgenic techniques offers promise to improve breeding efficiency for latex yield, and sequencing of the Hevea genome would uncover even more avenues leading to this end. The first draft Hevea genome was released by a Malaysian team7 that was participant to the recent boom in transcriptomic and proteomic studies of the species8,9,10,11. However, its low sequence coverage (∼13×) and a lack of large insert libraries (such as fosmid- or BAC-based clone libraries) have limited the success of genome assembly (a scaffold N50 size of 2,972 bp), precluding its application for furthering quality research in the field. Here, we report a high-quality genome assembly of Hevea Reyan7-33-97, an elite cultivar widely planted in China12,13 based on sequence data from both whole-genome shotgun (WGS) and pooled BAC clones. This assembly contains 7,453 scaffolds (N50 = 1.28 Mb), has a length of 1.37 Gb and covers ∼94% of the predicted genome size (1.46 Gb). Together with analysis of data from re-sequencing five other cultivars and comprehensive transcriptomic surveys, we aim to obtain new insights into the physiology of laticifers and molecular details of rubber biosynthesis, especially in relation to ethylene-stimulated rubber production.

The C677T polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene differs in frequency in various ethnic groups that have differing prevalence of age-related cognitive impairments. We used a series of neuro-psychological tests to examine the association of the MTHFR C677T polymorphism with cognition and depression and also to assess whether genotype modifies the association of folate and homocysteine with these outcomes. This study analyzed pooled cross-sectional data from 2 ethnically diverse cohorts of community-living adults: the Boston Puerto Rican Health Study (n = 939) and the Nutrition, Aging, and Memory in Elders study (n = 1017). Individuals in both cohorts underwent anthropometric and laboratory measurements and dietary and health assessments using validated questionnaires between the years 2003 and 2007. Cognitive outcomes included measures of global cognition [Mini-Mental Status Exam (MMSE)], depression (Center for Epidemiological Studies Depression Scale), and 3 factor scores for the domains of attention, executive function, and memory that were derived from a detailed set of neuropsychological tests. Low plasma vitamin B-12 concentrations were associated with poorer MMSE scores and higher depression scores, and low vitamin B-6 concentrations were associated with lower MMSE and worse attention and executive function in the multivariate analysis. In contrast, MTHFR genotype, folate, and homocysteine were not associated with cognition or depression in either ethnicity-pooled or stratified analysis. The current study did not find evidence of an association between the MTHFR C677T TT genotype and impaired cognition or depression in a population with adequate folate status and a high prevalence of cognitive impairment and depression.

Curcumin is a polyphenolic bioactive compound in turmeric. We examined if antioxidant effects of curcumin are associated with lifespan extension in Drosophila. In this experiment, females and males of Drosophila were fed diets either containing no curcumin (C0) or supplemented with curcumin at 0.5 (C1) and 1.0 (C2) mg/g of diet. The levels of malondialdehyde (MDA), enzyme activity of superoxide dismutase (SOD), and expression of seven age-related genes in females and males were analyzed. We found that C1 and C2 increased mean lifespan by 6.2 % and 25.8 % in females, and by 15.5 % and 12.6 % in males, respectively. Meanwhile, C1 and C2 significantly decreased MDA levels and increased SOD activity in both genders. Diets C1 in females and C2 in males are effective in extending mean lifespan and improving levels of two physiological and biochemical measures related to aging in Drosophila. Lifespan extension of curcumin in Drosophila was associated with the up-regulation of Mn-SOD and CuZn-SOD genes, and the down-regulation of dInR, ATTD, Def, CecB, and DptB genes. The present results suggest that curcumin increases mean lifespan of Drosophila via regulating gene expression of the key enzyme SOD and reducing accumulation of MDA and lipid peroxidation. This study provided new insights for understanding the anti-aging mechanism of curcumin in Drosophila.

Macronutrient intakes and genetic variants have been shown to interact to alter the risk of insulin resistance, but replication of gene-nutrient interactions across independent populations may be difficult to achieve. Saturated fat and carbohydrate were previously shown to interact with genotype for insulin resistance for a variant of perilipin (PLIN), the major adipocyte-associated protein and a regulator of adipocyte metabolism. We investigated the same interaction for PLIN 11482G>A (rs894160) on insulin resistance in US men(n=462) and women(n=508) (mean ±SD, 49±16 years). In multivariate linear regression models, we found a significant (PA for HOMA-IR (homeostasis model assessment of insulin resistance) in women. For carriers of the minor allele but not for non-carriers, as the ratio of saturated fat to carbohydrate intake increased, predicted HOMA-IR increased significantly (P=0.002). By dichotomizing the ratio of saturated fat to carbohydrate intake into high and low, we found significant interaction terms for insulin and HOMA-IR (P

Background and Aim Dietary n-3 polyunsaturated fatty acids (PUFAs) are associated with decreased plasma homocysteine (Hcy), an important biomarker for cardiovascular disease. The S-adenosylmethionine synthetase type-1 (MAT1A), an essential enzyme in the conversion of methionine to S-adenosylmethionine, plays a key role in homocysteine metabolism. This study investigated the interaction between dietary fatty acids and MAT1A genotypes on plasma Hcy concentrations among Boston Puerto Ricans. Methods and Results Plasma Hcy and MAT1A genotypes were determined in 994 subjects of the Boston Puerto Rican Health Study. Dietary fatty acid intakes were assessed by interviews using a questionnaire adapted from the NCI/Block food frequency form. Result In the cross-sectional analysis, genetic variant MAT1A 3U1510 displayed a significant interaction with dietary n-3:n-6 PUFA ratio in determining plasma Hcy ( p -value for interaction = 0.025). 3U1510G homozygotes had significantly lower plasma Hcy concentration than major allele homozygotes and heterozygotes (AA + AG) ( p -value for trend = 0.019) when the n-3:n-6 ratio was >0.09. Two other MAT1A variants, d18777 and i15752, also showed significant interactions with different constituents of dietary fat influencing Hcy concentrations. Furthermore, haplotypes consisting of three variants displayed a strong interaction with n3:n6 ratio influencing Hcy concentrations. Conclusions Our results suggest that MAT1A genotypes appear to modulate effects of dietary fat on plasma Hcy.

CYP7A1 encodes cholesterol 7α-hydroxylase, an enzyme crucial to cholesterol homeostasis. Its transcriptional activity is downregulated by fenofibrate. The goal of this study was to determine the effect of CYP7A1 polymorphisms on lipid changes in response to fenofibrate.We examined the associations of 3 tagging single nuclear polymorphisms (i6782CT, m204TG, 3U12536AC) at CYP7A1 with triglyceride (TG) and high-density lipoprotein cholesterol (HDL)-C responses to a 3-week treatment with 160 mg/d of fenofibrate in 864 US white participants from the Genetics of Lipid Lowering Drugs and Diet Network study.The m204TG variant was significantly associated with TG and HDL-C responses with fenofibrate. Individuals homozygous for the common T allele of m204TG single nuclear polymorphism displayed both the greater reduction of TG (-32% for TT, -28% for GT, -25% for GG, P = 0.004) and an increase of HDL-C response compared with noncarriers (4.1% for TT, 3.4% for GT, 1.2% for GG, P = 0.01). Conversely, individuals homozygous for the minor allele of i6782CT showed a greater increase in the HDL-C response compared with noncarriers (2.8% CC, 4.5% for CT, 5.8% for TT, P = 0.02), albeit no significant effect on TG response.Our data suggest that common variants at the CYP7A1 locus modulate the TG-lowering and HDL-C-raising effects of fenofibrate, and contribute to the interindividual variation of the drug responses.

Despite the evidence in support of the anti-inflammatory and triglyceride-lowering effects of fenofibrate, little is known about genetic determinants of the observed heterogeneity in treatment response. This study provides the first genome-wide examination of fenofibrate effects on systemic inflammation.Biomarkers of inflammation were measured in participants of the Genetics of Lipid Lowering Drugs and Diet Network (n=1092) before and after a 3-week daily treatment with 160 mg of fenofibrate. Two inflammatory patterns [high-sensitivity C-reactive protein-interleukin-6 and monocyte chemoattractant protein-1-tumor necrosis factor (MCP1-TNF-α)] were derived using principal component analysis. Associations between single nucleotide polymorphisms on the Affymetrix 6.0 chip and phenotypes were assessed using mixed linear models, adjusted for age, sex, study center, and ancestry as fixed effects and pedigree as a random effect.Before fenofibrate treatment, the strongest evidence for association was observed for polymorphisms near or within the IL2RA gene with the high-sensitivity C-reactive protein-interleukin-6 (IL6) pattern (rs7911500, P=5×10 and rs12722605, P=5×10). Associations of the MCP1-TNF-α pattern with loci in several biologically plausible genes [CYP4F8 (rs3764563), APBB1IP (rs1775246), COL13A1 (rs2683572), and COMMD10 (rs1396485)] approached genome-wide significance (P=3×10, 5×10, 6×10, and 7×10, respectively) before fenofibrate treatment. After fenofibrate treatment, the rs12722605 locus in IL2RA was also associated with the MCP1-TNF-α pattern (P=3×10). The analyses of individual biomarker response to fenofibrate did not yield genome-wide significant results, but the rs6517147 locus near the immunologically relevant IFNAR2 gene was suggestively associated with IL6 (P=7×10).We have identified several novel biologically relevant loci associated with systemic inflammation before and after fenofibrate treatment.

Scope Omega-3 PUFAs (n-3 PUFAs) reduce IL-6 gene expression, but their effects on transcription regulatory mechanisms are unknown. We aimed to conduct an integrated analysis with both population and in vitro studies to systematically explore the relationships among n-3 PUFA, DNA methylation, single nucleotide polymorphisms (SNPs), gene expression, and protein concentration of IL6. Methods and results Using data in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study and the Encyclopedia of DNA Elements (ENCODE) consortium, we found that higher methylation of IL6 promoter cg01770232 was associated with higher IL-6 plasma concentration (p = 0.03) and greater IL6 gene expression (p = 0.0005). Higher circulating total n-3 PUFA was associated with lower cg01770232 methylation (p = 0.007) and lower IL-6 concentration (p = 0.02). Moreover, an allele of IL6 rs2961298 was associated with higher cg01770232 methylation (p = 2.55 × 10(-7) ). The association between n-3 PUFA and cg01770232 methylation was dependent on rs2961298 genotype (p = 0.02), but higher total n-3 PUFA was associated with lower cg01770232 methylation in the heterozygotes (p = 0.04) not in the homozygotes. Conclusion Higher n-3 PUFA is associated with lower methylation at IL6 promoter, which may be modified by IL6 SNPs.

BackgroundRecent studies suggest that meat intake is associated with diabetes-related phenotypes. However, whether the associations of meat intake and glucose and insulin homeostasis are modified by genes related to glucose and insulin is unknown.ObjectiveWe investigated the associations of meat intake and the interaction of meat with genotype on fasting glucose and insulin concentrations in Caucasians free of diabetes mellitus.DesignFourteen studies that are part of the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium participated in the analysis. Data were provided for up to 50,345 participants. Using linear regression within studies and a fixed-effects meta-analysis across studies, we examined 1) the associations of processed meat and unprocessed red meat intake with fasting glucose and insulin concentrations; and 2) the interactions of processed meat and unprocessed red meat with genetic risk score related to fasting glucose or insulin resistance on fasting glucose and insulin concentrations.ResultsProcessed meat was associated with higher fasting glucose, and unprocessed red meat was associated with both higher fasting glucose and fasting insulin concentrations after adjustment for potential confounders [not including body mass index (BMI)]. For every additional 50-g serving of processed meat per day, fasting glucose was 0.021 mmol/L (95% CI: 0.011, 0.030 mmol/L) higher. Every additional 100-g serving of unprocessed red meat per day was associated with a 0.037-mmol/L (95% CI: 0.023, 0.051-mmol/L) higher fasting glucose concentration and a 0.049-ln-pmol/L (95% CI: 0.035, 0.063-ln-pmol/L) higher fasting insulin concentration. After additional adjustment for BMI, observed associations were attenuated and no longer statistically significant. The association of processed meat and fasting insulin did not reach statistical significance after correction for multiple comparisons. Observed associations were not modified by genetic loci known to influence fasting glucose or insulin resistance.ConclusionThe association of higher fasting glucose and insulin concentrations with meat consumption was not modified by an index of glucose- and insulin-related single-nucleotide polymorphisms. Six of the participating studies are registered at clinicaltrials.gov as NCT0000513 (Atherosclerosis Risk in Communities), NCT00149435 (Cardiovascular Health Study), NCT00005136 (Family Heart Study), NCT00005121 (Framingham Heart Study), NCT00083369 (Genetics of Lipid Lowering Drugs and Diet Network), and NCT00005487 (Multi-Ethnic Study of Atherosclerosis).

Hypertriglyceridemia, defined as a triglyceride measurement > 150 mg/dl, occurs in up to 34% of adults. Fenofibrate is a commonly used drug to treat hypertriglyceridemia, but response to fenofibrate varies considerably among individuals. We sought to determine if genetic variation in apolipoprotein B (APOB), an essential core of triglyceride-rich lipoprotein formation, may account for some of the inter-individual differences observed in triglyceride (TG) response to fenofibrate treatment. Participants (N = 958) from the Genetics of Lipid Lowering Drugs and Diet Network study completed a three-week intervention with fenofibrate 160 mg/day. Associations of four APOB gene single nucleotide polymorphisms (SNP) (rs934197, rs693, rs676210, and rs1042031) were tested for association with the TG response to fenofibrate using a mixed growth curve model where the familial structure was modeled as a random effect and cardiovascular risk factors were included as covariates. Three of these four SNPs changed the amino acid sequence of APOB, and the fourth was in the promoter region. TG response to fenofibrate treatment was associated with one APOB SNP, rs676210 (Pro2739Leu), such that participants with the TT genotype of rs676210 had greater TG lowering than those with the CC genotype (additive model, P = 0.0017). We conclude the rs676210 variant may identify individuals who respond best to fenofibrate for TG reduction.