title: Gene polymorphisms as risk factors for predicting the cardiovascular manifestations in Marfan syndrome. Role of folic acid metabolism enzyme gene polymorphisms in Marfan syndrome.
abstract: Folic acid metabolism enzyme polymorphisms are believed to be responsible for the elevation of homocysteine (HCY) concentration in the blood plasma, correlating with the pathogenesis of aortic aneurysms and aortic dissection. We studied 71 Marfan patients divided into groups based on the severity of cardiovascular involvement: no intervention required (n=27, Group A); mild involvement requiring intervention (n=17, Group B); severe involvement (n=27, Group C) subdivided into aortic dilatation (n=14, Group C1) and aortic dissection (n=13, Group C2), as well as 117 control subjects. We evaluated HCY, folate, vitamin B12 and the polymorphisms of methylenetetrahydrofolate reductase (MTHFR;c.665C>T and c.1286A>C), methionine synthase (MTR;c.2756A>G) and methionine synthase reductase (MTRR;c.66A>G). Multiple comparisons showed significantly higher levels of HCY in Group C2 compared to Groups A, B, C1 and control group (p<0.0001, p<0.0001, p=0.001 and p=0.003, respectively). Folate was lower in Group C2 than in Groups A, B, C1 and control subjects (p<0.0001, p=0.02, p<0.0001 and p<0.0001, respectively). Group C2 had the highest prevalence of homozygotes for all four gene polymorphisms. Multivariate logistic regression analysis revealed that HCY plasma level was an independent risk factor for severe cardiovascular involvement (Group C; odds ratio [OR] 1.85, 95% confidence interval [CI] 1.28-2.67, p=0.001) as well as for aortic dissection (Group C2; OR 2.49, 95%CI 1.30-4.78, p=0.006). In conclusion, severe cardiovascular involvement in Marfan patients, and especially aortic dissection, is associated with higher HCY plasma levels and prevalence of homozygous genotypes of folic acid metabolism enzymes than mild or no cardiovascular involvement. These results suggest that impaired folic acid metabolism has an important role in the development and remodelling of the extracellular matrix of the aorta.
authors.affiliation: Kálmán Benke, MD, Heart and Vascular Center, Semmelweis University, Városmajor str. 68, H-1122 Budapest, Hungary, Tel: +36 20 666 3858, E-mail: kalman.benke@gmail.com.
authors.forename: Kálmán
authors.initials: K
authors.lastname: Benke
authors.forename: Bence
authors.initials: B
authors.lastname: Ágg
authors.forename: Gábor
authors.initials: G
authors.lastname: Mátyás
authors.forename: Viola
authors.initials: V
authors.lastname: Szokolai
authors.forename: Gergely
authors.initials: G
authors.lastname: Harsányi
authors.forename: Bálint
authors.initials: B
authors.lastname: Szilveszter
authors.forename: Balázs
authors.initials: B
authors.lastname: Odler
authors.forename: Miklós
authors.initials: M
authors.lastname: Pólos
authors.forename: Pál
authors.initials: P
authors.lastname: Maurovich-Horvat
authors.forename: Tamás
authors.initials: T
authors.lastname: Radovits
authors.forename: Béla
authors.initials: B
authors.lastname: Merkely
authors.forename: Zsolt B
authors.initials: ZB
authors.lastname: Nagy
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Szabolcs
mesh_terms: D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / Q000235:genetics* / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000784:Aortic Dissection / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics* / Q000628:therapy; D001014:Aortic Aneurysm / Q000097:blood / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics* / Q000628:therapy; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D016009:Chi-Square Distribution; D005260:Female; D005287:Ferredoxin-NADP Reductase / Q000235:genetics* / Q000378:metabolism; D005492:Folic Acid / Q000097:blood*; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006710:Homocysteine / Q000097:blood; D006720:Homozygote; D006801:Humans; D016015:Logistic Models; D008297:Male; D008382:Marfan Syndrome / Q000097:blood / Q000150:complications / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics*; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D015999:Multivariate Analysis; D016017:Odds Ratio; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011237:Predictive Value of Tests; D012307:Risk Factors; D012720:Severity of Illness Index; D015854:Up-Regulation; D014805:Vitamin B 12 / Q000097:blood; D055815:Young Adult
chemical_list: D015415:Biomarkers; D006710:Homocysteine; D005492:Folic Acid; C111241:methionine synthase reductase; D005287:Ferredoxin-NADP Reductase; C573423:MTHFR protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; C585801:MTR protein, human; D014805:Vitamin B 12
keywords: Cardiology; HCY; matrix-metalloproteinases; single nucleotide polymorphism; vascular remodelling