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      Enrichment of MTHFR 677 T in a Chinese long-lived cohort and its association with lipid modulation

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          Abstract

          Background

          Variants in the Methylenetetrahydrofolate reductase (MTHFR) gene may result in a lowered catalytic activity and associate with subsequent elevated serum homocysteine (Hcy) concentration, abnormal DNA synthesis and methylation, cardiovascular risk, and unhealthy aging. Several investigations on the relationship of MTHFR C677T polymorphism with serum lipid profile and longevity have been conducted in some populations, but the findings remain mixed. Herein, we sought to look at the association between MTHFR C677T and lipid profile in a longevous cohort in Bama, a well-known home of longevity in China.

          Methods

          Genotyping of MTHFR C677T was undertaken in 516 long-lived inhabitants (aged 90 and older, long-lived group, LG) and 493 healthy controls (aged 60–75, non-long-lived group, non-LG) recruited from Bama area. Correlation between MTHFR genotypes and lipids was then evaluated.

          Results

          T allele and TT genotype were significantly more prevalent in LG (P = 0.001 and 0.002, respectively), especially in females, than in non-LG. No difference in the tested lipid measures among MTHFR C677T genotypes was observed in LG, non-LG and total population (P > 0.05 for all). However, female but not male T carriers exhibited higher TC and LDL-C levels than did T noncarriers in the total population and in LG after stratification by sex (P < 0.05 for each). These differences did not however remain through further subdivision by hyperlipidemia and normolipidemia.

          Conclusion

          The higher prevalence of MTHFR 677 T genotypes and its modest unfavorable impact on lipids in Bama long-lived individuals may imply an existence of other protective genotypes which require further determination.

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          Most cited references33

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          Unique lipoprotein phenotype and genotype associated with exceptional longevity.

          Individuals with exceptional longevity have a lower incidence and/or significant delay in the onset of age-related disease, and their family members may inherit biological factors that modulate aging processes and disease susceptibility. To identify specific biological and genetic factors that are associated with or reliably define a human longevity phenotype. In a case-control design, 213 Ashkenazi Jewish probands with exceptional longevity (mean [SD] age, 98.2 [5.3] years) and their offspring (n = 216; mean [SD] age, 68.3 [6.7] years) were recruited from 1998 to 2002, while an age-matched control group of Ashkenazi Jews (n = 258) and participants from the Framingham Offspring Study (n = 589) were accepted as control groups. Detailed questionnaires, physical examination, and blood samples were taken, including assessment of lipids and lipoprotein subclass levels and particle sizes by proton nuclear magnetic resonance. Samples were also genotyped for the codon 405 isoleucine to valine (I405V) variation in the cholesteryl ester transfer protein (CETP) gene, which is involved in regulation of lipoprotein and its particle sizes. High-density lipoprotein (HDL) and low-density lipoprotein (LDL) particle sizes were significantly higher in probands compared with both control groups (P =.001 for both), independent of plasma levels of HDL and LDL cholesterol and apolipoprotein A1 and B. This phenotype was also typical of the proband's offspring but not of the age-matched controls. The HDL and LDL particle sizes were significantly larger in offspring and controls without hypertension or cardiovascular disease, (P =.001 and P =.008, respectively). Furthermore, lipoprotein particle sizes, but not plasma LDL levels, were significantly higher in offspring and controls without the metabolic syndrome (P<.001). Probands and offspring had a 2.9- and 3.6-fold (in men) and 2.7- and 1.5-fold (in women) increased frequency, respectively, of homozygosity for the 405 valine allele of CETP (VV genotype), respectively, compared with controls (P<.001 for both). Those probands with the VV genotype had increased lipoprotein sizes and lower serum CETP concentrations. Individuals with exceptional longevity and their offspring have significantly larger HDL and LDL particle sizes. This phenotype is associated with a lower prevalence of hypertension, cardiovascular disease, the metabolic syndrome, and increased homozygosity for the I405V variant in CETP. These findings suggest that lipoprotein particle sizes are heritable and promote a healthy aging phenotype.
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            Geographical and ethnic variation of the 677C>T allele of 5,10 methylenetetrahydrofolate reductase (MTHFR): findings from over 7000 newborns from 16 areas world wide.

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              MTHFR 677C-->T polymorphism and risk of coronary heart disease: a meta-analysis.

              In observational studies, individuals with elevated levels of plasma homocysteine tend to have moderately increased risk of coronary heart disease (CHD). The MTHFR 677C-->T polymorphism is a genetic alteration in an enzyme involved in folate metabolism that causes elevated homocysteine concentrations, but its relevance to risk of CHD is uncertain. To assess the relation of MTHFR 677C-->T polymorphism and risk of CHD by conducting a meta-analysis of individual participant data from all case-control observational studies with data on this polymorphism and risk of CHD. Studies were identified by searches of the electronic literature (MEDLINE and Current Contents) for relevant reports published before June 2001 (using the search terms MTHFR and coronary heart disease), hand searches of reference lists of original studies and review articles (including meta-analyses) on this topic, and contact with investigators in the field. Studies were included if they had data on the MTHFR 677C-->T genotype and a case-control design (retrospective or nested case-control) and involved CHD as an end point. Data were obtained from 40 (34 published and 6 unpublished) observational studies involving a total of 11 162 cases and 12 758 controls. Data were collected on MTHFR 677C-->T genotype, case-control status, and plasma levels of homocysteine, folate, and other cardiovascular risk factors. Data were checked for consistency with the published article or with information provided by the investigators and converted into a standard format for incorporation into a central database. Combined odds ratios (ORs) for the association between the MTHFR 677C-->T polymorphism and CHD were assessed by logistic regression. Individuals with the MTHFR 677 TT genotype had a 16% (OR, 1.16; 95% confidence interval [CI], 1.05-1.28) higher odds of CHD compared with individuals with the CC genotype. There was significant heterogeneity between the results obtained in European populations (OR, 1.14; 95% CI, 1.01-1.28) compared with North American populations (OR, 0.87; 95% CI, 0.73-1.05), which might largely be explained by interaction between the MTHFR 677C-->T polymorphism and folate status. Individuals with the MTHFR 677 TT genotype had a significantly higher risk of CHD, particularly in the setting of low folate status. These results support the hypothesis that impaired folate metabolism, resulting in high homocysteine levels, is causally related to increased risk of CHD.
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                Author and article information

                Contributors
                Journal
                Lipids Health Dis
                Lipids Health Dis
                Lipids in Health and Disease
                BioMed Central
                1476-511X
                2014
                26 June 2014
                : 13
                : 104
                Affiliations
                [1 ]Department of Pathophysiology, School of Preclinical Medicine, Guangxi Medical University, Nanning 530021, Guangxi, People’s Republic of China
                [2 ]Department of Cell Biology & Genetics, School of Preclinical Medicine, Guangxi Medical University, Nanning 530021, Guangxi, People’s Republic of China
                [3 ]Department of Cardiology, Institute of Cardiovascular Diseases, The First Affiliated Hospital, Guangxi Medical University, 22 Shuangyong Road, Nanning 530021, Guangxi, People’s Republic of China
                Article
                1476-511X-13-104
                10.1186/1476-511X-13-104
                4092207
                24968810
                85d81d7d-0b0e-4c34-8a2d-51588237b8ab
                Copyright © 2014 Chen et al.; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 12 March 2014
                : 17 June 2014
                Categories
                Research

                Biochemistry
                Biochemistry

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