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Single nucleotide polymorphisms (SNPs) in the noncoding region of 9p21 have been associated with cardiovascular disease (CVD), but the mechanisms by which these genetic variants contribute to the pathogenesis of CVD remain unknown since no annotated proteins are present in this region of DNA. The objective of the current study was to determine if 9p21 genotypes are associated with distinct plasma proteins in young adults. Subjects were 1611 young adults aged 20-29 years from the Toronto Nutrigenomics and Health Study (1098 females and 513 males). DNA was isolated from fasting blood to analyze four SNPs in 9p21 (rs2383206, rs10757274, rs10757278, and rs1333049). Abundant plasma proteins ( n = 54) were measured using liquid chromatography multiple reaction monitoring mass spectrometry. Analysis of covariance was used to determine differences in plasma proteins between genotypes. In Caucasians ( n = 524), four SNPs were associated with apolipoprotein E and two with haptoglobin-β-chain concentration. In East Asians ( n = 388), three SNPs were associated with α-1b-Glycoprotein, two with apolipoprotein B-100, one with apolipoprotein E and one with haptoglobin-β-chain concentration. In South Asians ( n = 117), one SNP was associated with apolipoprotein B-100 concentration. Our findings suggest that 9p21 genotypes may play a role in various pathophysiological pathways that contribute to risk of CVD in early adulthood that might be distinct among different ethnocultural groups.

What is the central question of this study? Does a common genetic variant in the βThis study explored whether the β

BACKGROUND Single nucleotide polymorphisms (SNPs) in the 9p21 region have been associated with cardiovascular disease (CVD), but previous studies have focussed on older populations. The objective of this study was to determine the association between 9p21 genotypes and biomarkers of CVD risk in young adults from different ethnocultural groups. METHODS Subjects were 1,626 participants aged 20-29 years from the Toronto Nutrigenomics and Health Study. Fasting blood was collected to measure glucose, insulin, c-reactive protein and serum lipids, as well as to isolate DNA for genotyping subjects for five SNPs in 9p21. Analyses were conducted for the entire population and separately for women (n = 1,109), men (n = 517), Caucasians (n = 771), East Asians (n = 561) South Asians (n = 175) and Others (n = 119). ANOVA and ANCOVA were used to examine if 9p21 genotypes were associated with biomarkers of CVD risk. RESULTS In the entire group, the risk alleles of rs10757278 and rs2383206 were associated with higher mean insulin (p = 0.01). Risk alleles for rs4977574, rs10757278, rs2383206, rs1333049 and rs10757274 were associated with higher serum insulin in women (p = 0.008, p = 0.008, p = 0.0003, p = 0.002, and p = 0.001, respectively), but not in men (p = 0.41, p = 0.13, p = 0.31, p = 0.34, and 0.35, respectively). The association between 9p21 and insulin remained significant among women not taking hormonal contraceptives (HC), but was not significant among women taking HCs. CONCLUSION Our findings suggest that 9p21 genotypes may play a role in the development of insulin resistance in early adulthood among women, but not men, and the effects appear to be attenuated by HC use.

Personalized nutrition aims to prevent the onset and development of chronic diseases by targeting dietary recommendations to an individual’s genetic profile. Gene–diet interactions that affect metabolic pathways relevant to disease risk are continuously being uncovered. Discoveries in the field of nutrigenomics demonstrate that some individuals may benefit from adhering to different dietary guidelines than others, depending on their genotype. Certain industries have already begun to capitalize on the anticipation that knowledge of genomic information could help prevent the risk of developing diseases. Although disclosure of genetic information has been associated with the adoption of positive health-related behaviors under certain circumstances, the effect of providing gene-based dietary advice on motivating adherence to favorable dietary changes is largely unknown.

Many studies have examined the effect of caffeine on exercise performance, but findings have not always been consistent. The objective of this study was to determine whether variation in the CYP1A2 gene, which affects caffeine metabolism, modifies the ergogenic effects of caffeine in a 10-km cycling time trial.Competitive male athletes (n = 101; age = 25 ± 4 yr) completed the time trial under three conditions: 0, 2, or 4 mg of caffeine per kilogram body mass, using a split-plot randomized, double-blinded, placebo-controlled design. DNA was isolated from saliva and genotyped for the -163AC polymorphism in the CYP1A2 gene (rs762551).Overall, 4 mg·kg caffeine decreased cycling time by 3% (mean ± SEM) versus placebo (17.6 ± 0.1 vs 18.1 ± 0.1 min, P = 0.01). However, a significant (P0.0001) caffeine-gene interaction was observed. Among those with the AA genotype, cycling time decreased by 4.8% at 2 mg·kg (17.0 ± 0.3 vs 17.8 ± 0.4 min, P = 0.0005) and by 6.8% at 4 mg·kg (16.6 ± 0.3 vs 17.8 ± 0.4 min, P0.0001). In those with the CC genotype, 4 mg·kg increased cycling time by 13.7% versus placebo (20.8 ± 0.8 vs 18.3 ± 0.5 min, P = 0.04). No effects were observed among those with the AC genotype.Our findings show that both 2 and 4 mg·kg caffeine improve 10-km cycling time, but only in those with the AA genotype. Caffeine had no effect in those with the AC genotype and diminished performance at 4 mg·kg in those with the CC genotype. CYP1A2 genotype should be considered when deciding whether an athlete should use caffeine for enhancing endurance performance.

Background/Aims: To determine whether variation in the TAS1R2 gene affects sucrose taste perception and sugar intake. Methods: Participants were men (n = 238) and women (n = 458) aged 20-29 years. A subset (n = 95) with body mass index (BMI) data available completed a sensory analysis study. A food frequency questionnaire assessed dietary intake, and eight polymorphisms were genotyped (rs12033832, rs12137730, rs35874116, rs3935570, rs4920564, rs4920566, rs7513755 and rs9701796). Sucrose taste thresholds were determined by staircase procedure (solutions: 9 × 10-6 to 0.5 mol/l). Suprathreshold sensitivity to 0.01-1.0 mol/l sucrose solutions was assessed using general Labeled Magnitude Scales. Results: A significant genotype-BMI interaction was observed for rs12033832 (G>A) for suprathreshold sensitivity (p = 0.01) and sugar intake (p = 0.003). Among participants with a BMI ≥25, G allele carriers had lower sensitivity ratings (mean incremental area under the taste sensitivity curve ± SE; GG/GA 54.4 ± 4.1 vs. AA 178.5 ± 66.6; p = 0.006), higher thresholds (GG/GA 9.3 ± 1.1 vs. AA 4.4 ± 4.3 mmol/l; p = 0.004) and consumed more sugars (GG/GA 130 ± 4 vs. AA 94 ± 13 g/day; p = 0.009). G allele carriers with a BMI Conclusion: The rs12033832 single nucleotide polymorphism in TAS1R2 is associated with sucrose taste and sugar intake, but the effect differs depending on BMI.

Nutrigenetic research examines the effects of inter-individual differences in genotype on responses to nutrients and other food components, in the context of health and of nutrient requirements. A practical application of nutrigenetics is the use of personal genetic information to guide recommendations for dietary choices that are more efficacious at the individual or genetic subgroup level relative to generic dietary advice. Nutrigenetics is unregulated, with no defined standards, beyond some commercially adopted codes of practice. Only a few official nutrition-related professional bodies have embraced the subject, and, consequently, there is a lack of educational resources or guidance for implementation of the outcomes of nutrigenetic research. To avoid misuse and to protect the public, personalised nutrigenetic advice and information should be based on clear evidence of validity grounded in a careful and defensible interpretation of outcomes from nutrigenetic research studies. Evidence requirements are clearly stated and assessed within the context of state-of-the-art 'evidence-based nutrition'. We have developed and present here a draft framework that can be used to assess the strength of the evidence for scientific validity of nutrigenetic knowledge and whether 'actionable'. In addition, we propose that this framework be used as the basis for developing transparent and scientifically sound advice to the public based on nutrigenetic tests. We feel that although this area is still in its infancy, minimal guidelines are required. Though these guidelines are based on semi-quantitative data, they should stimulate debate on their utility. This framework will be revised biennially, as knowledge on the subject increases. © 2017 The Author(s).

ObjectivesCoeliac disease (CD) is a complex autoimmune disorder with known genetic risk factors. Approximately 1% of individuals of European ancestry have CD, but the prevalence among different ethnicities living in Canada remains unknown. The objective of the present study was to determine the prevalence of positive CD serology in a population of Canadian adults living in Toronto, and to determine whether the prevalence of CD seropositivity and predisposing human leucocyte antigen (HLA)-DQ2/DQ8 risk genotypes differ between major ethnocultural groups.DesignCross-sectional screening study of participants from the Toronto Nutrigenomics and Health and the Toronto Healthy Diet studies.SettingUniversity campus and households across Toronto, Canada.Participants: free-livingAdults (n=2832) of diverse ethnocultural backgrounds.Main outcome measuresPrevalence of positive CD serology was determined by screening for antitissue transglutaminase antibodies in individuals with predisposing HLA-DQ2/DQ8 genotypes. HLA genotypes were determined using six single nucleotide polymorphisms in the HLA gene region.ResultsOf the 2832 individuals screened, a total of 25 (0.88%; 95% CI 0.57% to 1.30%) were determined to have positive CD serology. The majority of seropositive CD cases were undiagnosed (87%). Prevalence was highest among Caucasians (1.48%; 95% CI 0.93% to 2.23%), and similar in those of ‘Other’ (0.74%; 95% CI 0.09% to 2.63%) or ‘Unknown’ (0.43; 95% CI 0.01% to 2.36%) ethnicity. No cases of positive CD serology were identified among East Asian or South Asian individuals. East Asians had a lower prevalence of HLA risk genotypes than Caucasians and South Asians (pConclusionsThe prevalence of positive CD serology among Canadian adults living in Toronto is likely ~1%, with 87% of cases being undiagnosed. These findings suggest the need for better screening in high genetic risk groups.Trial registration numberNCT00516620; Post-results.

We are retracting this Article as we no longer have confidence in the data to support our central conclusion – the detection of Brassica oleracea microRNAs in the bloodstream of humans who consumed broccoli.

Inflammation is a recognized risk factor for the development of chronic diseases, such as type 2 diabetes and atherosclerosis. Evidence suggests that individual fatty acids (FA) may have distinct influences on inflammatory processes. The goal of this study was to conduct a cross-sectional analysis to examine the associations between circulating FA and markers of inflammation in a population of young healthy Canadian adults. FA, high-sensitivity C-reactive protein (hsCRP), and cytokines were measured in fasted plasma samples from 965 young adults (22.6 ± 0.1 years). Gas chromatography was used to measure FA. The following cytokines were analyzed with a multiplex assay: regulated upon activation normal T cell expressed and secreted (RANTES/CCL5), interleukin 1-receptor antagonist (IL-1Ra), interferon-γ (IFN-γ), interferon-γ inducible protein 10 (IP-10), and platelet-derived growth factor β (PDGF-ββ). Numerous statistically significant associations (p < 0.05, corrected for multiple testing) were identified between individual FA and markers of inflammation using linear regression. Myristic (14:0), palmitic (16:0), palmitoleic (16:1n-7), and dihomo-γ-linolenic (20:3n-6) acids were positively associated with all markers of inflammation. In contrast, stearic acid (18:0) was inversely associated with hsCRP and RANTES, and linoleic acid (18:2n-6) was inversely associated with hsCRP, RANTES and PDGF-ββ. In conclusion, our results indicate that specific FA are distinctly correlated with various markers of inflammation. Moreover, the findings of this study suggest that FA profiles in young adults may serve as an early indicator for the development of future complications comprising an inflammatory component.

The relationship between vitamin D and cardiometabolic disease risk across ethnic groups is unclear, and it is not known whether the use of hormonal contraceptives (HCs), which affect vitamin D metabolism and are also associated with cardiometabolic disease risk, modifies this relationship. Our objectives were to determine the prevalence of vitamin D deficiency (plasma 25-hydroxyvitamin D [25(OH)D]30 nmol/L) to assess seasonal variation in concentrations of 25(OH)D, and to examine whether 25(OH)D is associated with cardiometabolic biomarkers across ethnic groups and across men, female HC nonusers, and female HC users in an ethnically diverse population of young adults living in Canada.The study population consisted of Caucasian, East Asian, and South Asian individuals (n = 1384, 69% female) aged 20-29 years. Participants provided overnight fasting blood samples, from which plasma 25(OH)D and cardiometabolic biomarkers were measured. Vitamin D status distributions were compared using χ(2) tests, and analysis of covariance (ANCOVA) was used to examine seasonal variations in 25(OH)D, as well as the association between 25(OH)D and cardiometabolic biomarkers, across groups.Plasma 25(OH)D concentrations fluctuated seasonally among Caucasians and East Asians and across men, female HC nonusers, and female HC users, but they remained low year-round in South Asians, half of whom were vitamin D deficient. Vitamin D deficiency was associated with higher insulin, homeostasis model assessment-estimated insulin resistance (HOMA-IR), and homeostasis model assessment (HOMA)-beta among Caucasians and East Asians and among men and female HC nonusers and with higher triglycerides among men only. No biomarkers were associated with 25(OH)D among South Asians and female HC users, although nonsignificant trends were observed for higher markers of glycemic dysregulation in those who were vitamin D deficient in both groups.Vitamin D deficiency varies between ethnic groups and is particularly high among South Asians, and it is associated with biomarkers of glycemic dysregulation; however, HC use among women may attenuate this association. Given the widespread use of HCs by women throughout the world, a better understanding of the extent to which these medications may modify the relationship between vitamin D and processes related to disease is warranted.

Introduction Past research has reported that single nucleotide polymorphisms (SNPs) in fatty acid desaturase 1 and 2 ( FADS1/2 ) can influence plasma fatty acid (FA) profiles. Changes in FA profiles are known to influence inflammatory processes; therefore both FA and SNPs in FADS1/2 may affect inflammation. The goals of this study were to (i) examine the relationships between individual n −6 FA and estimates of FA desaturation with circulating high sensitivity C-reactive protein (hsCRP) levels, and (ii) determine whether SNPs in FADS1/2 are associated with changes in hsCRP. Methods FA and hsCRP were measured in fasted plasma samples from 878 healthy young adults (20–29yrs). Circulating levels of plasma linoleic (LA), γ-linolenic (GLA), dihomo-γ-linolenic (DGLA) and arachidonic (AA) acids were measured by gas chromatography and used to calculate desaturase indices for FADS1/2 . Nineteen SNPs in FADS1/2 were genotyped in all subjects and six (rs174579, rs174593, rs174626, rs526126, rs968567 and rs17831757) were further analyzed. Results Significant inverse associations were found between LA and hsCRP ( p =8.55×10 −9 ) and the FADS1 desaturase index and hsCRP ( p =4.41×10 −6 ). A significant positive association was found between DGLA and hsCRP ( p =9.10×10 −11 ). Several SNPs were associated with circulating levels of individual FA and desaturase indices, with minor allele carriers having lower AA levels and reduced desaturase indices. A single SNP in FADS2 (rs526126) was weakly associated with hsCRP ( p =0.05). Conclusions This study highlights the relationships between FA and hsCRP, and confirms that FA are strongly influenced by SNPs in FADS1/2 . Furthermore, we found weak evidence that SNPs in FADS1/2 may influence hsCRP levels in young adults.

Vitamin C has been associated with a reduced risk of chronic diseases, but the biological pathways regulated by vitamin C are not all known. The objective was to use a proteomics approach to identify plasma proteins associated with circulating levels of ascorbic acid. Men and women (n=1022) 20-29 years of age from the Toronto Nutrigenomics and Health Study completed a general health and lifestyle questionnaire and a 196-item food frequency questionnaire and provided a fasting blood sample. Circulating ascorbic acid was analyzed by high-performance liquid chromatography, and a mass-spectrometry-based multiple reaction monitoring method was used to measure 54 proteins abundant in plasma that are involved in numerous physiologic pathways. Mean protein concentrations were compared across tertiles of serum ascorbic acid using analysis of covariance adjusted for sex, ethnocultural group, season of blood draw, hormonal contraceptive use among women, waist circumference and tertiles of plasma α-tocopherol. A Bonferroni significance level of P.0009 was applied, and analyses were adjusted for multiple comparisons using the Tukey-Kramer procedure. Levels of complement C9, ceruloplasmin, alpha-1-anti-trypsin, angiotensinogen, complement C3, vitamin D binding protein and plasminogen were inversely associated with levels of ascorbic acid. The inverse association between ascorbic acid and vitamin D binding protein was highest in those with higher levels of serum 25-hydroxyvitamin D. In conclusion, several plasma proteins from various physiologic pathways are significantly associated with circulating levels of ascorbic acid. These findings suggest that vitamin C may have novel physiological effects.

Studies of the relationship between vitamin D and inflammation are equivocal. This may be due to unaccounted confounding. Hormonal contraceptive (HC) use is associated with elevated circulating 25-hydroxyvitamin D [25(OH)D] in Caucasians and African-Americans, but its effects on 25(OH)D in other ethnicities are unclear. HC use is associated with elevated C-reactive protein (CRP), an inflammatory biomarker. Our objectives were to assess the effect of HC use on 25(OH)D across ethnic groups, and to examine the association between HC, 25(OH)D and CRP in an ethnically diverse population of young adults.We recruited Caucasian, East Asian, and South Asian individuals (n=1,403) from Toronto, Canada. Fasting blood measures of 25(OH)D and CRP were obtained.Across ethnic groups, women HC users (n=280) had higher 25(OH)D and CRP than women HC non-users (n=695) and men (n=428) (p0.008 and p0.0001, respectively). Circulating 25(OH)D was positively associated with CRP in the entire population in models not accounting for HC use (β=0.010±0.003; p0.0001). There was no association when men and women HC non-users were examined separately. Among women HC users, there was no association after accounting for hormone dose. A positive association between 25(OH)D and CRP among individuals above the median 25(OH)D (≥51.9 nmol/L) was not significant after adjustment for HC use. No association was observed among individuals below the median.HC use and 25(OH)D were positively associated across ethnic groups. We found no association between 25(OH)D and CRP when HC use was accounted for. HC use confounds the association between 25(OH)D and CRP.

Background/Aims: Vitamin D regulates gene transcription by binding to the vitamin D receptor (VDR), potentially affecting cardiometabolic disease risk. However, studies of 25-hydroxyvitamin D [25(OH)D] and cardiometabolic disease are inconsistent. Inconsistencies may result from unaccounted for interactions between VDR genetic variants and 25(OH)D. We examined the effect of 25(OH)D on the association between VDR variants and cardiometabolic disease biomarkers. Methods: The relationship between 25(OH)D, 24 VDR variants, and 10 cardiometabolic biomarkers was examined in 488 Caucasians aged 20-29 years. Covariate-adjusted general linear models were used to examine the interaction effect of 25(OH)D × VDR on each biomarker. When interactions were significant (p < 0.05), relationships were further examined with analysis of covariance, stratified by tertiles of 25(OH)D and adjusted for multiple comparisons. Results: In the lowest tertile of 25(OH)D, major allele homozygotes for rs3819545 had higher insulin and HOMA-IR than minor allele carriers (p ≤ 0.002). Fasting insulin and HOMA-IR were lower in the highest than the lowest tertile of 25(OH)D among major allele homozygotes (p < 0.0001), but minor allele carriers had similar levels regardless of vitamin D status. Conclusions: We identified 25(OH)D-dependent associations between rs3819545 and glycemic dysregulation biomarkers. Major allele homozygotes with low vitamin D status may be at increased risk of insulin resistance.

Recent research has indicated that part of the interindividual variability in cardiovascular responses to caffeine has a genetic basis. Therefore, knowledge of the individual's genetic constitution may allow an individual tailoring of dietary advice for the use of caffeine-containing beverages, yielding an example of the potential of practical translation of nutrigenetic information. This paper reviews the basis for possible nutrigenetic recommendations on the consumption of caffeine, discussing the current gaps in knowledge but also proposing a mode of action in this research area, which may be transposed to other types of similar recommendations.

While Brassica oleracea vegetables have been linked to cancer prevention, the exact mechanism remains unknown. Regulation of gene expression by cross-species microRNAs has been previously reported; however, its link to cancer suppression remains unexplored. In this study we address both issues. We confirm plant microRNAs in human blood in a large nutrigenomics study cohort and in a randomized dose-controlled trial, finding a significant positive correlation between the daily amount of broccoli consumed and the amount of microRNA in the blood. We also demonstrate that Brassica microRNAs regulate expression of human genes and proteins in vitro, and that microRNAs cooperate with other Brassica-specific compounds in a possible cancer-preventive mechanism. Combined, we provide strong evidence and a possible multimodal mechanism for broccoli in cancer prevention.

Background Dietary recommendations emphasize increased consumption of fruit, vegetables, and whole grain cereals for prevention of chronic disease. Objectives This study assessed the effect of dietary advice and/or food provision on body weight and cardiovascular disease risk factors. Methods Healthy overweight men (n = 209) and women (n = 710), mean age 44.7 years, body mass index [BMI] 32.4 kg/m2, were randomized between November 2005 and August 2009 to receive Health Canada’s food guide (control, n = 486) or 1 of 3 interventions: dietary advice consistent with both Dietary Approaches to Stop Hypertension (DASH) and dietary portfolio principles (n = 145); weekly food provision reflecting this advice (n = 148); or food delivery plus advice (n = 140). Interventions lasted 6 months with 12-month follow-up. Semiquantitative food frequency questionnaires and fasting blood, anthropometric and blood pressure measurements were obtained at baseline, 6 months, and 18 months. Results Participant retention at 6 and 18 months was 91% and 81%, respectively, after food provision compared to 67% and 57% when no food was provided (p Conclusions Provision of foods increased retention but only modestly increased intake of recommended foods. Current dietary recommendations showed small overall benefits in coronary heart disease risk factors. Additional dietary strategies to maximize these benefits are required. (Fruits, Vegetables, and Whole Grains: A Community-based Intervention; NCT00516620)

To determine whether common polymorphisms in the sweet taste receptor (TAS1R2) and glucose transporter (GLUT2) genes are associated with dental caries, 80 healthy Caucasian individuals aged 21–32 years were genotyped and grouped based on the TAS1R2 (Ile191Val) and GLUT2 (Thr110Ile) polymorphisms. Clinical and radiographic examinations were conducted by a single examiner who was blinded to the genotypes. To assess caries prevalence, three different caries scores were determined: DMFT (decayed, missing, and filled teeth), DMFT + X-ray and ICDAS (International Caries Detection and Assessment System). Associations between genotypes and caries prevalence were analyzed using Student’s t test. Based on the genotypes for each of the GLUT2 and TAS1R2 genes, individuals were stratified into four groups for comparison of caries scores. A higher DMFT score (mean ± SE; 4.3 ± 0.4 vs. 6.1 ± 1.2, p = 0.04) was observed among carriers of the Ile allele for GLUT2 (risk group). Carriers of the Val allele for TAS1R2 (resistant group) demonstrated lower caries scores: DMFT (4.1 ± 0.5 vs. 5.8 ± 0.9, p = 0.05), DMFT + X-ray (4.9 ± 0.6 vs. 7.5 ± 0.9, p = 0.01), and ICDAS (19.5 ± 2.2 vs. 26.14 ± 2.82, p = 0.03). Based on genotype stratification, caries scores were significantly lower in the double resistant group as compared to the double risk groups: DMFT (9.1 ± 0.08 vs. 4.2 ± 0.01, p < 0.01), DMFT + X-ray (10.5 ± 0.07 vs. 5.2 ± 0.01, p < 0.01) and ICDAS (32.9 ± 0.2 vs. 19.9 ± 0.01, p = 0.01). In conclusion, GLUT2 and TAS1R2 genotypes individually and in combination are associated with caries risk. Considering the combination of risk/resistance genotypes might further our understanding of genetic predispositions to dental caries and improve the accuracy of caries prediction models.

Background CRTh2 (chemoattractant-receptor homologous molecule expressed on Th2 cells) is expressed by Th2 cells and other cells involved in allergic inflammation. Single nucleotide polymorphisms (SNPs) in CRTh2 (rs11571288, rs545659, rs634681) have been associated with various phenotypes of allergy in ethnically distinct populations. Here, we assessed the association between CRTh2 rs533116 and allergic asthma, expression of CRTh2 and Th2 cytokine production. Methods CRTh2 rs533116 was genotyped in an ethnically diverse population (n = 1282). The proportion of cells expressing CRTh2 was determined in peripheral blood from subjects with allergic airways disease and controls as well as with in vitro differentiated Th2 cells. Receptor function was assessed by stimulating Th2 cells with the CRTh2-specific agonist 13,14-dihydro-15-keto-PGD2 (DK-PGD2) and measuring IL-4 and IL-13 by intracellular staining and ELISA. Results CRTh2 rs533116 was associated with allergic asthma in White people (2.67 [1.09–6.55], P

Background Nitrous oxide converts vitamin B12 to its nonmetabolically active form, inhibits methionine synthase, and results in an elevation of plasma total homocysteine (tHcy). The authors investigated the effect of nitrous oxide anesthesia on the plasma tHcy concentrations in children the morning after surgery and whether blood concentrations of folate and vitamins B12 and B6 were associated with any potential increase. Methods The authors measured plasma tHcy concentrations in 32 children before and 24 h after initial exposure to nitrous oxide (≥ 2 h). Genotype for methylenetetrahydrofolate reductase C677T and blood concentrations of folate, vitamins B12 and B6, and methylmalonic acid were measured before surgery. Results The median age of participants was 11 months (3-126 months). The median (first, third quartile) postoperative plasma tHcy concentration was significantly higher than the preoperative concentration (6.4 [4.7, 8.9] vs. 5.1[4.1, 6.4] μM, P < 0.0001), a 25% (2%, 42%) relative increase. Six of 28 (21%) children with normal, age-appropriate, preexposure plasma tHcy concentrations had postoperative plasma tHcy concentrations greater than the cutoff values. The duration of nitrous oxide exposure was associated positively with the rise in plasma tHcy concentration (R2 = 0.696, P = < 0.001). Conclusion Exposure to ≥ 2 h nitrous oxide is associated with a small, albeit statistically significant, increase in postoperative plasma tHcy concentrations the morning after surgery in young children. The clinical significance of this increase is unknown.

Personal genetic information has become increasingly accessible to the public as a result of direct-to-consumer (DTC) genetic tests; however, concerns have been raised over their value and potential risks. We compared the effects of providing genotype-based dietary advice with general recommendations on behavioral outcomes using a randomized controlled study. Participants were men and women from the Toronto Nutrigenomics and Health Study between the ages of 20–35 years (n = 149) who completed a survey to assess their awareness of DTC genetic tests and nutrigenomics, as well as potential motivations for undergoing genetic testing. Participants were then randomized into an intervention (I) or control (C) group and were given either genotype-based personalized dietary advice or general dietary advice, respectively. A second survey was administered to assess the participants’ opinions of the dietary reports they received. A greater proportion of participants in the intervention group agreed that they understood the dietary advice they were given (93% (I) vs. 78% (C); p = 0.009). Participants in the intervention group were more likely to agree that the dietary recommendations they received would be useful when considering their diet (88% (I) vs. 72% (C); p = 0.02) and wanted to know more about the recommendations (95% (I) vs. 76% (C); p

Oxidative stress develops as a result of an imbalance between the production and accumulation of reactive species and the body’s ability to manage them using exogenous and endogenous antioxidants. Exogenous antioxidants obtained from the diet, including vitamin C, vitamin E, and carotenoids, have important roles in preventing and reducing oxidative stress. Individual genetic variation affecting proteins involved in the uptake, utilization and metabolism of these antioxidants may alter their serum levels, exposure to target cells and subsequent contribution to the extent of oxidative stress. Endogenous antioxidants include the antioxidant enzymes superoxide dismutase, catalase, glutathione peroxidase, paraoxanase, and glutathione S-transferase. These enzymes metabolize reactive species and their by-products, reducing oxidative stress. Variation in the genes coding these enzymes may impact their enzymatic antioxidant activity and, thus, the levels of reactive species, oxidative stress, and risk of disease development. Oxidative stress may contribute to the development of chronic disease, including osteoporosis, type 2 diabetes, neurodegenerative diseases, cardiovascular disease, and cancer. Indeed, polymorphisms in most of the genes that code for antioxidant enzymes have been associated with several types of cancer, although inconsistent findings between studies have been reported. These inconsistencies may, in part, be explained by interactions with the environment, such as modification by diet. In this review, we highlight some of the recent studies in the field of nutrigenetics, which have examined interactions between diet, genetic variation in antioxidant enzymes, and oxidative stress.

Toll-like receptor 4 (TLR4) is a protein of the innate immune system hypothesized to mediate some of the effects of a high-fat diet on inflammation and insulin resistance. As both these factors are associated with the metabolic syndrome (MetS), genetic variation in TLR4 may affect the relationship between dietary lipids and MetS. The objective of the study was to determine whether 2 polymorphisms in TLR4 (rs4986790 Asp299Gly and rs5030728 G>A) modify the relationship between dietary fat and markers of the MetS. Participants were healthy young men and women of various ethnocultural backgrounds. Dietary intake was estimated using a 1-month semiquantitative food frequency questionnaire, and fasting blood samples were taken for genotyping and biomarker measurement. The Asp299Gly polymorphism in TLR4 was associated with increased insulin, homeostasis model assessment of insulin resistance (P < .05), and homeostasis model assessment of β-cell function (P < .05) and family history of diabetes (P = .0002). The intronic polymorphism rs5030728 modified the relationship between dietary saturated fatty acids (SFAs) and high-density lipoprotein (HDL) cholesterol (P = .003 for interaction). The SFA intake was inversely associated with HDL cholesterol among individuals homozygous for the G allele (β = −0.015 ± 0.007 mmol/L, P = .04), whereas a positive relationship was observed for heterozygotes (β = 0.025 ± 0.01 mmol/L, P = .02). There was no association between dietary SFAs and HDL cholesterol among individuals homozygous for the A allele. These observations suggest that both diet and innate immunity may interact to influence components of the MetS.

Consumption of almonds has been associated with increased bone mineral density, but the direct effects of almonds on bone cells are not known. We determined whether serum obtained following the consumption of a meal containing 60 g of almonds affects human osteoclast formation, function, and gene expression in vitro. Human osteoclast precursors were cultured in medium containing 10% serum obtained from 14 healthy subjects at baseline and 4 hours following the consumption of 3 test meals containing almonds, potatoes, and rice and balanced for macronutrient composition. Osteoclast formation was determined by the number of tartrate-resistant acid phosphatase (TRAP)(+) multinucleated cells, and osteoclast function was assessed by measuring TRAP activity in the culture medium and calcium released from OsteoAssay (Lonza Walkersville, Walkersville, MD, USA) plates. The expression of cathepsin K, receptor activator of nuclear factor kB, and matrix metalloproteinase-9 genes was measured by real-time reverse transcriptase-polymerase chain reaction. Compared with serum obtained at baseline, serum obtained 4 hours following the consumption of the almond meal reduced osteoclast formation by approximately 20%, TRAP activity by approximately 15%, calcium release by approximately 65%, and the expression of cathepsin K, receptor activator of nuclear factor kB, and matrix metalloproteinase-9 by 13% to 23%. No effects were observed with serum obtained from the other test meals. Serum obtained 4 hours following the consumption of an almond meal inhibits osteoclast formation, function, and gene expression in cultured human osteoclast precursors, and provides evidence for a positive effect of almonds on bone health.

Rationale: The mechanisms underlying the various acute effects of caffeine are not clear. Some of the physiological effects of caffeine may be mediated through increased catecholamines, which are metabolized by catechol-O-methyltransferase (COMT). A Val158Met polymorphism in COMT affects enzyme activity with Val/Val homozygotes having a 3–4-fold greater activity than Met/Met homozygotes. Objective: To determine whether the self-reported acute effects of caffeine are associated with the COMT Val158Met polymorphism (rs4680). Methods: Subjects were men (n=344) and women (n=801) aged 20–29 years who were participants of the Toronto Nutrigenomics and Health Study. Acute effects were assessed by questionnaire, and caffeine intake was assessed using a semiquantitative food frequency questionnaire. Odds ratios (OR) and 95% confidence intervals (CI) were calculated to determine if the likelihood of reporting an acute effect was associated with COMT genotype. Results: Among individuals consuming more than 200 mg/da...

Recent evidence indicates that genetic variation in fatty acid desaturases 1 and 2 ( FADS1 and FADS2 ) is associated with changes in plasma fatty acid profiles; however, the association with altered desaturase activity has not been examined in different ethnic populations. The present study examined whether genetic variation in the FADS gene cluster regulates desaturase activity in two populations of young Canadian adults (Caucasian and Asian) and whether altered desaturase activity was reflected in both n−3 and n−6 fatty acid profiles. FADS1 and FADS2 were genotyped in a random subset of participants (Caucasian, n = 78; Asian, n = 69) from the Toronto Nutrigenomics and Health study using MALDI-TOF mass spectrometry, and plasma fatty acids were measured by gas chromatography. Desaturase activities were estimated using the following fatty acid ratios: γ-linoleic acid to linoleic acid (GLA:LA), arachidonic acid to linoleic acid (AA:LA), arachidonic acid to dihomo-γ-linoleic acid (AA:DGLA), and eicosapentaneoic acid to α-linolenic acid (EPA:ALA). Nineteen single nucleotide polymorphisms (SNPs) were examined, and several SNPs (9 in Caucasians and 8 in Asians) were associated with various desaturase activities. The most significant association detected was between the FADS1 rs174547 SNP and AA:LA in both Caucasians (p = 4.0 × 10 − 8 ) and Asians (p = 5.0 × 10 − 5 ). Although the minor allele for this SNP differed between Caucasians (T) and Asians (C), carriers of the C allele had a lower desaturase activity than carriers of the T allele in both groups. To determine whether rs174547 was a dominant SNP in the FADS gene cluster, we constructed an additional model which included this SNP as a covariate. Only one SNP (rs498793 in FADS2 ) remained associated with the EPA:ALA ratio (p = 1.1 × 10 − 5 ) in Asians. This study shows that genetic variation in the FADS gene cluster (in particular rs174547) can alter desaturase activity in subjects of Caucasians and Asian descent.

We describe a simplified isocratic HPLC method for the simultaneous determination of all-trans-retinol, 3 tocopherols (α-, δ-, and γ- tocopherol), and 8 carotenoids (lutein, zeaxanthin, canthaxanthin, β-cryptoxanthin, all-trans-lycopene, 5-cis-lycopne, α-carotene, and β-carotene) in human plasma, which uses a single C18 reversed-phase column (4.6 × 250 mm, 3 µm). A photodiode array detector was used to measure the UV‐vis wavelength absorbance of retinol and the eight carotenoids, and fluorescence detection was used for the tocopherols. The linear ranges of the calibration curves for the calibration solutions injected into the HPLC column are 0.02‐6.0 µg/mL for all-trans-retinol, β-cryptoxanthin and α-carotene; 0.01‐3.0 µg/mL for δ-tocopherol, lutein, and lycopene; 0.08‐24.0 µg/mL for γ-tocopherol; 0.3‐90.0 µg/mL for α-tocopherol; 0.005‐1.5 µg/mL for zeaxanthin and canthaxanthin; and 0.04‐12.0 µg/mL for β-carotene.

Obesity is a major risk factor for type 2 diabetes mellitus (T2DM), which is a significant health problem worldwide. Active disease is associated with low-grade chronic inflammation resulting in part from the activation of the innate immune system. In obesity, this activation leads to the release of pro-inflammatory cytokines such as tumor necrosis factor-α, interleukin-1β and interleukin-6 that block major anabolic cascades downstream of insulin signaling and thus disrupt insulin homeostasis and action. Cytokines also trigger the production of acute-phase reactants such as C-reactive protein, plasminogen activator inhibitor-1, serum amyloid-A, and haptoglobin. The elevated synthesis of pro-inflammatory cytokines and acute-phase proteins (inflammatory network) characterizes the early (or pre-clinical) stages of T2DM and exhibits a graded increase with the disease progression. Current evidence suggests that understanding inflammatory networks can point to new biomarkers that may permit capturing the interaction between genetic and environmental risk factors in the pathogenesis of T2DM. Such biomarkers have a significant public health potential in the prediction of disease occurrence beyond risk factors presently monitored, such as family history, lifestyle assessment and standard clinical chemistry profiles. Furthermore, inflammatory markers may assist in the evaluation of novel strategies for prevention, particularly in relation to micronutrients. This review discusses the current knowledge linking T2DM risk to inflammatory signaling pathways interacting with the innate immunity system and the prospect of inflammatory markers serving as molecular targets for prevention and/or biomarkers for early risk prediction of T2DM. The potential of micronutrients replenishment to improve insulin action by attenuating inflammation is also evaluated in the context of the public health relevance of this approach.

We previously showed that polymorphisms in the tumor necrosis factor (TNF)-alpha gene, which is regulated by nuclear factor kappa B (NF-kappaB), modify the association between dietary polyunsaturated fatty acid (PUFA) intake and circulating HDL-cholesterol. Our objective was to determine whether a common polymorphism in the NFKB1 gene (-94Ins/Del ATTG) interacts with PUFA intake to affect HDL-cholesterol in two distinct populations. Participants were diabetes-free young adults (n=593) and older individuals with diet-treated type 2 diabetes (n=103). The NF-kappaB polymorphism modified the association between dietary PUFA intake and HDL-cholesterol in both populations (p=0.02 and 0.005 for interaction). Among individuals with the Ins/Ins genotype, each 1% increase in energy from PUFA was associated with a 0.03+/-0.01 mmol/L (p for slope=0.009) and 0.06+/-0.02 mmol/L (p=0.02) increase in HDL-cholesterol among participants from the diabetes-free and diabetic populations. An inverse relationship was observed among those with the Del/Del genotype, which was significantly different from that of the Ins/Ins groups in both populations (p=0.02 and 0.006). No effects were observed for the Ins/Del genotype in either population (p>0.05). These findings show that this functional polymorphism in the NF-kB gene modifies the association between PUFA intake and plasma HDL-cholesterol in two distinct populations.

Taste perception plays a key role in determining individual food preferences and dietary habits. Individual differences in bitter, sweet, umami, sour, or salty taste perception may influence dietary habits, affecting nutritional status and nutrition-related chronic disease risk. In addition to these traditional taste modalities there is growing evidence that "fat taste" may represent a sixth modality. Several taste receptors have been identified within taste cell membranes on the surface of the tongue, and they include the T2R family of bitter taste receptors, the T1R receptors associated with sweet and umami taste perception, the ion channels PKD1L3 and PKD2L1 linked to sour taste, and the integral membrane protein CD36, which is a putative "fat taste" receptor. Additionally, epithelial sodium channels and a vanilloid receptor, TRPV1, may account for salty taste perception. Common polymorphisms in genes involved in taste perception may account for some of the interindividual differences in food preferences and dietary habits within and between populations. This variability could affect food choices and dietary habits, which may influence nutritional and health status and the risk of chronic disease. This review will summarize the present state of knowledge of the genetic variation in taste, and how such variation might influence food intake behaviors.

Background/Aims: Vitamin C transporter proteins SVCT1 and SVCT2 are required for the absorption and transport of vitamin C in humans. This study aims to determine whether common SVCT genotypes modify the association between dietary vitamin C and serum ascorbic acid. Methods: Non-smoking men and women (n = 1,046) aged 20–29 were participants of the Toronto Nutrigenomics and Health Study. Overnight fasting blood samples were collected to determine serum ascorbic acid concentrations by HPLC and to genotype for two SVCT1 (rs4257763 and rs6596473) and two SVCT2 (rs6139591 and rs2681116) polymorphisms. Results: No diet-gene interactions were observed for the vitamin C transporter polymorphisms, however, the average (mean ± SE) serum ascorbic acid concentrations differed between rs4257763 genotypes (GG: 24.4 ± 1.3, GA: 26.8 ± 1.1, AA: 29.7 ± 1.4 µmol/l; p = 0.002). For this polymorphism, the correlation between dietary vitamin C and serum ascorbic acid was only significant in subjects with a G allele. The SVCT2 polymorphisms also appeared to modify the strength of the diet-serum correlation. Conclusions: Our findings demonstrate that genetic variation in SVCT1 can influence serum ascorbic acid concentrations and that SVCT1 and SVCT2 genotypes modify the strength of the correlation between dietary vitamin C and serum ascorbic acid.

Background/Aims:TAS2R38 belongs to the TAS2R bitter taste receptor gene family and polymorphisms are associated with differences in bitter taste perception of phenylthiocarbamide (PTC) and 6-n-propylthiouracil (PROP). The objectives were to test whether the genotype-phenotype relationship varies between ethnocultural groups and whether a filter paper method can predict TAS2R38 genotype. Methods: Subjects (n = 911) aged 20–29 rated the intensity of a PTC-containing filter paper on a scale of 1–9, from ‘not at all bitter’ to ‘extremely bitter’. The TAS2R38 A49P polymorphism was detected by real-time PCR. Results: The overall frequency of the 49A variant was 0.47 and the AA, AP, and PP genotype distribution was 0.24, 0.45 and 0.31, respectively. Those with AA, AP, or PP genotypes had mean bitterness rating scores of 2.3, 4.9, and 5.9, respectively. The 49A variant frequency was significantly lower among Asians (28%) as compared to Caucasians (55%), South Asians (60%) or others (56%) (p < 0.0001). The genotype-phenotype relationship was similar across ethnocultural groups, however, a stronger genotype-phenotype association was observed among women as compared to men. Conclusion: Our findings show that a simple PTC filter paper tasting method strongly predicts TAS2R38 genotype, and that the genotype-phenotype association is similar among ethnocultural groups.

Abrupt cessation of caffeine often results in several withdrawal symptoms among habitual caffeine consumers.The objective of the study was to determine whether caffeine withdrawal symptoms co-exist as clusters in some individuals.Withdrawal symptoms and caffeine intake were assessed for men (n=126) and women (n=369), aged 20-29, using a caffeine habits questionnaire and a semi-quantitative food frequency questionnaire, respectively. Principal components factor analysis was used to identify common underlying factors among 14 well-described caffeine withdrawal symptoms. Odds ratios (OR) and 95% confidence intervals (CI) were calculated to determine if the likelihood of reporting a withdrawal factor was associated with habitual caffeine consumption.The 14 withdrawal symptoms were grouped into three factors termed "fatigue and headache", "dysphoric mood", and "flu-like somatic". The likelihood of reporting the fatigue and headache and dysphoric mood factors increased with higher levels of habitual caffeine consumption. Compared to100 mg/day of caffeine, the ORs (95% CI) of reporting the fatigue and headache factor with a habitual intake of 100-200 mg/day and200 mg/day were 1.97 (1.21, 3.21) and 4.44 (2.50, 7.86), respectively. The corresponding ORs (95% CI) for the dysphoric mood factor were 1.55 (0.96, 2.52) and 3.34 (1.99, 5.60).The 14 well-described caffeine withdrawal symptoms factor into three clusters, suggesting the existence of three distinct underlying mechanisms of caffeine withdrawal. Increasing habitual caffeine consumption is associated with an increased likelihood of reporting the fatigue and headache and dysphoric mood symptoms, but not the flu-like somatic symptoms.

Glucose sensing in the brain has been proposed to be involved in regulating food intake, but the mechanism is not known. Glucose transporter type 2 (GLUT2)-null mice fail to control their food intake in response to glucose, suggesting a potential role for this transporter as a glucose sensor in the brain. Here we show that individuals with a genetic variation in GLUT2 (Thr110Ile) have a higher daily intake of sugars in two distinct populations. In the first population, compared with individuals with the Thr/Thr genotype, carriers of the Ile allele had a significantly higher intake of sugars as assessed from 3-day food records administered on two separate visits ( visit 1: 112 ± 9 vs. 86 ± 4 g/day, P = 0.01; visit 2: 111 ± 8 vs. 82 ± 4 g/day, P = 0.003), demonstrating within-population reproducibility. In a second population, carriers of the Ile allele also reported consuming a significantly greater intake of sugars (131 ± 5 vs. 115 ± 3 g/day, P = 0.007) over a 1-mo period as measured from a food frequency questionnaire. GLUT2 genotypes were not associated with fat, protein, or alcohol intake in either population. These observations were consistent across older and younger adults as well as among subjects with early Type 2 diabetes and healthy individuals. Taken together, our findings show that a genetic variation in GLUT2 is associated with habitual consumption of sugars, suggesting an underlying glucose-sensing mechanism that regulates food intake.

Background/Aims: Genetic polymorphisms in tumor necrosis factor-α (TNF-α) modify the association between polyunsaturated fatty acids (PUFA) and plasma high-density lipoprotein (HDL) cholesterol in a population with type 2 diabetes. The objective of this study was to determine whether this gene × diet interaction is observed in a diabetes-free population and whether it is due to n–3 or n–6 PUFA. Methods: Subjects (n = 595) were aged 20–29 years and genotyped for the TNF-α –238G>A and TNF-α –308G>A polymorphisms. Diet was assessed using a food frequency questionnaire. Subjects were grouped as having no minor A allele at both the –238 and –308 positions (0/0), or one minor A allele at either the –238 (1/0) or the –308 (0/1) position. Results: TNF-α genotypes modified the association between dietary PUFA and HDL-cholesterol concentrations (p = 0.04 for interaction). Among individuals with the 0/0 genotype, total PUFA was positively associated with HDL-cholesterol in both men (p = 0.008) and women (p = 0.03), and for both n–6 (p = 0.004) and n–3 (p = 0.04) PUFA. However, an inverse relationship was observed among men carrying the 1/0 genotype (p = 0.005). Conclusion: These findings demonstrate that TNF-α genotypes modify the association between dietary PUFA and HDL-cholesterol and provide further evidence that inflammation is involved in the reverse cholesterol transport.

The debate on the safety of and regulatory approaches for caffeine continues among various stakeholders and regulatory authorities. This decision-making process comes with significant challenges, particularly when considering the complexities of the available scientific data, making the formulation of clear science-based regulatory guidance more difficult. To allow for discussions of a number of key issues, the North American Branch of the International Life Sciences Institute (ILSI) convened a panel of subject matter experts for a caffeine-focused session entitled “Caffeine: Friend or Foe?,” which was held during the 2015 ILSI Annual Meeting. The panelists' expertise covered topics ranging from the natural occurrence of caffeine in plants and interindividual metabolism of caffeine in humans to specific behavioral, reproductive, and cardiovascular effects related to caffeine consumption. Each presentation highlighted the potential risks, benefits, and challenges that inform whether caffeine exposure warrants concern. This paper aims to summarize the key topics discussed during the session.

PURPOSE OF REVIEW: This review summarizes and highlights recent advances in current knowledge of the relationship between coffee and caffeine consumption and risk of coronary heart disease. Potential mechanisms and genetic modifiers of this relationship are also discussed. RECENT FINDINGS: Studies examining the association between coffee consumption and coronary heart disease have been inconclusive. Coffee is a complex mixture of compounds that may have either beneficial or harmful effects on the cardiovascular system. Randomized controlled trials have confirmed the cholesterol-raising effect of diterpenes present in boiled coffee, which may contribute to the risk of coronary heart disease associated with unfiltered coffee consumption. A recent study examining the relationship between coffee and risk of myocardial infarction incorporated a genetic polymorphism associated with a slower rate of caffeine metabolism and provides strong evidence that caffeine also affects risk of coronary heart disease. Several studies have reported a protective effect of moderate coffee consumption, which suggests that coffee contains other compounds that may be beneficial. SUMMARY: Diterpenes present in unfiltered coffee and caffeine each appear to increase risk of coronary heart disease. A lower risk of coronary heart disease among moderate coffee drinkers might be due to antioxidants found in coffee.

BACKGROUND Heterogeneity in circulating lipid concentrations in response to dietary polyunsaturated fatty acids (PUFAs) may be due, in part, to genetic variations. Tumor necrosis factor-alpha (TNF-alpha) is a proinflammatory cytokine that can induce hyperlipidemia and is known to be modulated by dietary PUFAs. OBJECTIVE The objective was to determine whether TNF-alpha genotypes modify the association between dietary PUFA intake and serum lipid concentrations. DESIGN The study involved 53 men and 56 women aged 42-75 y with type 2 diabetes. Dietary intakes were assessed with the use of a 3-d food record, and blood samples were collected to determine fasting serum lipids. DNA was isolated from blood for genotyping by polymerase chain reaction-restriction fragment length polymorphism for the TNF-alpha -238G-->A and -308G-->A polymorphisms. RESULTS PUFA intake was positively associated with serum HDL cholesterol in carriers of the -238A allele (beta = 0.06 +/- 0.03 mmol/L per 1% of energy from PUFAs; P = 0.03), but negatively associated in those with the -238GG genotype (beta = -0.03 +/- 0.01, P = 0.03) (P = 0.004 for interaction). PUFA intake was inversely associated with HDL cholesterol in carriers of the -308A allele (beta = -0.07 +/- 0.02, P = 0.002), but not in those with the -308GG genotype (beta = 0.02 +/- 0.02, P = 0.13) (P = 0.001 for interaction). A stronger gene x diet interaction was observed when the polymorphisms at the 2 positions (-238/-308) were combined (P = 0.0003). Similar effects were observed for apolipoprotein A-I, but not with other dietary fatty acids and serum lipids. CONCLUSION TNF-alpha genotypes modify the relation between dietary PUFA intake and HDL-cholesterol concentrations. These findings suggest that genetic variations affecting inflammation may explain some of the inconsistencies between previous studies relating PUFA intake and circulating HDL.

Tumor necrosis factor alpha (TNF-alpha) is a proinflammatory cytokine that impairs insulin action and alters lipid metabolism. We investigated the effects of genetic polymorphisms of TNF-alpha on circulating biomarkers of insulin resistance and lipid metabolism during an 8-hour metabolic profile test and a 2-hour oral glucose tolerance test in subjects with type 2 diabetes mellitus. Subjects (N = 123) recruited were type 2 diabetic men (n = 56) and women (n = 67) aged 36 to 75 years with a body mass index of at least 25 kg/m(2). Blood samples were collected to determine postprandial changes in circulating lipid levels and biomarkers of insulin resistance. Subjects were genotyped by polymerase chain reaction-restriction fragment length polymorphism for the TNF-alpha -238GA, -308GA, and -863CA polymorphisms. Compared with subjects who were homozygous for the -238G allele, carriers of the -238A allele had an altered ability to suppress postprandial free fatty acids as shown by an increased net incremental area under the curve (0.26 +/- 2.44 vs -1.33 +/- 2.71 mEq h(-1) L(-1), P = .002) during the 8-hour metabolic profile test. This effect was observed in obese (1.04 +/- 2.42 vs -1.68 +/- 2.70 mEq h(-1) L(-1), P = .0004) but not in non-obese (-0.63 +/- 2.20 vs -0.95 +/- 2.71 mEq h(-1) L(-1), P = .6) individuals. Among obese subjects, carriers of the -308A allele had greater insulin resistance as estimated by the homeostasis model assessment of insulin resistance index (4.36 +/- 2.83 vs 2.85 +/- 1.75, P = .01), but no differences were observed among non-obese subjects (2.19 +/- 1.24 vs 1.97 +/- 0.90, P = .6). Our findings suggest that the -238GA and -308GA polymorphisms of TNF-alpha alter circulating free fatty acids and insulin resistance in obese subjects with type 2 diabetes mellitus.

Inflammatory markers predict memory dysfunction in elderly patients, but their contribution to memory deficits in adults with Type 2 diabetes mellitus (T2DM) is less well understood. The present study determined whether specific single-nucleotide polymorphisms in the promoter region of tumor necrosis factor-alpha (TNF-alpha) predict verbal memory in older patients with T2DM. Immediate and delayed verbal memory were assessed using word list and paragraph recall tests in a cohort of subjects with T2DM during 2 sessions, separated by 48 weeks. The presence of the TNF-alpha-238A allele, which has been shown to decrease gene expression, consistently predicted better baseline performance and protected against memory decline over a period of 48 weeks. Therefore, inflammatory mediators may be important modulators of memory function in individuals with T2DM.