IGFBP-1 and IGFBP-2 are associated with a decreased pulse-wave velocity in young, healthy adults.

BACKGROUND AND AIMS: In healthy, young adults we analyzed a panel of cardiovascular disease related proteins in plasma and compared them with the vascular health of the subjects. The aim was to identify proteins with a relationship to the early atherosclerotic process in healthy individuals. METHODS: We employed the proximity extension assay from OLINK proteomics to analyze 92 cardiovascular disease (CVD) related proteins on 833 subjects (men and women, ages 18-26). The women were further divided into an estrogen-using group and non-users. Protein expression was analyzed using principal component analysis (PCA). The following vascular examinations were performed: Pulse-wave velocity (PWV), augmentation index (AIX), carotid-intima media thickness (cIMT). RESULTS: Three principal components were obtained using PCA to analyze the protein expression. None of the obtained principal components correlated significantly with AIX or cIMT. One of the components, explaining 6% of the total variance of the data, was significantly correlated with PWV. Upon examination of the proteins with the highest factor loadings on this component independently in a multivariable model, adjusting for established CVD risk biomarkers, insulin-like growth factor-binding protein 1 (IGFBP-1) and insulin-like growth factor-binding protein 2 (IGFBP-2) were found to independently, negatively correlate with PWV. Among the established risk factors included in the multivariable model, age was significantly and adversely correlated with all vascular measurements. CONCLUSIONS: In this population of healthy, young adults, groups of CVD related proteins correlate with PWV, but not AIX or cIMT. This group of proteins, of which IGFBP-1 and IGFBP-2 were independently, negatively correlated in a multivariable model with PWV, could have benificial effects on vascular stiffness. The robust association between age and PWV, AIX and cIMT provide insight into the impact of aging on the vasculature, which is detectable even in a population of young, healthy, non-smoking individuals of ages spanning only 8 years.

Mild impairment of renal function (shrunken pore syndrome) is associated with increased risk of a future first-ever myocardial infarction in women.

Impaired renal function is associated both with the development of cardiovascular disease and its prognosis. A new syndrome called 'Shrunken Pore Syndrome' has been suggested, as the estimated glomerular filtration rate for cystatin C (eGFRcystatin C) is affected earlier due to differences in molecular size compared to eGFRcreatinine. The aim was to investigate if a lower eGFRcystatin C/eGFRcreatinine ratio in a prospective setting increases the risk of later developing a first-ever myocardial infarction (MI) independently of other cardiovascular risk factors. We used a nested case-referent study design within the Northern Sweden Health and Disease Study, and 545 subjects (29.0% women) were identified who prospectively developed a first-ever MI, and their 1054 matched referents. For women, but not for men, one standard deviation (SD) increase of ln z-scores of eGFRcystatin C/eGFRcreatinine ratio was associated with a lower risk of a future MI: odds ratio [95% confidence interval] 0.58 [0.34-0.99], adjusted for apolipoprotein B/A1 ratio, CRP, homocysteine, systolic blood pressure, body mass index, and diabetes. Furthermore, a high eGFRcreatinine associated independently with an increased risk of future MI in men only: OR 1.25 [1.05-1.48]. Thus, for women, a lower eGFRcystatin C/eGFRcreatinine ratio is associated with a higher risk of having a future first-ever MI, and it may be a valuable, easily implemented biomarker for risk of cardiovascular disease.

Formate rescues neural tube defects caused by mutations in Slc25a32.

Periconceptional folic acid (FA) supplementation significantly reduces the prevalence of neural tube defects (NTDs). Unfortunately, some NTDs are FA resistant, and as such, NTDs remain a global public health concern. Previous studies have identified SLC25A32 as a mitochondrial folate transporter (MFT), which is capable of transferring tetrahydrofolate (THF) from cellular cytoplasm to the mitochondria in vitro. Herein, we show that gene trap inactivation of Slc25a32 (Mft) in mice induces NTDs that are folate (5-methyltetrahydrofolate, 5-mTHF) resistant yet are preventable by formate supplementation. Slc25a32gt/gt embryos die in utero with 100% penetrant cranial NTDs. 5-mTHF supplementation failed to promote normal neural tube closure (NTC) in mutant embryos, while formate supplementation enabled the majority (78%) of knockout embryos to complete NTC. A parallel genetic study in human subjects with NTDs identified biallelic loss of function SLC25A32 variants in a cranial NTD case. These data demonstrate that the loss of functional Slc25a32 results in cranial NTDs in mice and has also been observed in a human NTD patient.

Factor XII Concentrations and Risk of Intracerebral Haemorrhage. A Prospective Case-Referent Study.

OBJECTIVES: In a previous pilot study, we found an association between high factor XII levels and risk of haemorrhagic stroke suggesting that factor XII is a risk marker for intracerebral haemorrhage (ICH). The aim of this study was to further investigate the association between factor XII and risk of ICH in a larger population. MATERIALS AND METHODS: This study was conducted as a prospective nested case-referent study. All participants underwent a health examination and blood sampling for factor XII analysis at baseline. Cases were defined as participants who were diagnosed with a first-ever ICH between 1985 and 2000. Two referents were matched to each case. RESULTS: We identified 70 individuals with first-ever ICH and 137 matched referents who had undergone a health examination and donated blood samples before the ICH event. The mean age was 54 years, and 33% were women. The median time-to-event was 3.5 years (range 0.04 to 10.2 years). Conditional logistic regression showed no association between factor XII and risk of ICH, (odds ratio 1.06 per SD; [95% confidence interval: 0.57-1.97] in a multivariable model). CONCLUSIONS: A previous finding of an association between high concentration of factor XII and risk of ICH could not be replicated in this larger study.

Body fat percentage and CRP correlates with a composite score of vascular risk markers in healthy, young adults - The Lifestyle, Biomarkers, and Atherosclerosis (LBA) study.

BACKGROUND: Identification of early signs of atherosclerosis in young adults have the potential to guide early interventions to prevent later cardiovascular disease. We therefore analyzed measures of vascular structure and function and biomarkers of cardiovascular risk in a sample of young healthy adults. METHODS: Pulse-wave velocity (PWV), carotid-intima media thickness (cIMT) and augmentation index (AIX) were measured in 834 healthy non-smokers (ages 18.0-25.9). Emphasis was put on discriminating between individuals having a vascular structure and function associated with a higher or lower risk, and cluster analysis algorithms were employed to assign the subjects into groups based on these vascular measurements. In addition, a vascular status score (VSS) was calculated by summarizing the results according to quintiles of the vascular measurements. The associations between VSS and cardiovascular biomarkers were examined by regression analyses. RESULTS: The cluster analyses did not yield sufficiently distinct clustering (groups of individuals that could be categorized unequivocally as having either a vascular structure and function associated with a higher or lower CVD risk). VSS proved a better classificatory variable. The associations between VSS and biomarkers of cardiovascular risk were analyzed by univariable and multivariable regressions. Only body fat percentage and C-reactive protein (CRP) were independently associated with VSS. CONCLUSIONS: A VSS calculation, which integrates PWV, cIMT, and AIX measurements is better suited for cardiovascular risk evaluation in young adults than cluster analyses. The independent associations of VSS with body fat percentage and CRP highlight the decisive role of adiposity and systemic inflammation in early atherosclerotic progression and suggests a subordinate role of insulin and lipid metabolism in this age span.

Leptin levels are not affected by enalapril treatment after an uncomplicated myocardial infarction, but associate strongly with changes in fibrinolytic variables in men.

Leptin, an adipocyte-derived hormone, is involved in the regulation of body weight and is associated with obesity-related complications, notably cardiovascular disease (CVD). A putative link between obesity and CVD could be induction of plasminogen activator inhibitor-1 (PAI-1) synthesis by leptin. In this study, we hypothesized that the beneficial effect of the angiotensin-converting enzyme inhibitor (ACEi) enalapril on PAI-1 levels is mediated by effects on leptin levels. The association between leptin and components of the fibrinolytic system was evaluated in a non-prespecified post hoc analysis of a placebo-controlled randomized, double-blind trial where the effect of the ACEi enalapril on fibrinolysis was tested. A total of 46 men and 37 women were randomized to treatment with enalapril or placebo after (median 12 months) an uncomplicated myocardial infarction. At baseline, the participants were stable and had no signs of congestive heart failure. Leptin and fibrinolytic variables (mass concentrations of PAI-1, tissue plasminogen activator (tPA) and tPA-PAI complex) were measured at baseline, and after 10 days, 6 months and 12 months. Enalapril treatment did not change leptin levels, which increased significantly during 1 year of follow-up (p = .007). Changes in leptin levels were strongly associated with changes of tPA mass (p = .001), tPA-PAI complex (p = .003) and of PAI-1 (p = .006) in men, but not in women. Leptin levels are not influenced by treatment with an ACEi. In contrast, leptin associates strongly with changes in fibrinolytic variables notably with a sex difference, which could be of importance for obesity-related CVD.

Body fat percentage is more strongly associated with biomarkers of low-grade inflammation than traditional cardiometabolic risk factors in healthy young adults - the Lifestyle, Biomarkers, and Atherosclerosis study.

The primary aim was to appraise the relationship between body fat percentage and the inflammatory markers C-reactive protein (CRP) and orosomucoid in a population of young, non-smoking, healthy, Swedish adults, without any chronic diseases. A secondary aim was to compare whether these associations differed between the women using estrogen contraceptives and those who did not. We assessed the association in linear regression models between body fat percentage based on a bio-impedance measurement and plasma concentrations of CRP and orosomucoid in men and women aged 18-26 years, n = 834. Statistically significant associations were found between body fat percentage and both biomarkers of inflammation, with ß coefficients of 0.30 (95% CI 0.24-0.37) and 0.28 (0.22-0.35) for CRP and orosomucoid, respectively (p < .001). Adjustment for established risk factors marginally lowered the effects sizes (partial betas, 0.28 and 0.20, respectively), while the strong statistically significant associations remained. In the female cohort, estrogen and non-estrogen using subpopulations did not significantly differ in the correlations between body fat percentage and the inflammatory biomarkers, even adjusted for established cardiometabolic risk factors. In conclusion, in healthy young adults, higher levels of body fat percentage are associated with elevations in plasma biomarkers of inflammation, suggesting that a systemic inflammatory process, promoting atherosclerosis, may commence already at this early stage in life. CRP and orosomucoid plasma concentrations differed between users and non-users of estrogen contraceptives, but both subgroups showed similar correlations between increasing body fat percentage and increasing plasma concentrations of the biomarkers of inflammation.

D-Dimer Is Associated With First-Ever Intracerebral Hemorrhage.

Background and Purpose- Hypertension is the most important risk factor for intracerebral hemorrhage (ICH), but further characterization is needed for groups at high risk of ICH. One way to predict the risk of developing a disease is with plasma biomarkers. This study aimed to investigate the association between the biomarker, D-dimer, and ICH risk. Methods- This population-based, nested case-control study was conducted using data from 2 population-based surveys; the Västerbotten Intervention Programme and MONICA Northern Sweden (Monitoring Trends and Determinants in Cardiovascular Disease). All participants underwent a health examination and blood sampling at baseline before the event. Cases (n=141) were diagnosed with a first-ever ICH between 1985 and March 2007. One or 2 controls (n=255) were matched to each case. Results- The median age was 60 years; 39% of participants were women; and the median time from blood sampling to ICH was 5.2 years. When D-dimer was evaluated as a continuous variable, it was significantly associated with ICH. After multivariable adjustment (for hypertension, body mass index, cholesterol levels, diabetes mellitus, and smoking), the odds ratio was 1.36 per SD of D-dimer (95% CI, 1.05-1.77). When participants were stratified in 3 groups according to time from blood sampling at health examination to ICH, we found that the association between D-dimer levels and ICH was most pronounced in individuals with the shortest time from blood sampling to ICH event (<3.5 years; odds ratio, 1.78; 95% CI, 1.05-3.05). Conclusions- High plasma concentrations of D-dimer were associated with increased risk of a future ICH, after adjusting for cardiovascular risk factors. This association was predominantly driven by the cases with the shortest time from blood sampling to ICH event.

Expression of claudin 1, claudin 4, and claudin 7 in colorectal cancer and its relation with CLDN DNA methylation patterns.

Altered claudin expression has been described in colon, prostatic, ovarian, and breast carcinoma. However, the role of epigenetic modifications in these genes and their role in colorectal cancer is unknown. We aimed our study to investigate whether claudin protein expression and methylation of CLDN can influence the tumorigenesis of colorectal cancer. A total of 31 patients diagnosed with colorectal carcinoma was used in this study. Immunohistochemical staining was used to study protein expression in both tumor and the adjacent nonneoplastic mucosa of claudin 1, 4, and 7. To detect the DNA methylation pattern of CLDN1, 4, and 7, genomic DNA was extracted from both the tumor and the adjacent nonneoplastic mucosa. Methylation analysis was carried out using bisulfite pyrosequencing. Cell membrane staining intensity of all claudins was found significantly lower in colorectal cancer tissues when compared to paired normal mucosa (p ≤ 0.001). For claudin 4, the percentage of cells staining positively was also significantly reduced (p = 0.04). In normal mucosa, cytoplasm showed no staining for claudins in any patient, whereas in paired colorectal cancer tissues, significant cytoplasmic staining appeared both for claudin 1 (p = 0.04) and claudin 4 (p = 0.01). Tumor samples were significantly hypomethylated in CLDN1 (p < 0.05). In conclusion, our results show that CLDN1 is significantly hypomethylated in tumor samples and that the membrane staining intensity for claudin 1, 4, and 7 is significantly lower in colorectal cancer tissues than in adjacent nonneoplastic tissue. Colorectal cancer cells showed dystopic cytoplasmic location of claudins.

Plasma 1-carbon metabolites and academic achievement in 15-yr-old adolescents.

Academic achievement in adolescents is correlated with 1-carbon metabolism (1-CM), as folate intake is positively related and total plasma homocysteine (tHcy) negatively related to academic success. Because another 1-CM nutrient, choline is essential for fetal neurocognitive development, we hypothesized that choline and betaine could also be positively related to academic achievement in adolescents. In a sample of 15-yr-old children (n= 324), we measured plasma concentrations of homocysteine, choline, and betaine and genotyped them for 2 polymorphisms with effects on 1-CM, methylenetetrahydrofolate reductase (MTHFR) 677C>T, rs1801133, and phosphatidylethanolamineN-methyltransferase (PEMT), rs12325817 (G>C). The sum of school grades in 17 major subjects was used as an outcome measure for academic achievement. Lifestyle and family socioeconomic status (SES) data were obtained from questionnaires. Plasma choline was significantly and positively associated with academic achievement independent of SES factors (paternal education and income, maternal education and income, smoking, school) and of folate intake (P= 0.009,R(2)= 0.285). With the addition of thePEMTrs12325817 polymorphism, the association value was only marginally changed. Plasma betaine concentration, tHcy, and theMTHFR677C>T polymorphism did not affect academic achievement in any tested model involving choline. Dietary intake of choline is marginal in many adolescents and may be a public health concern.-Nilsson, T. K., Hurtig-Wennlöf, A., Sjöström, M., Herrmann, W., Obeid, R., Owen, J. R., Zeisel, S. Plasma 1-carbon metabolites and academic achievement in 15-yr-old adolescents.

Identification of novel genetic variants in the mutational hotspot region 14 kb upstream of the LCT gene in a Mexican population.

Several polymorphic loci linked to lactase persistence (LP) have been described, all located in a small mutational hotspot region far upstream (∼14 kb) of the lactase (LCT) gene. One is typically found in Europeans, LCT -13910C > T, several others are found in East Africans and Arabs, e.g. LCT -13907C > G and LCT -13915T > G. The possibility of similar loci, specific to populations in South and Central America, has not received much attention so far. To identify possible novel polymorphisms in the mutational hotspot region, we sampled 158 subjects from a rural area in South-Central Mexico. DNA was isolated from serum, and Sanger sequencing of a 501 bp region spanning the LCT -13910C > T hotspot was successfully performed in 150 samples. The frequency of the European-type LCT -13910 T-allele was q = 0.202, and 35% of the population was thus lactase-persistent (CT or TT). Sixteen novel genetic variants were found amongst 11 of the subjects, all were heterozygotes: seven of the subjects were also carriers of at least one LCT -13910 T-allele. Thus, the mutational hotspot region is also a hotspot in the rural Mexican population: 11/150 subjects carried a total of 16 previously unknown private mutations but no novel polymorphism was found. The relationship between such novel genetic variants in Mexicans and lactase persistence is worthy of more investigation.

High homocysteine and low folate plasma concentrations are associated with cardiovascular events but not bleeding during warfarin treatment.

BACKGROUND: Previous studies have shown that homocysteine and folate levels in plasma are associated with risk for cardiovascular events and mortality. The aim of this study was to investigate if plasma concentrations of total homocysteine and folate can predict major bleeding, cardiovascular events, and all-cause mortality in patients being treated with warfarin. METHODS: In a longitudinal cohort study, 719 patients who were taking warfarin were followed for 3001 treatment years. The following were recorded and classified: major bleeding; cardiovascular events including stroke, arterial emboli, and myocardial infarction (MI); and mortality. Blood samples collected at baseline were analysed for plasma homocysteine and folate levels. RESULTS: After adjustment for age, C-reactive protein, and creatinine, high homocysteine levels were associated with cardiovascular events [hazard ratio (HR) 1.23 per standard deviation (SD); 95% confidence interval (CI): 1.03-1.47], MI (HR 1.38 per SD; 95% CI: 1.03-1.85), and all-cause mortality (HR 1.41 per SD; 95% CI: 1.19-1.68). The highest tertile of folate compared to the lowest tertile was associated with decreased risk for both cardiovascular events (HR 0.64; 95% CI: 0.43-0.91) and MI (HR 0.45; 95% CI: 0.21-0.97). There was no association between major bleeding and homocysteine or folate levels. CONCLUSIONS: In patients receiving warfarin treatment, high homocysteine and low folate plasma concentrations are associated with increased risk for cardiovascular events but not major bleeding. For homocysteine levels, there is also an association with all-cause mortality.

DNA methylation and expression of the folate transporter genes in colorectal cancer.

Folate has a central role in the cell metabolism. This study aims to explore the DNA methylation pattern of the folate transporter genes FOLR1, PCFT, and RFC1 as well as the corresponding protein expressions in colorectal cancer (CRC) tissue and adjacent non-cancerous mucosa (ANCM). Our results showed statistically significant differences in the DNA-methylated fraction of all three genes at several gene regions; we identified three differentially methylated CpG sites in the FOLR1 gene, five CpG sites in the PCFT gene, and six CpG sites in the RFC1 gene. There was a pronounced expression of the FRα and RFC proteins in both the CRC and ANCM tissues, though the expression was attenuated in cancer compared to the paired ANCM tissues. The PCFT protein was undetectable or expressed at a very low level in both tissue types. Higher methylated fractions of the CpG sites 3-5 in the RFC1 gene were associated with a lower protein expression, suggestive of epigenetic regulation by DNA methylation of the RFC1 gene in the colorectal cancer. Our results did not show any association between the RFC and FRα protein expression and tumor stage, TNM classification, or tumor location. In conclusion, this is the first study to simultaneously evaluate both DNA methylation and protein expression of all three folate transporter genes, FOLR1, PCFT, and RFC1, in colorectal cancer. The results encourage further investigation into the possible prognostic implications of folate transporter expression and DNA methylation.

S100B concentrations increase perioperatively in jugular vein blood despite limited metabolic and inflammatory response to clinically uneventful carotid endarterectomy.

BACKGROUND: Our aim was to test the hypothesis that metabolic and inflammatory responses of the brain perioperatively during carotid endarterectomy (CEA) might affect blood brain barrier (BBB) integrity. METHODS: Twenty patients with >70% stenosis of internal carotid artery (ICA) were prospectively included. Surgery was performed under general anaesthesia. Blood was sampled from ipsilateral internal jugular vein and radial artery: just before, during, and after ICA clamping S100B protein, glucose, lactate, 20 amino acids, and key cytokines were analysed. RESULTS: Jugular vein S100B increased during clamping and reperfusion, while a marginal systemic increase was recorded, unrelated to stump pressure during clamping. Glucose increased during clamping in jugular vein blood and even more systemically, while jugular lactate values were higher than systemic values initially. Most amino acids did not differ significantly between jugular vein and systemic levels: glutamic acid and aspartic acid decreased during surgery while asparagine increased. Jugular vein interleukin (IL)-6 showed a transient non-significant increase during clamping and decreased systemically. IL-8 and IL-10 increased over time. CONCLUSIONS: Rising jugular vein S100B concentrations indicated reduced BBB integrity, and marginal secondary increase of S100B systemically. Limited ischaemic effects on the brain during cross-clamping, unrelated to S100B concentrations, were confirmed by lower brain glucose levels and higher lactate levels than in systemic blood. The lack of increased jugular vein glutamic acid disproves any major ischaemic brain injury following CEA. The inflammatory response was limited, did not differ greatly between jugular and systemic blood, and was unrelated to S100B.

Folic acid supplementation and methylenetetrahydrofolate reductase (MTHFR) gene variations in relation to in vitro fertilization pregnancy outcome.

OBJECTIVE: To study folic acid intake, folate status and pregnancy outcome after infertility treatment in women with different infertility diagnoses in relation to methylenetetrahydrofolate reductase (MTHFR) 677C>T, 1298A>C and 1793G>A polymorphisms. Also the use of folic acid supplements, folate status and the frequency of different gene variations were studied in women undergoing infertility treatment and fertile women. DESIGN: Observational study. SETTING: University hospital. POPULATION: Women undergoing infertility treatment and healthy, fertile, non-pregnant women. METHODS: A questionnaire was used to assess general background data and use of dietary supplements. Blood samples were taken to determine plasma folate and homocysteine levels, and for genomic DNA extraction. A comparison of four studies was performed to assess pregnancy outcome in relation to MTHFR 677 TT vs. CC, and 1298 CC vs. AA polymorphisms. MAIN OUTCOME MEASURES: Folic acid supplement intake, and plasma folate, homocysteine and genomic assays. RESULTS: Women in the infertility group used significantly more folic acid supplements and had better folate status than fertile women, but pregnancy outcome after fertility treatment was not dependent on folic acid intake, folate status or MTHFR gene variations. CONCLUSION: High folic acid intakes and MTHFR gene variations seem not to be associated with helping women to achieve pregnancy during or after fertility treatment.

Relative handgrip strength correlates inversely with increased body fat, inflammatory markers and increased serum lipids in young, healthy adults - The LBA study.

BACKGROUND: Handgrip strength (HGS) is a surrogate marker of whole body strength that has been observed to correlate inversely with the metabolic syndrome (MetS). In this study, we examined whether HGS in young, healthy individuals, was associated with surrogate endpoints of the MetS. A secondary goal was to examine whether absolute HGS (absHGS) or relative HGS (relHGS) was a stronger predictor of MetS. METHOD: 834 subjects (577 women), aged 18-26, were recruited. Surrogate endpoints for MetS were waist circumference, HDL, fasting glucose, fasting insulin, triglycerides, and systolic and diastolic blood pressure (BP). We also examined the association between HGS and body fat percentage, HOMA-IR, CRP, orosomucoid and apolipoprotein A-1 and apolipoprotein B. The associations were examined using multivariable linear regression. RESULTS: AbsHGS and relHGS were each associated with several surrogate endpoints of the metabolic syndrome, with RelHGS being statistically significantly associated with a greater number of the variables - all except fasting glucose and diastolic BP. CONCLUSION: RelHGS correlates with components of the MetS even in young, healthy populations. It is a better predictor of MetS components than absHGS. As a cheap and easy to use biomarker, relHGS holds merit as a screening tool for metabolic dysfunction even in preclinical contexts.

Handgrip strength reference intervals in Swedish, young, healthy adults: The LBA study.

OBJECTIVES: Handgrip strength (HGS) is a surrogate marker of general risk and nutritional status, frequently used in clinical practice. This study aimed to determine clinically useful reference intervals for healthy, young adults from Northern Europe. METHODS: This cross-sectional study was conducted in central Sweden, recruiting 834 young, nonsmoking adults ages 18 to 26 y. Subjects responded to a questionnaire on general health status, medication (including contraceptives), exercise habits, and parental and their own country of birth. Anthropometry, bioimpedance analysis for determination of fat-free mass (FFM), and HGS was measured. Reference intervals were calculated as mean and standard deviation. Differences between men, women, and women using estrogen contraceptives were analyzed using an analysis of variance with Tukey's post hoc test. Associations between HGS and determinant variables were analyzed using Spearman and linear regressions. RESULTS: Men and women differed in HGS, but no significant difference was found in average HGS based on contraceptive use in women. Mean HGS was 53 kg in men and 34 kg in women, with a range of 22 kg to 90 kg in men and 16 kg to 73 kg in women. Height correlated with HGS. Subjects with a body mass index (BMI) <20 had statistically significantly lower HGS than those in higher BMI groups. There was no statistically significant mean difference between the group of subjects with a BMI of 20 to 25 and those with BMI >25 in neither men nor women. HGS in both sexes showed a gradual increase through tertiles of FFM. In linear regression models, sex, height, and FFM were the main determinants of HGS. CONCLUSIONS: In this study, we established reference intervals for HGS in healthy Swedish adults ages 18 to 26 y. As a surrogate marker of whole-body muscle mass, these reference intervals can be used in health assessments and the planning of health-promoting measures in the individual young adults. Differences in HGS based on height warrant height-specific reference intervals that should be established locally.

CTH G1208T and MTHFR A1298C polymorphisms are associated with a higher risk of a first myocardial infarction with fatal outcome among women.

OBJECTIVES: Cystathionine-gamma-lyase (CSE) in the transsulfuration pathway generates hydrogen sulfide (H2S), suggested regulating cardiovascular function. The G1208T polymorphism in the CTH gene, rs1021737, has, in addition to MTHFR, been found to increase homocysteine, related to myocardial infarction (MI) risk. This study aimed, for the first time, to investigate the associations of the polymorphisms CTH G1208T, MTHFR C677T, and A1298C with the prospective risk of developing a fatal or non-fatal first MI. METHODS: This case-referent study included 545 cases later developing a first-ever MI and 1,054 referents from the Northern Sweden Health and Disease Study. Fatal MI was defined as death within 28 days after MI symptoms. RESULTS: Women, but not men, had a positive association between fatal MI and the CTH G1208T, odds ratio [95% confidence interval] 3.14 [1.16-8.54] for heterozygotes, and the dominant model 3.22 [1.22-8.51], and for the MTHFR A1298C heterozygotes 3.24 [1.26-8.34] and the dominant model 2.63 [1.06-6.50]. The MTHFR C677T polymorphism was not related to MI. CONCLUSIONS: This study indicates that the minor alleles of CTH G1208T and MTHFR A1298C polymorphisms are associated with a higher risk for a fatal MI among women but not for non-fatal MI. No association was found in men.

A folate receptor alpha double-mutated haplotype 1816delC-1841A is distributed throughout Eurasia and associated with lower erythrocyte folate levels.

Folate is crucial for various cellular functions. Several transport mechanisms allow folate to enter the intracellular compartment with folate receptor-α being the major high-affinity receptor. Rare genetic variations in exons of the FR-α gene, FOLR1, were recently shown to cause severe folate deficiency accompanied by neurological and other disturbances. So far, similar effects by genetic variation in noncoding parts of the FOLR1 gene have not been identified. The aim of our study was to determine biochemically the haplotype structure of two linked polymorphisms in the FOLR1 gene, 1816delC and 1841G>A, the prevalences of the mutated alleles across Eurasia, and their possible effects on physiological folate levels in vivo. For this purpose we employed allele-specific PCR and Pyrosequencing technology and performed genotyping in 738 subjects from Spain, 387 from Sweden, 952 from Estonia, and 47 from Korea. We demonstrate the presence of an ancient double-mutated haplotype 1816delC-1841A in the FOLR1 gene, with the prevalence of the mutated allele being highest among Koreans (q = 0.074), lower in Estonians (q = 0.017), Spaniards (q = 0.0061), and the lowest among Swedes (q = 0.0026). Erythrocyte folate levels were studied in the Spanish population sample, where subjects carrying the double-mutated FOLR1 haplotype had significantly reduced levels by 27% (P = 0.039), adjusted for serum vitamin B(12) levels and MTHFR 677C>T genotype, while the mean serum folate levels were only 20% lower among the carriers (P = 0.11). Plasma homocysteine and cobalamin levels did not differ. Thus, we have demonstrated by molecular haplotyping an ancient double-mutated haplotype 1816delC-1841A in the FOLR1 gene, spread over the whole Eurasian continent, which may be of functional importance for uptake of folate in red blood cells.