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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. [ABSTRACT FROM AUTHOR]

Objective: We aimed to identify hemoglobin A1c (HbA1c)-associated genetic variants and examine their implications for glycemic status evaluated by HbA1c in U.S. Hispanics/Latinos with diverse genetic ancestries.Research Design and Methods: We conducted a genome-wide association study (GWAS) of HbA1c in 9,636 U.S. Hispanics/Latinos without diabetes from the Hispanic Community Health Study/Study of Latinos, followed by a replication among 4,729 U.S. Hispanics/Latinos from three independent studies.Results: Our GWAS and replication analyses showed 10 previously known and novel loci associated with HbA1c at genome-wide significance levels (P < 5.0 × 10-8). In particular, two African ancestry-specific variants, HBB-rs334 and G6PD-rs1050828, which are causal mutations for sickle cell disease and G6PD deficiency, respectively, had ∼10 times larger effect sizes on HbA1c levels (β = -0.31% [-3.4 mmol/mol]) and -0.35% [-3.8 mmol/mol] per minor allele, respectively) compared with other HbA1c-associated variants (0.03-0.04% [0.3-0.4 mmol/mol] per allele). A novel Amerindian ancestry-specific variant, HBM-rs145546625, was associated with HbA1c and hematologic traits but not with fasting glucose. The prevalence of hyperglycemia (prediabetes and diabetes) defined using fasting glucose or oral glucose tolerance test 2-h glucose was similar between carriers of HBB-rs334 or G6PD-rs1050828 HbA1c-lowering alleles and noncarriers, whereas the prevalence of hyperglycemia defined using HbA1c was significantly lower in carriers than in noncarriers (12.2% vs. 28.4%, P < 0.001). After recalibration of the HbA1c level taking HBB-rs334 and G6PD-rs1050828 into account, the prevalence of hyperglycemia in carriers was similar to noncarriers (31.3% vs. 28.4%, P = 0.28).Conclusions: This study in U.S. Hispanics/Latinos found several ancestry-specific alleles associated with HbA1c through erythrocyte-related rather than glycemic-related pathways. The potential influences of these nonglycemic-related variants need to be considered when the HbA1c test is performed. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 (β = -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 (β = -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. [ABSTRACT FROM AUTHOR]

Lipoprotein subclass concentrations are modifiable markers of cardiovascular disease risk. Fenofibrate is known to show beneficial effects on lipoprotein subclasses, but little is known about the role of genetics in mediating the responses of lipoprotein subclasses to fenofibrate. A recent genomewide association study (GWAS) associated several single nucleotide polymorphisms (SNPs) with lipoprotein measures, and validated these associations in two independent populations. We used this information to construct genetic risk scores (GRSs) for fasting lipoprotein measures at baseline (pre-fenofibrate), and aimed to examine whether these GRSs also associated with the responses of lipoproteins to fenofibrate. Fourteen lipoprotein subclass measures were assayed in 817 men and women before and after a three week fenofibrate trial. We set significance at a Bonferroni corrected alpha <0.05 (p < 0.004). Twelve subclass measures changed with fenofibrate administration (each p = 0.003 to <0.0001). Mixed linear models which controlled for age, sex, body mass index (BMI), smoking status, pedigree and study-center, revealed that GRSs were associated with eight baseline lipoprotein measures (p < 0.004), however no GRS was associated with fenofibrate response. These results suggest that the mechanisms for changes in lipoprotein subclass concentrations with fenofibrate treatment are not mediated by the genetic risk for fasting levels. [ABSTRACT FROM AUTHOR]