Diet Quality Scores Are Positively Associated with Whole Blood-Derived Mitochondrial DNA Copy Number in the Framingham Heart Study.

BACKGROUND: The association between diet quality and mitochondrial DNA copy number (mtDNA-CN) remains to be examined. OBJECTIVES: We aimed to study the relation between diet quality and mtDNA-CN. METHODS: We analyzed data from 2931 Framingham Heart Study (FHS) participants (mean age of 57 y, 55% females). Whole-genome sequencing was used to calculate mtDNA-CN from whole-blood samples. We examined the cross-sectional associations between 3 diet quality scores, the Dietary Approaches to Stop Hypertension (DASH) score, the Alternative Healthy Eating Index (AHEI), and the Mediterranean diet score (MDS), and mtDNA-CN. Linear mixed models were used to account for maternal lineage. RESULTS: We observed that a higher DASH score was positively associated with mtDNA-CN after adjusting for sex, age, energy intake, smoking status, alcohol intake, and physical activity level. A 1-SD increase in the DASH score was associated with a 0.042-SD greater mtDNA-CN (95% CI: 0.007, 0.077; P = 0.02). Similarly, for each SD increase in AHEI and MDS, the mtDNA-CN SD increased by 0.056 (95% CI: 0.019, 0.092; P = 0.003) and 0.047 (95% CI: 0.01, 0.083; P = 0.01), respectively. Diet quality scores were associated with neutrophil and lymphocyte counts but not platelet counts, e.g., for a 1-SD increase in the DASH, neutrophils decreased by 0.8% (95% CI: 0.5%, 1.1%; P = 4.1 × 10-6), lymphocytes increased by 0.7% (95% CI: 0.4%, 1%, P = 1.2 × 10-5), and there was no significant change in platelet number (0.1 × 1000/µL; 95% CI: -1.6, 1.9; P = 0.89). Further adjustment for neutrophil, lymphocyte, and platelet counts and the associations between diet quality scores and mtDNA-CN were completely attenuated to nonsignificant (P = 0.95, 0.54, and 0.91, respectively). CONCLUSIONS: We observed that higher diet quality is associated with a greater whole-blood derived mtDNA-CN in middle-aged to older adult FHS participants, and that blood cell composition, particularly neutrophil counts, attenuated the association between diet quality and mtDNA-CN.

Metabolite patterns link diet, obesity, and type 2 diabetes in a Hispanic population.

INTRODUCTION: Obesity is a precursor of type 2 diabetes (T2D). OBJECTIVES: Our aim was to identify metabolic signatures of T2D and dietary factors unique to obesity. METHODS: We examined a subsample of the Boston Puerto Rican Health Study (BPRHS) population with a high prevalence of obesity and T2D at baseline (n = 806) and participants (without T2D at baseline) at 5-year follow-up (n = 412). We determined differences in metabolite profiles between T2D and non-T2D participants of the whole sample and according to abdominal obesity status. Enrichment analysis was performed to identify metabolic pathways that were over-represented by metabolites that differed between T2D and non-T2D participants. T2D-associated metabolites unique to obesity were examined for correlation with dietary food groups to understand metabolic links between dietary intake and T2D risk. False Discovery Rate method was used to correct for multiple testing. RESULTS: Of 526 targeted metabolites, 179 differed between T2D and non-T2D in the whole sample, 64 in non-obese participants and 120 unique to participants with abdominal obesity. Twenty-four of 120 metabolites were replicated and were associated with T2D incidence at 5-year follow-up. Enrichment analysis pointed to three metabolic pathways that were overrepresented in obesity-associated T2D: phosphatidylethanolamine (PE), long-chain fatty acids, and glutamate metabolism. Elevated intakes of three food groups, energy-dense takeout food, dairy intake and sugar-sweetened beverages, associated with 13 metabolites represented by the three pathways. CONCLUSION: Metabolic signatures of lipid and glutamate metabolism link obesity to T2D, in parallel with increased intake of dairy and sugar-sweetened beverages, thereby providing insight into the relationship between dietary habits and T2D risk.

Risk Factors Associated with Vitamin D Status among Older Puerto Rican Adults.

BACKGROUND: Vitamin D deficiency has been associated with health problems globally, but there is limited information on vitamin D status and associated risk factors among adults in underserved populations. OBJECTIVE: This study aimed to identify risk factors for vitamin D deficiency/insufficiency among Puerto Rican adults from the Boston Puerto Rican Health Study (BPRHS). METHODS: A total of 822 adults (45-75 y, at baseline) were included in these analyses. Deficiency was defined as serum 25-hydroxyvitamin D [25(OH)D] <30 and insufficiency as 30 to <50 nmol/L. Dietary intake was assessed with a validated FFQ. Associations between risk factors, including dietary vitamin D, supplement use, ancestry, skin pigmentation, months in the past year spent in a southern climate, and serum 25(OH)D were assessed with multivariable general linear models. RESULTS: Approximately 13% of participants were deficient in 25(OH)D and another 43% insufficient. Skin pigment was associated with 25(OH)D using 3 measures, greater African ancestry (ß ± SE) (-7.74 ± 2.91, P = 0.01); interviewer assessed dark or medium, compared with white, skin tone, (-5.09 ± 2.19, P = 0.02 and -5.89 ± 1.58, P < 0.001, respectively); and melanin index of the upper inner right arm, assessed using a spectrophotometer (-2.04 ± 0.84, P = 0.02). After adjusting for ancestry, factors associated with lower serum 25(OH)D included smoking (-4.49 ± 1.58, P = 0.01); BMI (-0.21 ± 0.10, P = 0.04); and spring compared with autumn blood draw (-4.66 ± 1.68, P = 0.004). Factors associated with higher serum 25(OH)D included female sex compared with male (4.03 ± 1.58, P = 0.01); dietary vitamin D intake µg/d (0.71 ± 0.25, P < 0.004); vitamin D supplement use (4.50 ± 1.87, P = 0.02); income to poverty ratio (0.01 ± 0.01, P = 0.06), and months in a southern climate during the past year (0.96 ± 0.56, P = 0.09). CONCLUSIONS: Vitamin D deficiency/insufficiency was prevalent in this Puerto Rican population living in the northeastern USA. Several factors were associated with this, which may assist in identifying those at risk. Interventions are needed to improve serum 25(OH)D concentration, particularly among those with limited exposure to sunlight.

Salivary AMY1 Copy Number Variation Modifies Age-Related Type 2 Diabetes Risk.

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.

Mediterranean Diet Adherence Modulates Anthropometric Measures by TCF7L2 Genotypes among Puerto Rican Adults.

BACKGROUND: Transcription factor 7-like 2 (TCF7L2) genetic variants that predispose individuals to type 2 diabetes (T2D) show inconsistent associations with anthropometric traits. Interaction between TCF7L2 genotypes and dietary factors may help explain these observations. OBJECTIVE: We aimed to examine the potential modulation of TCF7L2-rs7903146 and rs12255372 on anthropometric markers by a Mediterranean diet (MedDiet). METHODS: Cross-sectional analysis was conducted in 1120 participants (aged 45-75 y) of the Boston Puerto Rican Health Study. Anthropometric variables were measured, and polymorphisms were genotyped using standardized protocols. Diet was assessed using a validated FFQ. The MedDiet was defined based on adherence to 9 food and nutrient components using sex-specific population-based median cut-offs; high adherence was defined as meeting ≥4 components. Haplotypes were tested for association with obesity traits, independently and via interaction with the MedDiet. RESULTS: TCF7L2-rs7903146 showed significant interaction with the MedDiet influencing BMI, weight, and waist circumference. The T risk-allele carriers (CT + TT) with a high MedDiet score had lower weight (77.3 ± 1.0 compared with CC 80.9 ± 1.0 kg; P = 0.013) and waist circumference (99.2 ± 0.9 compared with CC 102.2 ± 0.9 cm; P = 0.021), when compared with CC participants. A low MedDiet score resulted in no significant differences between genotypes. For TCF7L2-rs12255372, we found significant interactions with the MedDiet for weight (P-interaction = 0.034) and BMI (P-interaction = 0.036). The T allele carriers with a higher MedDiet score showed a trend of lower but no significant differences when compared with CC participants for BMI (P = 0.19), weight (P = 0.09), and waist circumference (P = 0.11). We found significant interactions between the 2 risk-carrying haplotypes and the MedDiet compared with the common haplotype (GC), with lower BMI (ß ± SE, TT: -1.53 ± 0.68; P-interaction = 0.024), weight (TT: -4.16 ± 1.77; P-interaction = 0.019), and waist circumference (GT: -5.07 ± 2.50; P-interaction = 0.042) at a high MedDiet score. CONCLUSION: Puerto Ricans with the TCF7L2-rs7903146 and rs12255372 T2D risk genotypes, although still high, had better anthropometric profiles when adhering to a MedDiet, suggesting that this diet may offset unfavorable genetic predisposition.

Dietary epicatechin improves survival and delays skeletal muscle degeneration in aged mice.

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.

Development of a Genetic Score to Predict an Increase in HDL Cholesterol Concentration After a Dietary Intervention in Adults with Metabolic Syndrome.

BACKGROUND: Dietary intervention (DI) is a primary strategy to attenuate some of the metabolic abnormalities associated with metabolic syndrome (MetS), including low HDL cholesterol. There is no biomarker that can identify individuals who respond to DI by increasing HDL cholesterol. OBJECTIVE: The aim of this study was to assess the predictive power of a genetic predisposition score (GPS) in Mexican adults with MetS to identify HDL cholesterol responders to DI. METHODS: This study followed a prospective cohort design. Sixty-seven Mexican adults aged 20-60 y (21% men) with BMI ≥25 and ≤39.9 kg/m², who had at least 3 of 5 positive criteria for MetS, were included. Participants consumed a low saturated fat diet for 2.5 mo (<7% energy as saturated fat, <200 mg of cholesterol/d) and reduced their usual diet by ∼440 kcal/d, a reduction in total energy intake of about 25%. Anthropometry and serum biochemical markers, including HDL cholesterol, were measured before and after DI. A multilocus GPS was constructed using previously reported genetic variants associated with response to diet in subjects with MetS. GPS values, designed to predict the response of HDL cholesterol to the DI, were computed for each individual as the sum of the number of effect alleles across 14 SNPs. RESULTS: Individuals were dichotomized as high and low GPS according to median GPS (-2.12) and we observed a difference in HDL cholesterol changes on DI of +3 mg/dL (6.3%) in subjects with low GPS, whereas those with high GPS had HDL cholesterol decreases of -3 mg/dL (-7.9%) (P = 0.04). CONCLUSIONS: Individuals with low GPS showed greater increases in their HDL cholesterol than those with high GPS. Therefore, the GPS can be useful for predicting the HDL cholesterol response to diet.

Environmental and epigenetic regulation of postprandial lipemia.

PURPOSE OF REVIEW: Postprandial lipemia (PPL), the prolonged increase in plasma triglyceride-rich lipoproteins following food consumption, is an independent risk factor for cardiovascular disease. Genetic variation, environment and the interplay between these direct an individual's postprandial lipid response. From such interplay, inducible and reversible epigenetic changes arise. Increasing evidence suggests epigenetic variation contributes to postprandial response in lipids and risk. RECENT FINDINGS: Diet and exercise are central agents affecting postprandial lipemia - triglyceride, but heterogeneity of the findings warrant more and larger studies. Several epigenetic loci identified from a human intervention study account for a substantial proportion of PPL phenotype variation, but the burden to conduct an intervention study of postprandial responses likely limits translation to personalized nutrition. SUMMARY: The impact of both DNA methylation patterns and environmental factors such as diet, exercise, sleep and medication on PPL is multifaceted. Discovery of interactions that modify the association between CpG (oligodeoxydinucleotide) methylation and postprandial phenotypes is unfolding.

Detection of gene-environment interactions in a family-based population using SCAD.

Gene-environment interaction (GxE) is emphasized as one potential source of missing genetic variation on disease traits, and the ultimate goal of GxE research is prediction of individual risk and prevention of complex diseases. However, there are various challenges in statistical analysis of GxE. In this paper, we focus on the three methodological challenges: (i) the high dimensions of genes; (ii) the hierarchical structure between interaction effects and their corresponding main effects; and (iii) the correlation among subjects from family-based population studies. In this paper, we propose an algorithm that approaches all three challenges simultaneously. This is the first penalized method focusing on an interaction search based on a linear mixed effect model. For verification, we compare the empirical performance of our new method with other existing methods in simulation study. The results demonstrate the superiority of our method under overall simulation setup. In particular, the outperformance obviously becomes greater as the correlation among subjects increases. In addition, the new method provides a robust estimate for the correlation among subjects. We also apply the new method on Genetics of Lipid Lowering Drugs and Diet Network study data. Copyright © 2017 John Wiley & Sons, Ltd.

Genetic admixture and body composition in Puerto Rican adults from the Boston Puerto Rican Osteoporosis Study.

Population admixture plays a role in the risk of chronic conditions that are related to body composition; however, our understanding of these associations in Puerto Ricans, a population characterized by multiple ancestries, is limited. This study investigated the relationship between genetic admixture and body composition in 652 Puerto Ricans from the Boston Puerto Rican Osteoporosis Study. Genetic ancestry was estimated from 100 ancestry-informative markers. Body composition measures were obtained from dual-energy X-ray absorptiometry. Multivariable linear regression analyses examined associations between bone mineral density (BMD) of the hip and lumbar spine and percent fat mass and lean mass with genetic admixture. In Puerto Ricans living on the US mainland, European ancestry was associated with lower BMD at the trochanter (P = 0.039) and femoral neck (P = 0.01), and Native American ancestry was associated with lower BMD of the trochanter (P = 0.04). African ancestry was associated with a higher BMD at the trochanter (P = 0.004) and femoral neck (P = 0.001). Ancestry was not associated with percent fat mass or lean mass or waist circumference. Our findings are consistent with existing research demonstrating inverse associations between European and Native American ancestries and BMD and positive relationships between African ancestry and BMD. This work contributes to our understanding of the high prevalence of chronic disease experienced by this population and has implications for other ethnic minority groups, particularly those with multiple ancestries. Future research should consider interactions between ancestry and environmental factors, as this may provide individualized approaches for disease prevention.

Epigenome-wide association study of triglyceride postprandial responses to a high-fat dietary challenge.

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.

A critical role for the Drosophila dopamine D1-like receptor Dop1R2 at the onset of metamorphosis.

BACKGROUND: Insect metamorphosis relies on temporal and spatial cues that are precisely controlled. Previous studies in Drosophila have shown that untimely activation of genes that are essential to metamorphosis results in growth defects, developmental delay and death. Multiple factors exist that safeguard these genes against dysregulated expression. The list of identified negative regulators that play such a role in Drosophila development continues to expand. RESULTS: By using RNAi transgene-induced gene silencing coupled to spatio/temporal assessment, we have unraveled an important role for the Drosophila dopamine 1-like receptor, Dop1R2, in development. We show that Dop1R2 knockdown leads to pre-adult lethality. In adults that escape death, abnormal wing expansion and/or melanization defects occur. Furthermore we show that salivary gland expression of this GPCR during the late larval/prepupal stage is essential for the flies to survive through adulthood. In addition to RNAi-induced effects, treatment of larvae with the high affinity D1-like receptor antagonist flupenthixol, also results in developmental arrest, and in morphological defects comparable to those seen in Dop1R2 RNAi flies. To examine the basis for pupal lethality in Dop1R2 RNAi flies, we carried out transcriptome analysis. These studies revealed up-regulation of genes that respond to ecdysone, regulate morphogenesis and/or modulate defense/immunity. CONCLUSION: Taken together our findings suggest a role for Dop1R2 in the repression of genes that coordinate metamorphosis. Premature release of this inhibition is not tolerated by the developing fly.

Gain-of-function lipoprotein lipase variant rs13702 modulates lipid traits through disruption of a microRNA-410 seed site.

Genome-wide association studies (GWAS) have identified hundreds of genetic variants that are associated with lipid phenotypes. However, data supporting a functional role for these variants in the context of lipid metabolism are scarce. We investigated the association of the lipoprotein lipase (LPL) variant rs13702 with plasma lipids and explored its potential for functionality. The rs13702 minor allele had been predicted to disrupt a microRNA (miR) recognition element (MRE) seed site (MRESS) for the human microRNA-410 (miR-410). Furthermore, rs13702 is in linkage disequilibrium (LD) with several SNPs identified by GWAS. We performed a meta-analysis across ten cohorts of participants that showed a statistically significant association of rs13702 with triacylglycerols (TAG) (p = 3.18 × 10(-42)) and high-density lipoprotein cholesterol (HDL-C) (p = 1.35 × 10(-32)) with each copy of the minor allele associated with 0.060 mmol/l lower TAG and 0.041 mmol/l higher HDL-C. Our data showed that an LPL 3' UTR luciferase reporter carrying the rs13702 major T allele was reduced by 40% in response to a miR-410 mimic. We also evaluated the interaction between intake of dietary fatty acids and rs13702. Meta-analysis demonstrated a significant interaction between rs13702 and dietary polyunsaturated fatty acid (PUFA) with respect to TAG concentrations (p = 0.00153), with the magnitude of the inverse association between dietary PUFA intake and TAG concentration showing -0.007 mmol/l greater reduction. Our results suggest that rs13702 induces the allele-specific regulation of LPL by miR-410 in humans. This work provides biological and potential clinical relevance for previously reported GWAS variants associated with plasma lipid phenotypes.

The Omega-3 Index Is Inversely Associated with Depressive Symptoms among Individuals with Elevated Oxidative Stress Biomarkers.

BACKGROUND: Omega-3 (n-3) fatty acid (FA) consumption is thought to improve depressive symptoms. However, current evidence is limited, and whether this association exists among Puerto Ricans, a population burdened by depression, remains uncertain. OBJECTIVES: We examined the association between ω-3 FA biomarkers and depressive symptoms as well as the potential influence of oxidative stress. METHODS: Baseline and longitudinal analyses were conducted in the Boston Puerto Rican Health Study (n= 787; participants aged 57 ± 0.52 y, 73% women). Urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) concentration, a measure of oxidative stress, and erythrocyte FA composition were collected at baseline. We calculated the omega-3 index as the sum of eicosapentaenoic and docosahexaenoic acids, expressed as a percentage of total FAs. Baseline and 2-y depressive symptoms were characterized by using the Center for Epidemiological Studies-Depression Scale (CES-D). Statistical analyses included linear and logistic regression. RESULTS: Urinary 8-OHdG concentration tended to modify the relation between the erythrocyte omega-3 index and baseline CES-D score (P-interaction = 0.10). In stratified analyses, the omega-3 index was inversely associated with CES-D score (ß = -1.74, SE = 0.88;P= 0.02) among those in the top quartile of 8-OHdG concentration but not among those in the lower quartiles. The relation between the omega-3 index and CES-D at 2 y was more clearly modified by 8-OHdG concentration (P-interaction = 0.04), where the omega-3 index was inversely associated with CES-D at 2 y, adjusted for baseline (ß = -1.66, SE = 0.66;P= 0.02), only among those with elevated 8-OHdG concentrations. Among individuals not taking antidepressant medications and in the top tertile of urinary 8-OHdG concentration, the omega-3 index was associated with significantly lower odds of a CES-D score ≥16 at baseline (OR: 0.72; 95% CI: 0.53, 0.96) but not at 2 y (OR: 0.83; 95% CI: 0.60, 1.15). CONCLUSIONS: An inverse association between the omega-3 index and depressive symptoms was observed among participants with elevated oxidative stress biomarkers. These data suggest that oxidative stress status may identify those who might benefit from ω-3 FA consumption to improve depressive symptoms.

CD209a expression on dendritic cells is critical for the development of pathogenic Th17 cell responses in murine schistosomiasis.

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-1ß 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-1ß 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.

Genome-wide interaction of genotype by erythrocyte n-3 fatty acids contributes to phenotypic variance of diabetes-related traits.

BACKGROUND: Little is known about the interplay between n-3 fatty acids and genetic variants for diabetes-related traits at the genome-wide level. The present study aimed to examine variance contributions of genotype by environment (GxE) interactions for different erythrocyte n-3 fatty acids and genetic variants for diabetes-related traits at the genome-wide level in a non-Hispanic white population living in the U.S.A. (n = 820). A tool for Genome-wide Complex Trait Analysis (GCTA) was used to estimate the genome-wide GxE variance contribution of four diabetes-related traits: HOMA-Insulin Resistance (HOMA-IR), fasting plasma insulin, glucose and adiponectin. A GxE genome-wide association study (GWAS) was conducted to further elucidate the GCTA results. Replication was conducted in the participants of the Boston Puerto Rican Health Study (BPRHS) without diabetes (n = 716). RESULTS: In GOLDN, docosapentaenoic acid (DPA) contributed the most significant GxE variance to the total phenotypic variance of both HOMA-IR (26.5%, P-nominal = 0.034) and fasting insulin (24.3%, P-nominal = 0.042). The ratio of arachidonic acid to eicosapentaenoic acid + docosahexaenoic acid contributed the most significant GxE variance to the total variance of fasting glucose (27.0%, P-nominal = 0.023). GxE variance of the arachidonic acid/eicosapentaenoic acid ratio showed a marginally significant contribution to the adiponectin variance (16.0%, P-nominal = 0.058). None of the GCTA results were significant after Bonferroni correction (P < 0.001). For each trait, the GxE GWAS identified a far larger number of significant single-nucleotide polymorphisms (P-interaction ≤ 10E-5) for the significant E factor (significant GxE variance contributor) than a control E factor (non-significant GxE variance contributor). In the BPRHS, DPA contributed a marginally significant GxE variance to the phenotypic variance of HOMA-IR (12.9%, P-nominal = 0.068) and fasting insulin (18.0%, P-nominal = 0.033). CONCLUSION: Erythrocyte n-3 fatty acids contributed a significant GxE variance to diabetes-related traits at the genome-wide level.

Genome-wide association studies identified novel loci for non-high-density lipoprotein cholesterol and its postprandial lipemic response.

Non-high-density lipoprotein cholesterol(NHDL) is an independent and superior predictor of CVD risk as compared to low-density lipoprotein 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 Study. Our replication cohorts included 3,313 subjects from the Heredity and Phenotype Intervention Heart Study and Family Heart Study. 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, r (2) = 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.

Circulating 25-hydroxyvitamin D, IRS1 variant rs2943641, and insulin resistance: replication of a gene-nutrient interaction in 4 populations of different ancestries.

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 ß = -0.008, 95% CI: -0.016 to -0.001, P interaction = 0.004] and insulin (log transformed) (pooled ß = -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.

Quantifying diet for nutrigenomic studies.

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.

Genome-wide association study of osteoporosis identifies genetic risk and interactions with DASH diet and sugar sweetened beverages in a Hispanic cohort of older adults.

BACKGROUND: Osteoporosis (OP) and low bone mass can be debilitating and costly conditions if not acted on quickly. This disease is also difficult to diagnose as symptoms develop unnoticed until fracture occurs. Therefore, gaining understanding of the genetic risk associated with these conditions could be beneficial for healthcare professionals in early detection and prevention. METHODS: The Boston Puerto Rican Osteoporosis (BPROS) study, an ancillary study to the Boston Puerto Rican Health Study (BPRHS), collected information regarding bone and bone health. All bone measurements were taken during regular BPROS visits using dual-energy x-ray absorptiometry. Osteoporosis was defined as T-score ≤ -2.5 (2.5 SD or more below peak bone mass). Dietary variables were collected at the second wave of the BPRHS via food frequency questionnaire. We conducted genome-wide associations with bone outcomes including bone mineral density (BMD) and OP for 978 participants. We also examined interactions with dietary quality on the relationships between genotype and bone outcomes. We further tested if candidate genetic variants described in previous GWAS on OP and BMD contribute to OP risk in this population. RESULTS: Four variants were associated with OP: rs114829316 (IQCJ), rs76603051, rs12214684 (MCHR2), and rs77303493 (RIN2), and two variants with BMD of lumbar spine (rs11855618, CGNL1) and hip (rs73480593, NTRK2), reaching the genome-wide significance threshold of P ≤ 5E-08. In a gene-diet interaction analysis, we found that one SNP showed a significant interaction with the overall DASH score, and 7 SNPs with sugar-sweeten beverages, a major contributor to the DASH score. CONCLUSION: This study identifies new genetic markers related to osteoporosis and BMD in older Hispanic adults. Additionally, we uncovered unique genetic markers that interact with dietary quality, specifically sugar-sweetened beverages, in relation to bone health. These findings may be useful to guide early detection and preventative care.