Leah Cahill

Nutrigenetics and nutrigenomics: viewpoints on the current status and applications in nutrition research and practice.

Nutrigenetics and nutrigenomics hold much promise for providing better nutritional advice to the public generally, genetic subgroups and individuals. Because nutrigenetics and nutrigenomics require a deep understanding of nutrition, genetics and biochemistry and ever new ‘omic’ technologies, it is often difficult, even for educated professionals, to appreciate their relevance to the practice of preventive approaches for optimising health, delaying onset of disease and diminishing its severity. This review discusses (i) the basic concepts, technical terms and technology involved in nutrigenetics and nutrigenomics; (ii) how this emerging knowledge can be applied to optimise health, prevent and treat diseases; (iii) how to read, understand and interpret nutrigenetic and nutrigenomic research results, and (iv) how this knowledge may potentially transform nutrition and dietetic practice, and the implications of such a transformation. This is in effect an up-to-date overview of the various aspects of nutrigenetics and nutrigenomics relevant to health practitioners who are seeking a better understanding of this new frontier in nutrition research and its potential application to dietetic practice.

Changes in Intake of Fruits and Vegetables and Weight Change in United States Men and Women Followed for Up to 24 Years: Analysis from Three Prospective Cohort Studies

Background Current dietary guidelines recommend eating a variety of fruits and vegetables. However, based on nutrient composition, some particular fruits and vegetables may be more or less beneficial for maintaining or achieving a healthy weight. We hypothesized that greater consumption of fruits and vegetables with a higher fiber content or lower glycemic load would be more strongly associated with a healthy weight. Methods and Findings We examined the association between change in intake of specific fruits and vegetables and change in weight in three large, prospective cohorts of 133,468 United States men and women. From 1986 to 2010, these associations were examined within multiple 4-y time intervals, adjusting for simultaneous changes in other lifestyle factors, including other aspects of diet, smoking status, and physical activity. Results were combined using a random effects meta-analysis. Increased intake of fruits was inversely associated with 4-y weight change: total fruits -0.53 lb per daily serving (95% CI -0.61, -0.44), berries -1.11 lb (95% CI -1.45, -0.78), and apples/pears -1.24 lb (95% CI -1.62, -0.86). Increased intake of several vegetables was also inversely associated with weight change: total vegetables -0.25 lb per daily serving (95% CI -0.35, -0.14), tofu/soy -2.47 lb (95% CI, -3.09 to -1.85 lb) and cauliflower -1.37 lb (95% CI -2.27, -0.47). On the other hand, increased intake of starchy vegetables, including corn, peas, and potatoes, was associated with weight gain. Vegetables having both higher fiber and lower glycemic load were more strongly inversely associated with weight change compared with lower-fiber, higher-glycemic-load vegetables (p < 0.0001). Despite the measurement of key confounders in our analyses, the potential for residual confounding cannot be ruled out, and although our food frequency questionnaire specified portion size, the assessment of diet using any method will have measurement error. Conclusions Increased consumption of fruits and non-starchy vegetables is inversely associated with weight change, with important differences by type suggesting that other characteristics of these foods influence the magnitude of their association with weight change.

Vitamin C Deficiency in a Population of Young Canadian Adults

A cross-sectional study of the 979 nonsmoking women and men aged 20-29 years who participated in the Toronto Nutrigenomics and Health Study from 2004 to 2008 was conducted to determine the prevalence of serum ascorbic acid (vitamin C) deficiency and its association with markers of chronic disease in a population of young Canadian adults. High performance liquid chromatography was used to determine serum ascorbic acid concentrations from overnight fasting blood samples. A 1-month, 196-item food frequency questionnaire was used to assess dietary intakes. Results showed that 53% of subjects had adequate, 33% had suboptimal, and 14% had deficient levels of serum ascorbic acid. Subjects with deficiency had significantly higher measurements of mean C-reactive protein, waist circumference, body mass index, and blood pressure than did subjects with adequate levels of serum ascorbic acid. The odds ratio for serum ascorbic acid deficiency was 3.43 (95% confidence interval: 2.14, 5.50) for subjects who reported not meeting the recommended daily intake of vitamin C compared with those who did. Results suggest that 1 of 7 young adults has serum ascorbic acid deficiency, in part, because of unmet recommended dietary intakes. Furthermore, serum ascorbic acid deficiency is associated with elevated markers of chronic disease in this population of young adults, which may have long-term adverse health consequences.

Effect of fish oil on circulating adiponectin: a systematic review and meta-analysis of randomized controlled trials.

CONTEXT Seafood long-chain polyunsaturated omega-3 fatty acids (n-3 PUFAs) improve insulin sensitivity in animal experiments, but findings remain inconsistent in humans. Adiponectin is a robust marker for insulin sensitivity and adipocyte function. Whether n-3 PUFAs affect adiponectin in humans is unknown. OBJECTIVE Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, the objective of the study was to perform a systematic review and meta-analysis of randomized, placebo-controlled clinical trials (RCTs) to determine the effect of n-3 PUFA consumption on circulating adiponectin in humans. DATA SOURCES MEDLINE, EMBASE, CABI (CAB abstracts), Cochrane Central Registry of Controlled Trials, ClinicalTrials.gov, SIGLE, and Faculty of 1000 were searched through to June 2012, supplemented with author contact and reference list searches. STUDY SELECTION RCTs of either fish oil supplementation or isocaloric fish meal feeding that evaluated adiponectin as an outcome were selected for the study. DATA EXTRACTION Two investigators independently extracted the data. Effect estimates were pooled using inverse-variance weighted, random-effects meta-analysis. Heterogeneity was assessed by the I(2) and Q statistic. Prespecified sources of heterogeneity were investigated by meta-regression. Publication bias was assessed using funnel plots and Eggers test. DATA SYNTHESIS Of 110 studies, 14 RCTs met inclusion criteria. Fourteen trial arms evaluated fish oil (fish oil, n = 682; placebo, n = 641). Fish oil increased adiponectin by 0.37 μg/mL [95% confidence interval (CI) 0.07; 0.67, P = .02]. Although effects in 11 of 14 trials were 0 or greater, statistical heterogeneity was evident (I(2) = 72.9%), unexplained by n-3 PUFA dose or duration, study quality score, study location, or baseline body mass index (meta-regression P > .05 each). The funnel plot was asymmetric in favor of smaller trials with greater effects (Eggers P = .11); the fill-and-trim method suggested a theoretical pooled effect of 0.18 μg/mL (95% CI -0.15; +0.52, P = .28). Only 2 trial arms evaluated fish feeding (n = 136 intervention and 68 control subjects), for which the pooled effect on adiponectin was not statistically significant (-0.01 μg/mL, 95% CI -0.65; 0.64, P = 0.99), although CIs were broad due to the small number of subjects. CONCLUSIONS In placebo-controlled RCTs, fish oil moderately increases circulating adiponectin, although with unexplained heterogeneity as well as potential publication bias. These findings provide no evidence for harm and support possible benefits of n-3 PUFA consumption on insulin sensitivity and adipocyte function.

Functional genetic variants of glutathione S-transferase protect against serum ascorbic acid deficiency

BACKGROUND Glutathione S-transferases (GSTs) are detoxifying enzymes that contribute to the glutathione-ascorbic acid (vitamin C) antioxidant cycle. OBJECTIVE The objective was to determine whether GST genotypes modify the association between dietary vitamin C and serum ascorbic acid. DESIGN Nonsmoking men and women (n = 905) between 20 and 29 y of age were participants in the Toronto Nutrigenomics and Health Study. Overnight fasting blood samples were collected to determine serum ascorbic acid concentrations by HPLC and to genotype for deletion polymorphisms in GSTM1 and GSTT1 and an Ile105Val substitution in GSTP1. A 196-item food-frequency questionnaire was used to estimate vitamin C intake. RESULTS A gene-diet interaction on serum ascorbic acid was observed for GSTM1 (P = 0.04) and GSTT1 (P = 0.01) but not for GSTP1 (P = 0.83). The odds ratio (95% CI) for serum ascorbic acid deficiency (<11 micromol/L) was 3.20 (1.88, 5.44) for subjects who did not meet the Recommended Dietary Allowance of vitamin C compared with those who did. The corresponding odds ratios (95% CIs) were 2.17 (1.10, 4.28) and 12.28 (4.26, 33.42), respectively, for individuals with the GSTT1*1/*1 +*1/*0 (functional) and GSTT1*0/*0 (null) genotypes and 2.29 (0.96, 5.45) and 4.03 (2.01, 8.09), respectively, for the GSTM1*1/*1+GSTM1*1/*0 and GSTM1*0/*0 genotypes. CONCLUSIONS The recommended intake of vitamin C protects against serum ascorbic acid deficiency, regardless of genotype. Individuals with GST null genotypes had an increased risk of deficiency if they did not meet the Recommended Dietary Allowance for vitamin C, which suggests that the GST enzymes protect against serum ascorbic acid deficiency when dietary vitamin C is insufficient.

Comparison of body mass index and waist circumference as predictors of cardiometabolic health in a population of young Canadian adults

BackgroundThis study aimed to investigate whether waist circumference (WC) or body mass index (BMI) is a better predictor of blood lipid concentrations among young men and women from different ethnocultural groups.MethodsParticipants were 1181 healthy men (n = 358) and women (n = 823) aged 20-29 years taken from the cross-sectional Toronto Nutrigenomics and Health Study. Analyses were conducted separately for men and women, and for Caucasian and East Asian ethnocultural groups. Serum triglycerides (TG) and total to HDL cholesterol ratio (TC:HDL cholesterol) were used as outcomes. Associations between the adiposity and blood lipid measures were examined using partial correlations and odds ratios derived from logistic regression models.ResultsWC had a stronger association with serum lipid concentrations than BMI. WC was significantly related to TG and TC:HDL cholesterol after adjusting for BMI and covariates among men and women (P ≤ 0.01). However, after adjusting for WC and covariates, BMI was not significantly associated with the two serum lipid measures. WC was a better predictor of TG and TC:HDL among all sex and ethnocultural subgroups except among East Asian women where little difference between the two measures was observed.ConclusionsWC is a stronger predictor of cardiometabolic health when compared with BMI among young adults, especially among men.

Vitamin C transporter gene polymorphisms, dietary vitamin C and serum ascorbic acid.

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.

Novel metabolic biomarkers of cardiovascular disease

Coronary heart disease (CHD) accounts for one in every six deaths in US individuals. Great advances have been made in identifying important risk factors for CHD, such as hypertension, diabetes mellitus, smoking and hypercholesterolaemia, which have led to major developments in therapy. In particular, statins represent one of the greatest successes in the prevention of CHD. While these standard risk factors are important, an obvious opportunity exists to take advantage of ongoing scientific research to better risk-stratify individuals and to identify new treatment targets. In this Review, we summarize ongoing scientific research in a number of metabolic molecules or features, including lipoproteins, homocysteine, calcium metabolism and glycaemic markers. We evaluate the current state of the research and the strength of evidence supporting each emerging biomarker. We also discuss whether the associations with CHD are strong and consistent enough to improve current risk stratification metrics, and whether these markers enhance our understanding of the underlying biology of CHD and thus point towards new treatment options.

Haptoglobin genotype modifies the association between dietary vitamin C and serum ascorbic acid deficiency

BACKGROUND Haptoglobin (which is encoded by the Hp gene) is a hemoglobin-binding protein that has antioxidant properties and a common polymorphism that consists of 2 structurally different alleles: Hp1 and Hp2. The capacity of Hp2 to inhibit oxidation and vitamin C depletion is less than that of Hp1, but the influence on vitamin C requirements remains unknown. OBJECTIVE This study aimed to determine whether the Hp polymorphism modifies the association between dietary vitamin C and serum ascorbic acid deficiency (<11 μmol/L). DESIGN Nonsmoking men and women (n = 1046) between 20 and 29 y of age participated in the Toronto Nutrigenomics and Health Study. Blood samples were collected after the subjects had fasted overnight to determine serum ascorbic acid concentrations by HPLC and for genotyping. A 196-item food-frequency questionnaire was used to estimate vitamin C intake. RESULTS A gene-diet interaction on serum ascorbic acid was observed (P = 0.02). The overall odds ratio (95% CI) for serum ascorbic acid deficiency was 2.84 (1.73, 4.65) for subjects who did not meet the Recommended Dietary Allowance for vitamin C compared with those who did. The corresponding odds ratios were 4.77 (2.36, 9.65) for the Hp2-2 genotype and 1.69 (0.80, 3.63) for carriers of the Hp1 allele. CONCLUSIONS Individuals with the Hp2-2 genotype had an increased risk of deficiency if they did not meet the Recommended Dietary Allowance for vitamin C, whereas carriers of the Hp1 allele did not. The findings suggest that the greater antioxidant capacity of Hp1 might spare serum ascorbic acid.

Currently available versions of genome-wide association studies cannot be used to query the common haptoglobin copy number variant.

We recently reported in the Journal that the common biallelic haptoglobin (Hp) copy number variant (CNV) (rs72294371) is predictive of coronary heart disease (CHD) among patients with elevated glycoslylated hemoglobin (HbA1c) (1). In 2 independent populations, we observed that participants with both the Hp2-2 genotype (homozygous for presence of CNV) and an HbA1c ≥6.5% had a 10-fold higher risk of CHD compared with those with at least 1 Hp1 allele and HbA1c <6.5% (1). Our study used a candidate gene approach, and an accompanying editorial (2) suggested that the recently completed genome wide association (GWA) studies of millions of single nucleotide polymorphisms (SNPs) should identify the same genetic predictor of CHD, to confirm our findings. However, the Hp CNV is not a SNP; it is a 1.7 kb replication, and as detailed in the following text, our investigations and the work of 2 different groups (3,4) show that currently available GWA studies cannot tag Hp CNV or identify the association between this variant and risk of disease. From our original published investigation of the Hp CNV and risk of CHD in the Nurses’ Health Study, we also had GWA data available on 726 women (~700,000 SNPs genotyped using the Affymetrix Genome-Wide Human 6.0 array, as previously reported [2]). In this sample, several SNPs were significantly associated with the Hp CNV when we conducted a GWA analysis of the Hp CNV as either an ordinal endpoint or coded dichotomously; the smallest p value was ~10−60, and 48 SNPs were identified with p values of <10−10. We assessed the 3 × 3 genotype frequency tables for the Hp CNV and the SNPs with significant p values. Although none of the SNPs had alleles in perfect correspondence with the Hp CNV alleles, the contingency tables identified a few SNPs with similarities in genotype frequencies as the Hp CNV. For example, all Hp2-2s had the 0 genotype for rs17669033. However, not all participants with the 0 genotype for rs17669033 had the Hp2-2 genotype, and the overall correlation of rs17669033 and Hp CNV was r2 = 0.01. Therefore, rs17669033 cannot be used as a surrogate for the Hp CNV’s genotype. We used PLINK (5) and Haploview (6) software to calculate pairwise r2, linkage disequilibrium (LD), and haplotypes between the Hp CNV and all SNPs 20 kb upstream and downstream of the Hp CNV on chromosome 16. We used both the genotyped GWA SNPs, and in addition, included all SNPs from the genome wide imputations to HapMap (7) phase II (MACH software version 1.0.16) and 1,000G. Many SNPs and 1 haplotype were significantly associated with the Hp polymorphism, but the r2 values observed were all <0.10, and they could not predict the Hp CNV genotype. We ran stepwise regression models in SAS (version 9.2; SAS Institute, Cary, North Carolina) to investigate whether groups of SNPs could be used to predict the Hp CNV genotype. However, the highest model r2 we could achieve was r2 = 0.27, when SNPs from 6 different haplotypes were in the model, and this model did not predict the Hp CNV genotype. Furthermore, none of the GWA study groups of SNPs, individual SNPs, or haplotypes replicated our findings for the association between the Hp CNV and risk of CHD. Our data clearly show that currently available GWA studies have a blind spot for the Hp CNV polymorphism. Rodriguez et al. (3) used several methods to test for the existence of tagging SNP(s) for the Hp CNV. Similar to our results, individual SNPs and haplotypes were in LD with the Hp CNV with D′ = 1, but none had r2 values >0.16, and they could not tag the Hp CNV (3). A similar GWA analysis was also performed in the Diabetes Heart Study; when LD was assessed using both D′ and r2 between SNPs and the Hp CNV, no SNPs could tag the Hp CNV (4). These studies published these results as secondary findings, which were not included in abstracts and titles that could surface in literature reviews, preventing the misconception that the association between the Hp CNV and CHD could be captured by GWA (8). It is important to understand the limitations of GWA studies with polymorphisms such as deletions and CNVs, and that a direct candidate-gene approach may be necessary for certain non-SNP polymorphisms. Difficulty in tagging non-SNP polymorphisms with GWA studies has been widely encountered in complex genomic regions. In conclusion, we decisively demonstrate in a large population study of CHD that the Hp CNV polymorphism cannot be identified through the use of SNPs. Individual SNPs and haplotypes can be strongly associated with the Hp CNV without being of any use as a diagnostic predictor of the Hp CNV genotype. Therefore, one cannot use GWA studies to query the role of the Hp genotype in determining the risk of disease. To test whether the interaction we reported between the Hp CNV genotype and HbA1c on risk of CHD (1) is replicable in other populations, a study design in which the Hp CNV is directly assessed in its association with incident disease is necessary.