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1.  Circulating Biomarkers of One-Carbon Metabolism in Relation to Renal Cell Carcinoma Incidence and Survival 
The etiology of renal cell carcinoma (RCC) is only partially understood, but a metabolic component appears likely. We investigated biomarkers of one-carbon metabolism and RCC onset and survival.
The European Prospective Investigation into Cancer and Nutrition (EPIC) recruited 385747 participants with blood samples between 1992 and 2000, and this analysis included 556 RCC case-control pairs. A subsequent replication study included 144 case-control pairs nested within the Melbourne Collaborative Cohort Study (MCCS). Plasma concentrations of vitamin B2, vitamin B6, folate, vitamin B12, methionine and homocysteine were measured in prediagnostic samples and evaluated with respect to RCC risk using conditional and unconditional logistic regression models, and to all-cause mortality in RCC cases using Cox regression models. All statistical tests were two-sided.
EPIC participants with higher plasma concentrations of vitamin B6 had lower risk of RCC, the odds ratio comparing the 4th and 1st quartiles (OR4vs1) being 0.40 95% confidence interval [CI] = 0.28 to 0.57, P trend < .001. We found similar results after adjusting for potential confounders (adjusted P trend < .001). In survival analysis, the hazard ratio for all-cause mortality in RCC cases when comparing the 4th and 1st quartiles (HR4vs1) of vitamin B6 was 0.57 (95% CI = 0.37 to 0.87, P trend < .001).
Subsequent replication of these associations within the MCCS yielded very similar results for both RCC risk (OR4vs1 = 0.47, 95% CI = 0.23 to 0.99, P trend = .07) and all-cause mortality (HR4vs1 = 0.56, 95% CI = 0.27 to 1.17, P trend = .02). No association was evident for the other measured biomarkers.
Study participants with higher circulating concentrations of vitamin B6 had lower risk of RCC and improved survival following diagnosis in two independent cohorts.
PMCID: PMC4273895  PMID: 25376861
2.  Intra-individual variation in one-carbon metabolism plasma biomarkers 
Interest in the relationship between one-carbon metabolism (OCM) and carcinogenesis is intensifying, leading to increased use of related biomarkers as measures of exposure. Little is known, however, about intra-individual variation in these markers and if use of a single measure is appropriate for assessing exposure-disease relationships in epidemiologic studies. We evaluated intra-individual variation in plasma concentrations of 19 OCM biomarkers in a sample of 147 African American and 68 non-Hispanic white participants from the Southern Community Cohort Study who donated blood samples and responded to questionnaires at two points in time from 2005–2008. Weighted kappa coefficients (κ) were calculated to assess agreement between quartile assignments based on the repeated measures. Adjusted intra-class correlation coefficients (ICCs) were also used to assess the consistency of the two measurements. Most (16 of 19) OCM biomarkers showed moderate or better agreement for quartile assignment at the two timepoints, with only methionine, methionine sulfoxide, and cystathionine having κ ≤ 0.40. The median adjusted ICC across the 19 biomarkers was 0.60. Reproducibility was highest for flavin mononucleotide (ICC=0.84, 95% confidence interval (CI) 0.79–0.87) and lowest for methionine and its oxidative product methionine sulfoxide (ICC=0.22, 95%CI 0.09–0.34; ICC=0.20, 95%CI 0.07–0.32, respectively). Overall, intra-individual variation in OCM biomarkers was similar for African Americans and whites, and for males and females. Our results suggest that, with the exception of methionine and methionine sulfoxide, OCM biomarkers generally have good intra-individual reproducibility and can be considered reliable exposure measures in epidemiologic studies.
PMCID: PMC4104117  PMID: 23950212
One-carbon metabolism; intra-class correlation; biological markers; prospective studies; reproducibility of results
3.  Maternal B vitamin status in pregnancy week 18 according to reported use of folic acid supplements 
Epidemiological studies on the association between pregnancy outcomes and use of periconceptional folic acid are often based on maternal reported intake. Use of folic acid during pregnancy is associated with a higher socioeconomic status known to have an impact on diet quality. We have studied plasma B vitamin status according to reported use of folic acid supplements during the periconceptional period in Norwegian women.
Methods and results
Plasma levels of folate, cobalamin, pyridoxal 5′-phosphate (vitamin B6), riboflavin and the metabolic markers total homocysteine, methylmalonic acid and 3-hydroxykynurenine were measured in pregnancy week 18 and related to reported intake of folic acid from 4 weeks prior to conception throughout week 18 in 2911 women from the Norwegian Mother and Child Cohort Study (MoBa) conducted by the Norwegian Institute of Public Health.
Being a folic acid user during the periconceptional period was associated with a better socioeconomic status, and a higher intake of several micronutrients, including vitamins, trace-metals and omega 3 fatty acids. Folic acid users had a significantly better plasma B vitamin status.
Epidemiological data based on maternal reported intake of folic acid supplements during pregnancy, should take into account the numerous nutritional implications, in addition to higher blood folate levels, of being a folic acid user.
PMCID: PMC3774931  PMID: 23001761
Folic acid; periconceptional; B vitamin status; pregnancy; micronutrients
4.  Use of Folic Acid Supplements in Early Pregnancy in Relation to Maternal Plasma Levels in Week 18 of Pregnancy 
Molecular nutrition & food research  2012;57(4):10.1002/mnfr.201200116.
We compared plasma-folate at week 18 of gestation with self-reported use of supplements containing folic acid from before pregnancy to 17 weeks gestation. Birth cohorts typically measure plasma-folate in mid-gestation, but effects of folic acid supplementation are sometimes specific to the periconceptional period. The relationship between mid-gestation plasma-folate and periconceptional supplementation is not known.
The sample comprised 2911 women from The Norwegian Mother and Child Cohort Study. For women reporting continuous supplementation from gestational week -4-17 (N=238), median plasma-folate was 15.72 at week 18 (in nmol/L). This was about threefold higher than the median plasma-folate of 5.67 for women reporting no supplementation from week -4-17 (N=844), but only slightly higher than the median plasma-folate of 13.34 for all women reporting supplementation in week 13-17 (N=1158). Reported supplementation before week 8 was not associated with plasma-folate at week 18, in an analysis that adjusted for continued supplementation after week 8.
Overall we found a strong and coherent relationship between self-reported folic acid use and plasma-folate at week 18. We also found that plasma-folate at week 18 did not reflect self-reported supplementation before 8 weeks. For periconceptional supplementation per se, self-report data may offer a better measure.
PMCID: PMC3882014  PMID: 23065724
Folic acid; maternal report; periconceptional; plasma; pregnancy cohort
5.  Smoking and Body Fat Mass in Relation to Bone Mineral Density and Hip Fracture: The Hordaland Health Study 
PLoS ONE  2014;9(3):e92882.
Lower bone mineral density (BMD) in smokers may be attributable to lower body weight or fat mass, rather than to a direct effect of smoking. We analyzed the effects of smoking exposure, assessed by plasma cotinine, and body fat on BMD and the risk of subsequent hip fracture. In the community-based Hordaland Health Study (HUSK), 3003 participants 46–49 years and 2091 subjects 71–74 years were included. Cotinine was measured in plasma and information on health behaviors was obtained from self-administered questionnaires. BMD and total body soft tissue composition were measured by dual X-ray absorptiometry. Information on hip fracture was obtained from computerized records containing discharge diagnoses for hospitalizations between baseline examinations 1997–2000 through December 31st, 2009. In the whole cohort, moderate and heavy smokers had stronger positive associations between fat mass and BMD compared to never smokers (differences in regression coefficient (95% CI) per % change in fat mass = 1.38 (0.24, 2.52) and 1.29 (0.17, 2.4), respectively). In moderate and heavy smokers there was a nonlinear association between BMD and fat mass with a stronger positive association at low compared to high levels of fat mass (Davies segmented test, p<0.001). In elderly women and men, heavy smokers had an increased risk of hip fracture compared to never smokers (hazard ratio = 3.31, 95% CI: 2.05, 5.35; p<0.001). In heavy smokers there was a tendency of a lower risk of hip fracture with higher percentage of fat mass. The deleterious effect of smoking on bone health is stronger in lean smokers than in smokers with high fat mass.
PMCID: PMC3965480  PMID: 24667849
7.  Serial Plasma Choline Measurements after Cardiac Arrest in Patients Undergoing Mild Therapeutic Hypothermia: A Prospective Observational Pilot Trial 
PLoS ONE  2013;8(9):e76720.
Choline is related to phospholipid metabolism and is a marker for global ischaemia with a small reference range in healthy volunteers. The aim of our study was to characterize the early kinetics of plasma free choline in patients after cardiac arrest. Additionally, we investigated the potential of plasma free choline to predict neurological outcome.
Twenty patients admitted to our medical intensive care unit were included in this prospective, observational trial. All patients were enrolled between May 2010 and May 2011. They received post cardiac arrest treatment including mild therapeutic hypothermia which was initiated with a combination of cold fluid and a feedback surface cooling device according to current guidelines. Sixteen blood samples per patient were analysed for plasma free choline levels within the first week after resuscitation. Choline was detected by liquid chromatography-tandem mass spectrometry.
Most patients showed elevated choline levels on admission (median 14.8 µmol/L; interquartile range; IQR 9.9-20.1) which subsequently decreased. 48 hours after cardiac arrest choline levels in all patients reached subnormal levels at a median of 4.0 µmol/L (IQR 3-4.9; p = 0.001). Subsequently, choline levels normalized within seven days. There was no significant difference in choline levels when groups were analyzed in relation to neurological outcome.
Our data indicate a choline deficiency in the early postresucitation phase. This could potentially result in impaired cell membrane recovery. The detailed characterization of the early choline time course may aid in planning of choline supplementation trials. In a limited number of patients, choline was not promising as a biomarker for outcome prediction.
PMCID: PMC3786938  PMID: 24098804
8.  Circulating folate, vitamin B12, homocysteine, vitamin B12 transport proteins and risk of prostate cancer: a case-control study, systematic review and meta-analysis 
Disturbed folate metabolism is associated with an increased risk of some cancers. Our objective was to determine whether blood levels of folate, vitamin B12 and related metabolites were associated with prostate cancer risk.
Matched case-control study nested within the UK population-based ProtecT study of PSA-detected prostate cancer in men aged 50–69 years. Plasma concentrations of folate, B12 (cobalamin), holo-haptocorrin, holo- and total-transcobalamin, and total homocysteine (tHcy) were measured in 1,461 cases and 1,507 controls. ProtecT study estimates for associations of folate, B12, and tHcy with prostate cancer risk were included in a meta-analysis, based on a systematic review.
In the ProtecT study, increased B12 and holo-haptocorrin concentrations showed positive associations with prostate cancer risk (highest vs lowest quartile of B12 odds ratio (OR)=1.17 (95% CI 0.95–1.43), P-for-trend=0.06; highest vs lowest quartile of holo-haptocorrin OR=1.27 (1.04–1.56), P-for-trend=0.01); folate, holo-transcobalamin and tHcy were not associated with prostate cancer risk. In the meta-analysis, circulating B12 levels were associated with an increased prostate cancer risk (pooled OR=1.10 (1.01–1.19) per 100 pmol/L increase in B12, P=0.002); the pooled OR for the association of folate with prostate cancer was positive (OR=1.11 (0.96–1.28) per 10 nmol/L, P=0.2) and conventionally statistically significant if ProtecT (the only case-control study) was excluded (OR=1.18 (1.00–1.40) per 10 nmol/L, P=0.02).
Vitamin B12 and (in cohort studies) folate were associated with increased prostate cancer risk.
Given current controversies over mandatory fortification, further research is needed to determine whether these are causal associations.
PMCID: PMC3759018  PMID: 20501771
folate; vitamin B12; cobalamin; transcobalamin; haptocorrin; homocysteine; folate-mediated one-carbon metabolism; prostate cancer
9.  Maternal Tryptophan and Kynurenine Pathway Metabolites and Risk of Preeclampsia 
Obstetrics and Gynecology  2012;119(6):1243-1250.
To estimate the association of maternal plasma concentrations of tryptophan and 6 kynurenine pathway metabolites with the risk of preeclampsia.
The study was based on a subsample of 2,936 pregnant women who delivered singleton infants in the Norwegian Mother and Child Cohort Study in 2002–2003. Maternal blood plasma was obtained approximately at gestational week 18 and measured for tryptophan, kynurenine, kynurenic acid, anthranilic acid, 3-hydroxykynurenine, xanthurenic acid, and 3-hydroxyanthranilic acid.
Of the 2,936 pregnant women included in this study, 116 (4.0%, 95% confidence interval 3.2 – 4.7) were subsequently diagnosed with preeclampsia. The prevalence of preeclampsia was significantly higher among women with plasma kynurenic acid concentrations greater than the 95th percentile than among those with concentrations in the 25th–75th percentile (11.0% compared with 3.3%, P < 0.001; adjusted odds ratio 3.6, 95% confidence interval 1.9 – 6.8). This association was significantly stronger in women with prepregnancy body mass index of 25 kg/m2 or more (P for interaction = .03; 20.4% compared with 4.2%, P < 0.001). No statistically significant associations of preeclampsia with other tryptophan metabolites were found.
Elevated maternal plasma kynurenic acid concentrations in early pregnancy are associated with a substantial increased risk of preeclampsia in obese women.
PMCID: PMC3360419  PMID: 22617590
10.  Self-reported smoking status and plasma cotinine concentrations among pregnant women in the Norwegian Mother and Child Cohort Study 
Pediatric research  2012;72(1):101-107.
Underreporting of smoking in epidemiologic studies is common and may constitute a validity problem, leading to biased association measures. In this prospective study, we validated self-reported tobacco use against nicotine exposure assessed by plasma cotinine in the Norwegian Mother and Child Cohort Study (MoBa).
The study was based on a subsample of 2,997 women in MoBa who delivered during the period 2002–2003. Self-reported tobacco use (test variable) and plasma cotinine concentrations (gold standard) were assessed around gestational week 18.
Daily smoking was reported by 9%, occasional smoking by 4% and non-smoking by 86% of the women. Sensitivity and specificity for self-reported smoking status were calculated by using a cotinine cut-off estimated from the current material (30 nmol/l). Plasma cotinine concentrations ≥ 30 nmol/l were found for 94% of self-reported daily smokers, 66% of occasional smokers and 2% of non-smokers. Adding the self-reported non-smokers with cotinine concentrations above cut-off increased the daily smoking prevalence from 9% to 11%. The sensitivity and specificity for self-reported daily smoking using 30 nmol/l as cut-off were 82% and 99%, respectively.
These findings suggest that self-reported tobacco use is a valid marker for tobacco exposure in the MoBa cohort.
PMCID: PMC3630336  PMID: 22441375
11.  Omega-3 Status and the Relationship between Plasma Asymmetric Dimethylarginine and Risk of Myocardial Infarction in Patients with Suspected Coronary Artery Disease 
Background. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase. A previous rat study revealed an ADMA lowering effect following treatment with omega-3 polyunsaturated fatty acids (n-3 PUFAs). We sought to examine if an association between plasma ADMA and risk of acute myocardial infarction (AMI) was modified by serum n-3 PUFA status. Methods. The cohort included 1364 patients who underwent coronary angiography for suspected coronary artery disease in 2000-2001. Fatal and nonfatal AMI events were registered until December 31, 2006. Risk associations with AMI were estimated across ADMA quartiles (linear trend) and the upper decile. Results. No association between concentration of any n-3 PUFA and ADMA was observed. Only ADMA levels in upper decile were significantly associated with AMI with a multivariate adjusted hazard ratio (HR) (95% confidence interval) versus the rest of the population of 2.11 (1.34, 3.32). The association was strengthened among patients with below median levels of α-linolenic acid (ALA) (HR 3.12 (1.64, 5.93)), but was only influenced by longer chain n-3 PUFA after additional adjustments for HbA1c, estimated glomerular filtration rate, and hypercholesterolemia. Conclusions. The association of ADMA with risk of AMI is influenced by serum n-3 PUFA and particularly ALA.
PMCID: PMC3549394  PMID: 23346455
12.  A U-shaped association between plasma folate and pancreatic cancer risk in the European Prospective Investigation into Cancer and Nutrition 
Folate intake has shown an inverse association with pancreatic cancer; nevertheless, results from plasma measurements were inconsistent. The aim of this study is to examine the association between plasma total homocysteine, methionine, folate, cobalamin, pyridoxal 5′-phosphate, riboflavin, and flavin mononucleotide and pancreatic cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC). We conducted a nested case-control study in the EPIC cohort, which has an average of 9.6 years of follow-up (1992–2006), using 463 incident pancreatic cancer cases. Controls were matched to each case by center, sex, age (+/−1y), date (+/−1y) and time (+/−3h) at blood collection, and fasting status. Conditional logistic regression was used to calculate the odds ratios (OR) and 95% confidence intervals (CI), adjusting for education, smoking status, plasma cotinine concentration, alcohol drinking, body mass index and diabetes status. We observed a U-shaped association between plasma folate and pancreatic cancer risk The ORs for plasma folate ≤5, 5–10, 10–15 (reference), 15–20, and >20 nmol/L were 1.6 (95% CI=0.7–3.5), 1.4 (0.9–2.1), 1.0 (reference), 0.8 (0.5–1.2), and 1.3 (0.9–2.0), respectively. Methionine was associated with an increased risk in men (per quintile increment: OR=1.2 95% CI=1.0–1.4) but not in women (OR=0.9, 95% CI=0.8–1.1; p for heterogeneity<0.01). Our results suggest a U-shaped association between plasma folate and pancreatic cancer risk in both men and women. The positive association that we observed between methionine and pancreatic cancer may be sex dependent and may differ by time of follow-up. However, the mechanisms behind the observed associations warrant further investigation.
PMCID: PMC3500543  PMID: 21411310
folate; one-carbon metabolism; pancreatic cancer; EPIC
13.  Metabolic Profiling in Maturity-Onset Diabetes of the Young (MODY) and Young Onset Type 2 Diabetes Fails to Detect Robust Urinary Biomarkers 
PLoS ONE  2012;7(7):e40962.
It is important to identify patients with Maturity-onset diabetes of the young (MODY) as a molecular diagnosis determines both treatment and prognosis. Genetic testing is currently expensive and many patients are therefore not assessed and are misclassified as having either type 1 or type 2 diabetes. Biomarkers could facilitate the prioritisation of patients for genetic testing. We hypothesised that patients with different underlying genetic aetiologies for their diabetes could have distinct metabolic profiles which may uncover novel biomarkers. The aim of this study was to perform metabolic profiling in urine from patients with MODY due to mutations in the genes encoding glucokinase (GCK) or hepatocyte nuclear factor 1 alpha (HNF1A), type 2 diabetes (T2D) and normoglycaemic control subjects. Urinary metabolic profiling by Nuclear Magnetic Resonance (NMR) and ultra performance liquid chromatography hyphenated to Q-TOF mass spectrometry (UPLC-MS) was performed in a Discovery set of subjects with HNF1A-MODY (n = 14), GCK-MODY (n = 17), T2D (n = 14) and normoglycaemic controls (n = 34). Data were used to build a valid partial least squares discriminate analysis (PLS-DA) model where HNF1A-MODY subjects could be separated from the other diabetes subtypes. No single metabolite contributed significantly to the separation of the patient groups. However, betaine, valine, glycine and glucose were elevated in the urine of HNF1A-MODY subjects compared to the other subgroups. Direct measurements of urinary amino acids and betaine in an extended dataset did not support differences between patients groups. Elevated urinary glucose in HNF1A-MODY is consistent with the previously reported low renal threshold for glucose in this genetic subtype. In conclusion, we report the first metabolic profiling study in monogenic diabetes and show that, despite the distinct biochemical pathways affected, there are unlikely to be robust urinary biomarkers which distinguish monogenic subtypes from T2D. Our results have implications for studies investigating metabolic profiles in complex traits including T2D.
PMCID: PMC3408469  PMID: 22859960
14.  Baseline plasma total homocysteine and adenoma recurrence: results from a double blind randomized clinical trial of aspirin and folate supplementation 
Elevated plasma total homocysteine (tHcy) is an accepted marker of functional folate deficiency but may have independent effects on colorectal neoplasia risk. It is uncertain whether plasma tHcy is associated with risk at the low levels common in a folate-fortified population.
Study subjects, about half of which were recruited after fortification of grain products with folic acid in the US and Canada, were 871 individuals with a recent history of one or more colorectal adenomas who were randomized to receive either a 1 mg/day folic acid supplement or a placebo within one of three randomly assigned aspirin treatment groups (placebo, 81 or 325 mg/d). Non-fasting plasma tHcy was determined by a GC-MS method. We estimated adjusted risk ratios and 95% confidence intervals for one or more adenoma recurrences for each quartile of baseline plasma tHcy using generalized linear regression with an overdispersed poisson approximation to the binomial.
The Q4/Q1 adjusted RR for any adenoma was 0.98; 95% CI 0.70-1.38, p-trend =0.17 in the placebo group, and 0.81; 95% CI 0.58-1.12, p-trend=0.17 in the folic acid group. Results were similar for adenomas with advanced features. There was no modification by sex, aspirin treatment group or MTHFR 677C>T genotype.
Plasma tHcy is not an independent marker for an increase in colorectal adenoma recurrence risk in post-fortification populations where plasma tHcy levels are in the lower range of values.
Controlling plasma tHcy levels is unlikely to favorably modify adenoma recurrence risk in folate fortified populations.
PMCID: PMC2952048  PMID: 20841390
Homocysteine; Colorectal Adenoma; Folic Acid; One Carbon Metabolism; Randomized Clinical Trial; MTHFR
15.  Bioinformatic and Genetic Association Analysis of MicroRNA Target Sites in One-Carbon Metabolism Genes 
PLoS ONE  2011;6(7):e21851.
One-carbon metabolism (OCM) is linked to DNA synthesis and methylation, amino acid metabolism and cell proliferation. OCM dysfunction has been associated with increased risk for various diseases, including cancer and neural tube defects. MicroRNAs (miRNAs) are ∼22 nt RNA regulators that have been implicated in a wide array of basic cellular processes, such as differentiation and metabolism. Accordingly, mis-regulation of miRNA expression and/or activity can underlie complex disease etiology. We examined the possibility of OCM regulation by miRNAs. Using computational miRNA target prediction methods and Monte-Carlo based statistical analyses, we identified two candidate miRNA “master regulators” (miR-22 and miR-125) and one candidate pair of “master co-regulators” (miR-344-5p/484 and miR-488) that may influence the expression of a significant number of genes involved in OCM. Interestingly, miR-22 and miR-125 are significantly up-regulated in cells grown under low-folate conditions. In a complementary analysis, we identified 15 single nucleotide polymorphisms (SNPs) that are located within predicted miRNA target sites in OCM genes. We genotyped these 15 SNPs in a population of healthy individuals (age 18–28, n = 2,506) that was previously phenotyped for various serum metabolites related to OCM. Prior to correction for multiple testing, we detected significant associations between TCblR rs9426 and methylmalonic acid (p  =  0.045), total homocysteine levels (tHcy) (p  =  0.033), serum B12 (p < 0.0001), holo transcobalamin (p < 0.0001) and total transcobalamin (p < 0.0001); and between MTHFR rs1537514 and red blood cell folate (p < 0.0001). However, upon further genetic analysis, we determined that in each case, a linked missense SNP is the more likely causative variant. Nonetheless, our Monte-Carlo based in silico simulations suggest that miRNAs could play an important role in the regulation of OCM.
PMCID: PMC3134459  PMID: 21765920
16.  Maternal folate levels in pregnancy and asthma in children at age three years 
Capsule summary
This is the first study to examine measured folate levels in pregnancy in relation to respiratory outcomes in the children. Higher pregnancy levels of folate were associated with increased risk of asthma at age 3.
PMCID: PMC3108064  PMID: 21094522
Asthma; Case-Control Studies; Child; preschool; Cohort Studies; folate; folic acid; Norway; Plasma; Pregnancy
17.  Plasma vitamins B2, B6, B12, and related genetic variants as predictors of colorectal cancer risk 
B-vitamins are essential for one-carbon metabolism and have been linked to colorectal cancer (CRC). Although associations with folate have frequently been studied, studies on other plasma vitamins B2, B6, and B12 and CRC are scarce or inconclusive.
Nested case-control study within the European Prospective Investigation into Cancer and Nutrition, including 1365 incident CRC cases and 2319 controls matched for study center, age, and sex. We measured the sum of B2 species riboflavin and flavin mononucleotide, and the sum of B6 species pyridoxal 5′-phosphate, pyridoxal, and 4-pyridoxic acid as indicators for vitamin B2 and B6 status, as well as vitamin B12 in plasma samples collected at baseline. In addition, we determined eight polymorphisms related to one-carbon metabolism. Relative risks (RRs) for CRC were estimated using conditional logistic regression, adjusted for smoking, education, physical activity, BMI, alcohol consumption, and intakes of fiber, red- and processed meat.
RRs comparing highest to lowest quintile (95% confidence interval, Ptrend) were: 0.71 (0.56–0.91, 0.02) for vitamin B2, 0.68 (0.53–0.87, <0.001) for vitamin B6, and 1.02 (0.80–1.29, 0.19) for vitamin B12. The associations for vitamin B6 were stronger in males who consumed ≥ 30g alcohol/day. The polymorphisms were not associated with CRC.
Higher plasma concentrations of vitamins B2 and B6 are associated with a lower CRC risk.
This European population-based study is the first to indicate that vitamin B2 is inversely associated with CRC, and is in agreement to previously suggested inverse associations of vitamin B6 with CRC.
PMCID: PMC3025315  PMID: 20813848
Plasma vitamins B2, B6, and B12; genetic variants; colorectal cancer; prospective study
18.  Plasma folate, related genetic variants and colorectal cancer risk in EPIC 
A potential dual role of folate in colorectal cancer (CRC) is currently subject to debate. Previous studies on plasma folate and CRC risk were small and inconclusive. We therefore investigate associations between plasma folate, a number of relevant folate-related polymorphisms and CRC risk. In this nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, 1367 incident CRC cases were matched to 2325 controls for study center, age and sex. Risk ratios (RR) were estimated with conditional logistic regression and further adjusted for smoking, education, physical activity, and intake of alcohol and fiber. Overall analyses did not reveal associations of plasma folate with CRC. The RR (95% CI), Ptrend) for the fifth vs. the first quintile of folate status was 0.94 ((0.74; 1.20), 0.44). The polymorphisms MTHFR 677C→T, MTHFR 1298A→C, MTR 2756A→G, MTRR 66A→G, and MTHFD1 1958G→A were not associated with CRC risk. However, in individuals with the lowest plasma folate concentrations, the MTHFR 677TT genotype showed a statistically non-significant increased CRC risk (RR (95% CI, Ptrend) TT vs. CC =1.39 (0.87; 2.21), 0.12), whereas in those with the highest folate concentrations showed a non-significant decreased CRC risk (RR TT vs. CC=0.74 (0.39; 1.37), 0.34). The SLC19A1 80G→A showed a positive association with CRC risk (RR AA vs. GG1.30 (1.06; 1.59), <0.01).
Within this large European prospective multicenter study we did not observe an association of CRC risk with plasma folate status, nor with the MTHFR polymorphisms.
PMCID: PMC2880712  PMID: 20447924
Plasma folate; genetic variants; colorectal cancer; prospective study
19.  Oral facial clefts and gene polymorphisms in metabolism of folate/one-carbon and vitamin A: a pathway-wide association study 
Genetic epidemiology  2009;33(3):247-255.
An increased risk of facial clefts has been observed among mothers with lower intake of folic acid or vitamin A around conception. We hypothesized that the risk of clefts may be further moderated by genes involved in metabolizing folate or vitamin A. We included 425 case-parent triads in which the child had either cleft lip with or without cleft palate (CL/P) or cleft palate only (CPO), and no other major defects. We analyzed 108 SNPs and one insertion in 29 genes involved in folate/one-carbon metabolism and 68 SNPs from 16 genes involved in vitamin A metabolism. Using the Triad Multi Marker (TRIMM) approach we performed SNP, gene, chromosomal region, and pathway-wide association tests of child or maternal genetic effects for both CL/P and CPO. We stratified these analyses on maternal intake of folic acid or vitamin A during the periconceptional period.
As expected with this high number of statistical tests, there were many associations with p-values < 0.05; although there were fewer than predicted by chance alone. The strongest association in our data (between fetal FOLH1 and CPO, p=0.0008) is not in agreement with epidemiologic evidence that folic acid reduces the risk of CL/P in these data, not CPO. Despite strong evidence for genetic causes of oral facial clefts and the protective effects of maternal vitamins, we found no convincing indication that polymorphisms in these vitamin metabolism genes play an etiologic role.
PMCID: PMC2677659  PMID: 19048631
cleft lip; cleft palate; dietary supplements; folic acid; genetics; metabolism; vitamin A
20.  Choline concentrations in human maternal and cord blood and intelligence at 5 y of age2 
Animal studies indicate that maternal prenatal choline supplementation leads to permanent enhancement of attention and spatial memory abilities in offspring, whereas dietary choline restriction during pregnancy impairs cognitive function in offspring. The association between gestational choline concentrations and neurodevelopmental outcome in humans has not been studied.
Our objective was to assess the relation between maternal and cord blood choline concentrations and child intelligence quotient (IQ) scores at 5 y of age.
With data and samples from a prospective study (n = 404 maternal-child pairs), serum concentrations of free and total choline were measured in maternal serum at 4 gestational age intervals (16–18 wk, 24–26 wk, 30–32 wk, and 36–38 wk) and in cord blood. Child IQ at 5 y of age was assessed with the Wechsler Preschool and Primary Scale of Intelligence-Revised. Multiple regression techniques were used to estimate the relation between choline concentrations and Full Scale IQ, Verbal and Performance IQ, and subscales that assess spatial relation and memory ability while adjusting for other factors that affect IQ.
There was no effect at gestational ages 16–18 wk, 24–26 wk, 30–32 wk, and 36–38 wk or in cord blood of serum concentrations of free or total choline on Full Scale child IQ or on selected scales related to visuospatial processing and memory.
Gestational and newborn choline concentrations in the physiologic range showed no correlation with childhood intelligence.
PMCID: PMC2423009  PMID: 18400712
21.  Folate and One-Carbon Metabolism Gene Polymorphisms and Their Associations With Oral Facial Clefts 
Folate metabolism plays a critical role in embryonic development. Prenatal folate supplementation reduces the risk of neural tube defects and probably oral facial clefts. Previous studies of related metabolic genes have associated polymorphisms in cystathionine-beta-synthase (CBS) and 5,10-methylenetetrahydrofolate reductase (MTHFR) with cleft risk. We explored associations between genes related to one-carbon metabolism and clefts in a Norwegian population-based study that included 362 families with cleft lip with or without cleft palate (CL/P) and 191 families with cleft palate only (CPO). We previously showed a 39% reduction in risk of CL/P with folic acid supplementation in this population. In the present study we genotyped 12 polymorphisms in nine genes related to one-carbon metabolism and looked for associations of clefting risk with fetal polymorphisms, maternal polymorphisms, as well as parent-of-origin effects, using combined likelihood-ratio tests (LRT). We also stratified by maternal periconceptional intake of folic acid (>400 μg) to explore gene-exposure interactions. We found a reduced risk of CL/P with mothers who carried the CBS C699T variant (rs234706); relative risk was 0.94 with one copy of the T allele (95% CI 0.63-1.4) and 0.50 (95% CI 0.26-0.96) with two copies (P = 0.008). We found no evidence of interaction of this variant with folate status. We saw no evidence of risk from the MTHFR C677T variant (rs1801133) either overall or after stratifying by maternal folate intake. No associations were found between any of the polymorphisms and CPO. Genetic variations in the nine metabolic genes examined here do not confer a substantial degree of risk for clefts. Published 2008 Wiley-Liss, Inc.†
PMCID: PMC2366099  PMID: 18203168
alleles; cleft lip; cleft palate; dietary supplements; folic acid; metabolism; humans; single nucleotide polymorphisms

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