Associations of methylenetetrahydrofolate reductase C677T polymorphism with markers of subclinical atherosclerosis: The Cardiovascular Risk in Young Finns Study

Objective. To study whether the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism or serum homocysteine concentration is associated with carotid artery intima media thickness (IMT), carotid artery compliance (CAC) or brachial artery flow mediated dilatation (FMD) in a healthy Finnish adult population. Methods. Cross‐sectional data obtained in 2001 for the Cardiovascular Risk in Young Finns Study were used. Carotid artery IMT, CAC and brachial FMD were measured by ultrasound and serum homocysteine concentrations using a commercial immunoassay kit. We studied 1,440 subjects (aged 24–39 years). Genotyping was performed using the 5′ nuclease TaqMan assay. Results. Homocysteine values differed between genotypes in women and men (ANOVA, p<0.001 for both sex groups): the genotype raised values in the order of CC, CT, TT. There was a significant difference in CAC values between the MTHFR genotypes in men (ANOVA, p = 0.008), and the CC genotype had the lowest values. In multivariate linear regression analysis adjusted for other major coronary risk factors (e.g. age, smoking, body mass index, systolic blood pressure, C‐reactive protein), the association remained significant (R² = 25.8?%, beta = 0.091; p = 0.02). Homocysteine level was directly associated with CAC in the whole population (R² = 18.0?%, beta = 0.012; p = 0.014) and in women (R² = 9.3%, beta = 0.02; p = 0.013), but not in men (R² = 15.2?%, beta = 0.004; p = 0.444). We found no association between homocysteine level or the MTHFR polymorphism and carotid IMT or brachial artery FMD. Conclusions. The findings suggest that the MTHFR polymorphism does not influence IMT or FMD, but that the T allele may have an effect on CAC in men.     

The influence of smoking and homocysteine on subclinical atherosclerosis is modified by the connexin37 C1019T polymorphism - The Cardiovascular Risk in Young Finns Study

BACKGROUND: A polymorphism C1019T on the connexin37 (Cx37) gene has been found to associate with coronary artery disease. There are conflicting results on which allele confers risk, and the possibility of interactions between the polymorphism and risk factors has been raised. In this study, we examined interactions between the Cx37 polymorphism and common risk factors and their associations to early vascular parameters of atherosclerosis: carotid artery intima-media thickness (IMT), and carotid artery compliance (CAC) and brachial artery flow mediated dilatation (FMD). METHODS: A population of 1440 healthy young adults from the Cardiovascular Risk in Young Finns Study was studied. The subjects were genotyped and their cardiovascular risk factor and ultrasound data gathered in 2001 were used for the statistical analyses. RESULTS: In the whole population, homocysteine in subjects with the TT genotype was found to be associated with higher FMD values (p for interaction 0.038) and remained so in three different adjusted models (p for interaction 0.022-0.038). In women with the CC genotype, smoking was found to be associated with higher FMD values and the smoking-by-genotype interaction remained significant in three adjusted models (p for interaction 0.001-0.041). In women with TT genotype, the effect of smoking was opposite, i.e., FMD values for smokers were lower compared to non-smokers. In men, physical activity interacted with Cx37 on CAC in the CT and TT genotypes (p for interaction 0.011). No significant interactions were found to predict IMT. CONCLUSIONS: The effect of smoking and homocysteine levels on arterial endothelial functions and elasticity were modified by the allelic variation of the Cx37 gene. These data suggest that variation in the connexin gene may modify effects risk factors have on vascular function.     

Homocysteine, methylenetetrahydrofolate reductase C677T polymorphism and the B-vitamins: a facet of nature-nurture interplay.

BACKGROUND: Methylenetetrahydrofolate reductase 677 (MTHFR 677) polymorphism may provoke hyperhomocysteinemia when folate status is low. The influence of MTHFR 677 mutation on homocysteine (HCY) levels in relation to vitamin B12 and folate status was investigated in the current study. SUBJECTS AND METHODS: 113 vegetarians, 123 omnivorous Germans, and 117 omnivorous Syrians were recruited. MTHFR 677 genotype, HCY, methylmalonic acid (MMA), total serum vitamin B12, serum folate, and vitamin B6 were determined using conventional methods. RESULTS: Omnivorous Germans displayed the lowest HCY levels compared with vegetarians and Syrians (median 8.0, 10.4, and 11.3 micromol/l, respectively). The highest serum folate and the highest MMA levels were found in vegetarians (median folate = 30.0; MMA = 355 nmol/l). Among vegetarians and Syrians, TT subjects had higher HCY levels than other genotypes which were, however, no longer significant in the highest folate tertiles. When the data were pooled, the odds ratio (OR, 95% CI) for HCY > 12 micromol/l was 3.81 (1.55-9.34) in TT compared with CC subjects. The OR increased to 28.85 (4.63-179.62) in TT subjects who had folate in the lowest tertile, and to 21.84 (4.81-99.1) in TT subjects who had MMA in the highest MMA tertile. CONCLUSION: MTHFR 677 TT individuals are more liable to hyperhomocysteinemia under vitamin B12 deficiency than the other two genotypes. In such a case, relative folate shortage may progressively increase HCY levels. TT individuals may have increased folate and vitamin B12 requirements compared to the other CC and CT genotypes.     

The methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and cancer risk: the Croatian case-control study

OBJECTIVES: Methylation abnormalities appear to be important for the pathogenesis of many cancer types. Since methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in the methylation process catalyzing reduction of 5,10-methylenetetrahydrofolate to 5-methyl-tetrahydrofolate, C677T polymorphism, which decreases enzyme activity, may be associated with cancer susceptibility. The aim of this work was to investigate the distribution of MTHFR C677T polymorphism between various types of cancer and cancer-free controls and to assess if there is a difference in frequency. MATERIALS AND METHODS: 269 Cancer cases (95 prostate cancer, PC; 81 head and neck, HN; and 93 breast cancers, BC) and 102 healthy controls, free of cancer, were genotyped for C677T MTHFR polymorphism using the PCR-RFLP method. RESULTS: There was no overall difference in C677T genotype distribution between total cancer cohort and controls (p=0.064). However, a significant difference and protective OR was found for the C/T genotype (OR=0.574, 95% CI=0.352-0.935). In a comparison of different cancer types and respective controls, genotype frequencies were significantly different between head and neck carcinoma and controls (p=0.004), again with protective role of C/T genotype (OR=0.356, 95% CI=0.189-0.671). Moderate overrepresentation of C/T was found in respective male controls when compared with prostate cancer patients (p value was 0.074 for C/T vs. C/C comparison). The OR for heterozygous C/T genotype in prostate cancer group was 0.404, pointing to its putative protective role. Genotype and allelic frequencies did not differ significantly between 93 breast cancer patients and their 65 age-matched female controls. CONCLUSION: Our data indicate that the C677T MTHFR polymorphism does not significantly contribute to the inherited genetic susceptibility to breast and prostate cancer, while we show some evidence for possible genetic contribution of this polymorphism to the development of head and neck carcinoma.     

Croatian population data for the C677T polymorphism in methylenetetrahydrofolate reductase: frequencies in healthy and atherosclerotic study groups

BACKGROUND: The aim of this study was to investigate the frequency of C677T methylenetetrahydrofolate reductase (MTHFR) mutation in healthy Croatian volunteers and in patients with atherosclerosis. METHODS: The C677T MTHFR gene mutation was determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 640 subjects, residents of the Zagreb city or Zagreb surroundings. Control group (n=298) was healthy blood donors. Patients (n=342) were divided into two groups of those with coronary heart disease, CAD (n=247) and those with >60% carotid stenosis, CS (n=95). RESULTS: CC genotype was recorded in 45% of healthy volunteers and 46% of patients (46.3% with CS and 46.2% with CAD). TC genotype was found in 49% of healthy volunteers and 45% of patients (46.3% with CS and 44.9% with CAD). There was no significant difference (p>0.05) from the control group in the genotype or allele frequency either for the overall group of patients with atherosclerosis or for the patient subgroups. CONCLUSION: The preliminary study of MTHFR polymorphism in control subjects and cardiovascular disease/carotid stenosis patients revealed that in Croats there was a low frequency of TT genotype (6% in controls vs. 9% in patients) and T allele (31% for cases and controls). Additionally, our results did not show significantly higher frequency of MTHFR mutation in CAD and CS studied groups.     

Nonarteritic anterior ischemic optic neuropathy: associations with homozygosity for the C677T methylenetetrahydrofolate reductase mutation

The association between nonarteritic anterior ischemic optic neuropathy (NAION) and coagulation disorders was prospectively assessed at least 3 months after the occurrence of ocular vascular events in 12 white patients in an outpatient clinical research center. Two community-based ophthalmologists evaluated the 12 NAION patients in the consecutive order of their referral. Polymerase chain reaction-complementary DNA assays of gene mutations associated with coagulation disorders and serologic coagulation measurements in study patients were compared with those in 36 healthy, normal race-, sex-, and age-matched controls, with 3 controls matched for each case. Of the 12 patients, 4 men and 8 women (mean age 62 +/- 15 years, 3 of them 55 years or older), 8 had unilateral NAION (bilateral in 4). The 12 patients with NAION were more likely than controls to demonstrate homozygosity for the methylenetetrahydrofolate reductase (MTHFR) C677T mutation (50% vs 11 %; Fisher's P =.009, with the likelihood of a type I error quite small, 0.9%). Our sample size had a power of 80% to detect this case-control difference in C677T MTHFR homozygosity at an alpha value of.05. Of the 12 NAION patients, 7 (58%) had at least 1 gene mutation in the C677T MTHFR, G1691A V Leiden, or G20210A prothrombin gene, compared with 5 of 36 controls (14%) (chi(2) = 9.48, P =. 002, with the likelihood of a type I error quite small, 0.2%). Our sample size had a power of 85% to detect this case-control difference at alpha =. 05. Of the 8 women with NAION, 5 (63%) first experienced the condition while taking hormone replacement therapy (n = 4) or during pregnancy (n = 1), with superposition of estrogen-induced thrombophilia on heritable thrombophilia and hypofibrinolysis. Confirmation of a causal relationship between coagulation disorders and NAION should facilitate its prevention and treatment and help protect against thrombi in other vascular beds.     

Systemic hemodynamics in young adults with the metabolic syndrome: The Cardiovascular Risk in Young Finns Study

Abstract

Objective. We conducted the present study to examine associations of three different metabolic syndrome (MetS) definitions and their components to arterial stiffness, systemic vascular resistance, and left ventricular function at population level. In addition, the objective of the study was to examine associations of spontaneous recovery from MetS over 6 years’ follow-up to systemic hemodynamics.

Methods. The study population consisted of 1,741 Finnish young adults (aged 30–45 years) who had complete MetS risk factor and hemodynamic data available at 2007. Associations of spontaneous recovery from MetS to systemic hemodynamics was studied on a subpopulation of 1,391 subjects who had also complete MetS risk factor data available at 2001. Hemodynamic measurements were performed using a whole-body impedance cardiography device.

Results. MetS and increasing number of MetS components were associated with lower stroke index (P < 0.001) and higher systemic vascular resistance index (P < 0.005) and arterial pulse wave velocity (P < 0.005). In MetS persistent group, stroke index was lower (P = 0.024), and pulse wave velocity was higher (P = 0.003) compared to MetS recovery group.

Conclusion. All current MetS definitions identify young adults with altered systemic hemodynamics, and recovery from MetS is associated with a favorable hemodynamic profile.     

Association of liver enzymes with metabolic syndrome and carotid atherosclerosis in young adults. The Cardiovascular Risk in Young Finns Study

Abstract

Objective. We examined whether metabolic syndrome (MetS) predicts increased alanine aminotransferase (ALT) and gamma-glutamyltransferase (GGT) levels in young adults, whether spontaneous recovery from MetS has a favorable effect on liver enzyme activities, and whether these enzymes contribute to the atherogenicity of MetS (assessed by carotid intima-media thickness (IMT)).

Methods. The study included 1,553 subjects (base-line age 31.5 ± 5.0 years). ALT and GGT were measured in 2007. MetS was diagnosed by the new Joint Interim Societies definition.

Results. ALT and GGT levels were higher in subjects with MetS compared to those without in 2007. The association was independent of alcohol intake and BMI. In multivariable models adjusted for base-line age, LDL cholesterol, CRP, alcohol intake, and adiponectin, MetS in 2001 predicted increased ALT (β ± SEM = 0.320 ± 0.062, P < 0.0001 in men; 0.134 ± 0.059, P = 0.02 in women) and GGT (β ± SEM = 0.222 ± 0.067, P < 0.0001 in men; 0.236 ± 0.060, P < 0.0001 in women) levels after 6 years. Subjects with MetS only at base-line (2001) had lower ALT levels after 6 years compared to subjects with persistent and incident MetS. No statistically significant interaction for MetS*ALT (P = 0.81) or MetS*GGT (P = 0.92) on IMT was observed.

Conclusion. In young adults MetS may induce liver enzyme changes that indicate increased risk of non-alcoholic fatty liver disease, but we found no evidence that increased enzyme levels would amplify the atherogenicity of MetS.     

Association of high sensitive C-reactive protein with apolipoprotein E polymorphism in children and young adults: the Cardiovascular Risk in Young Finns Study.

BACKGROUND: A relation between apolipoprotein E (APOE) genotypes and high sensitive C-reactive protein (hsCRP) has been observed in some studies with elderly subjects and different patient groups. We studied whether serum hsCRP levels are linked with common APOE (epsilon 2, epsilon 3, epsilon 4) polymorphism already in children and young adults. METHODS: The study cohort included 1221 subjects participating in the Cardiovascular Risk in Young Finns Study at age 3-18 years at baseline in 1980. These subjects were reexamined at the 21-year follow-up at age 24-39 years in 2001. APOE phenotypes were examined in 1986, serum hsCRP was measured from fresh samples in 2001 and baseline hsCRP (in 1980) was measured from frozen samples in 2005. RESULTS: Serum hsCRP was significantly associated with APOE phenotypes in children and young adults using multivariate analysis adjusted for age, body mass index, smoking, total cholesterol and low-density lipoprotein cholesterol. Male epsilon 4 carriers had significantly lower hsCRP levels both in childhood (p=0.003) and in adulthood (p=0.013). hsCRP increased in both phenotype classes (epsilon 4+ and epsilon 4-) during the 21-year follow-up. Female epsilon 4 carriers had lower hsCRP levels in childhood (p=0.032) but not in adulthood (p=0.995). An interaction effect between time and APOE phenotype (p=0.045) in relation to hsCRP was observed in females during the 21-year follow-up. CONCLUSIONS: Common APOE polymorphism affects the level of circulating hsCRP already in children and young adults. Male APOE epsilon 4 carriers have consistently lower hsCRP levels. In females, APOE epsilon 4 carriers had lower hsCRP levels in childhood but not in adulthood.     

Elevated plasma total homocysteine and C677T mutation of the methylenetetrahydrofolate reductase gene in patients with spina bifida

Total plasma homocysteine (tHcy) was significantly higher in 28 children with spina bifida (median 6.05 mumol/l) as compared with 76 controls (median 4.94 mumol/l). This difference was confined to a subgroup of patients (16/28) with one or two C677T-mutated alleles in the methylenetetrahydrofolate reductase gene. Since we found no significant difference between patients and controls in serum folate, erythrocyte folate, serum cobalamin or serum methylmalonic acid, which were within the normal range for both patients and controls, the elevated tHcy could not be attributed to vitamin deficiencies. Our findings point to an additional genetic defect involving folate- dependent enzymes in a subgroup of patients with neural-tube defects.      

Cardiovascular risk factors of young adults in relation to parental socioeconomic status: the Cardiovascular Risk in Young Finns Study

The socioeconomic status (SES) of the family influences the cardiovascular risk status of children and adolescents; however, it is not as well known whether parental SES has any effect on the risk factor profile of young adults. The aim of the present study was to investigate the relations of different aspects of parental SES, namely occupation, education, income and living area, to the common cardiovascular risk factors of their offspring (n = 919) aged 18, 21 and 24 years as a part of the Cardiovascular Risk in Young Finns Study in 1986. Subjects from farming families and rural areas had the highest serum total and low-density lipoprotein cholesterol values, and the lowest diastolic blood pressure compared with subjects from other occupational groups and subjects from urban regions. The diet of young adults from farming families and from rural areas contained more saturated fatty acids and less monounsaturated and polyunsaturated fatty acids. In addition, the body mass index was lower in subjects from urban regions compared with rural regions, and physical inactivity was less common in the urban group. Subjects with the highest parental occupational status smoked less compared with those with the lowest status. Parental education related inversely to physical inactivity and directly to dietary polyunsaturated fatty acids. The income level of the family associated positively with frequent inebriation by alcoholic beverages and inversely with the percentage of dietary energy from fat. In conclusion, there were modest inverse associations between different indicators of the SES of parents and some of the traditional risk factors of their offspring in young adulthood, which may contribute to the future risk of cardiovascular diseases.     

Adult-type hypolactasia is not a predisposing factor for the early functional and structural changes of atherosclerosis: the Cardiovascular Risk in Young Finns Study

Individuals suffering from ATH (adult-type hypolactasia), defined by the LCT (gene encoding lactase-phlorizin hydrolase) C/C(-13910) genotype (rs4988235), use less milk and dairy products and may have higher plasma HDL (high-density lipoprotein) and lower triacylglycerol (triglyceride) concentrations than their counterparts without ATH. To investigate the effects of ATH status on the early markers of atherosclerosis, we examined its association with CIMT (carotid intima-media thickness), CAC (carotid artery compliance) and brachial artery FMD (flow-mediated dilation) in a young population-based cohort of otherwise healthy individuals. As part of the Cardiovascular Risk in Young Finns Study, we performed CIMT, CAC and FMD analyses, LCT C/T(-13910) genotyping and risk factor determination in 2109 young subjects 24-39 years of age (45% males) at the time of the examination. The consumption of both milk and dairy products was lowest and the consumption of alcohol highest in subjects with the C/C(-13910) genotype (P<0.001 for all) in comparison with subjects without ATH (TT+CT). In multivariate analysis, no significant association between ATH status and CIMT, CAC or brachial artery FMD was found after adjustment for the use of alcohol, dairy products and all other major risk factors of coronary artery disease. In otherwise similar statistical analysis, the results remained non-significant when females and males were analysed in their own groups. In conclusion, the finding does not support the involvement of ATH in the pathogenesis of early atherosclerosis.     

Association of methylenetetrahydrofolate reductase T677 allele with early development of chronic allograft nephropathy

OBJECTIVES: The aim of this study was to evaluate the role of genetic polymorphisms on the development of chronic allograft nephropathy (CAN). DESIGN AND METHODS: Using the polymerase chain reaction (PCR), polymorphisms of methylenetetrahydrofolate reductase (MTHFR C677T), interleukin-6 (IL-6 G-174C) and CD14 (C-260T) were evaluated in 92 kidney transplant recipients with stable renal graft function and no signs of acute rejection in a protocol that included graft biopsy at 12 months after kidney transplantation. A normal population sample (n = 365) was also included. Multivariate analysis was used to evaluate the effect of different variables on the CAN appearance. RESULTS: There were no differences in alleles and genotypes distribution between transplant group and normal population sample. The CAN+ group (n = 69) significantly differed from CAN- (n = 23) in both MTHFR (P < 0.05) and IL-6 (P < 0.01) genotype distribution. Using logistic regression multivariate analysis, MTHFR T677 allele (OR: 3.91, CI: 1.11-13.8; P < 0.05), patient age (OR: 0.94, CI: 0.88-0.98; P < 0.01) and proteinuria (OR: 3.63, CI: 1.25-10.6; P < 0.05) were associated with CAN. Although the IL-6 G-174 allele was shown to be associated with CAN development in univariate analysis (P < 0.01), the multivariate analysis did not show an association. There was no relation between CD14 gene polymorphism and CAN. CONCLUSION: The MTHFR T677 allele is associated with the presence of CAN in kidney graft biopsies 12 months after transplantation.     

Childhood predictors of the metabolic syndrome in adulthood. The Cardiovascular Risk in Young Finns Study

Background. Obese youths may be susceptible to develop the metabolic syndrome (MS) later in life.

Aim. To study childhood predictors of MS in adulthood.

Method. Prospective cohort study including 2,195 subjects, aged 3–18 years at base-line in 1980, who were re-examined in 1983, 1986, and 2001.

Results. In adults (aged 24–39 years) in 2001, the prevalence of MS (using the International Diabetes Federation criteria) was 19% in men and 12% in women. Multivariable logistic regression model selected obesity, male sex, high triglycerides, high insulin, high C-reactive protein (CRP), and family history of hypertension and type 2 diabetes, as independent predictors of adult MS. Youth obesity (body mass index (BMI)>80^th age- and sex-specific percentile) was the strongest risk factor for MS. During the 21-year follow-up, there was an increasing trend in BMI, insulin, systolic blood pressure, and triglycerides, and a decreasing trend in high-density lipoprotein cholesterol in obese subjects who developed MS in adulthood compared to those obese subjects who did not develop MS.

Conclusions. Youth determinants of adult MS included obesity, high triglycerides, high insulin, high CRP, and family history of hypertension and type 2 diabetes. Identifying these risk factors at an early stage could help identifying children and adolescence at greater risk of developing MS later in life.     

Association of thyrotropin with arterial pulse wave velocity in young adults: The Cardiovascular Risk in Young Finns Study

Abstract

Objective. Limited data are available regarding the relationship of thyrotropin (TSH) and arterial pulse wave velocity (PWV) at population level. Therefore, we conducted the present study to determine whether TSH is related to PWV assessed in young adulthood. Methods. The study population consisted of 1598 Finnish white young adults (aged 30–45 years, 47.4% males) who had TSH, traditional cardiovascular risk factors, and PWV measured in 2007. PWV measurements were performed using a whole-body impedance cardiography device. Results. In bivariate association analyses, TSH level was significantly associated with body mass index (BMI), smoking, diastolic blood pressure, triglyceride and insulin levels (p < 0.001). In multivariable regression model, TSH (β = 0.055, p = 0.015) was associated with PWV when adjusted with age (β = 0.295, p < 0.001) and sex (β = 0.345, p < 0.001). The association of TSH with PWV was however diluted to non-significant after further adjustment with traditional risk factors (β = 0.027, p = 0.218 for TSH). Conclusion. Serum TSH was associated with PWV on population level when adjusted with age and sex. This association was diluted when cardiovascular risk factors were added in the model, suggesting that the association of thyroid hormone on arterial stiffening is not independent of changes in the traditional risk factor levels.