MTHFR C677T and MTR A2756G polymorphisms and the homocysteine lowering efficacy of different doses of folic acid in hypertensive Chinese adults.

0.21 MB·English

by  Qin, Xianhui

Qinetal.NutritionJournal2012,11:2
http://www.nutritionj.com/content/11/1/2
RESEARCH Open Access
MTHFR C677T and MTR A2756G polymorphisms
and the homocysteine lowering efficacy of
different doses of folic acid in hypertensive
Chinese adults
Xianhui Qin1, Jianping Li2, Yimin Cui3, Zeyuan Liu4, Zhigang Zhao5, Junbo Ge6, Deming Guan7, Jian Hu8,
Yanni Wang9, Fumin Zhang10, Xin Xu11, Xiaobin Wang12, Xiping Xu1* and Yong Huo2*
Abstract
Background: This study aimed to investigate if the homocysteine-lowering efficacy of two commonly used
physiological doses (0.4 mg/d and 0.8 mg/d) of folic acid (FA) can be modified by individual
methylenetetrahydrofolate reductase (MTHFR) C677T and/or methionine synthase (MTR) A2756G polymorphisms in
hypertensive Chinese adults.
Methods: Atotalof480subjectswithmildormoderateessentialhypertensionwererandomlyassignedtothree
treatmentgroups:1)enalaprilonly(10mg,controlgroup);2)enalapril-FAtablet[10:0.4mg(10mgenalaprilcombined
with0.4mgofFA),lowFAgroup];and3)enalapril-FAtablet(10:0.8mg,highFAgroup),oncedailyfor8weeks.
Results: After 4 or 8 weeks of treatment, homocysteine concentrations were reduced across all genotypes and FA
dosage groups, except in subjects with MTR 2756AG /GG genotype in the low FA group at week 4. However,
compared to subjects with MTHFR 677CC genotype, homocysteine concentrations remained higher in subjects
with CT or TT genotype in the low FA group (P < 0.05 for either of these genotypes) and TT genotype in the high
FA group (P < 0.05). Furthermore, subjects with TT genotype showed a greater homocysteine-lowering response
than did subjects with CC genotype in the high FA group (mean percent reduction of homocysteine at week 8:
CC 10.8% vs. TT: 22.0%, P = 0.005), but not in the low FA group (CC 9.9% vs. TT 11.2%, P = 0.989).
Conclusions: This study demonstrated that MTHFR C677T polymorphism can not only affect homocysteine
concentration at baseline and post-FA treatment, but also can modify therapeutic responses to various dosages of
FA supplementation.
Keywords: Folic acid supplementation, MTHFR C677T polymorphism, MTR A2756G polymorphism, Homocysteine-
lowering efficacy
Background hyperhomocysteinemia on the risk of CVD has received
Traditionalrisk factors areestimatedtoaccountforonly great attention [3]. Our previous meta-analysis [4] sug-
part ofcardiovascular disease (CVD) risk[1]. Non-tradi- gestedthatfolicacid(FA) supplementationcouldsignifi-
tionalriskfactorssuchasincreasedhomocysteineconcen- cantly reduce the risk of stroke by 18% [Relative Risk
trations are believed to be causally related to CVD [2]. (RR):0.82, 95% Confidence Interval (CI): 0.68-1.00; P =
The interactive effect between hypertension and 0.045), and an even greater beneficial effect was seen in
those trials with no or partial FA fortification (RR: 0.75,
95%CI:0.62-0.91;P=0.003).Furthermore,FAsupplemen-
*Correspondence:[email protected];[email protected]
1InstituteofBiomedicine,AnhuiMedicalUniversity,Hefei,China tation was found to significantly reduce CVD risk in
2DepartmentofCardiologyandHeartCenter,PekingUniversityFirstHospital, patientswithendstagerenaldiseaseoradvancedchronic
Beijing,China kidneydisease(creatinineclearance<30mL/min)by15%
Fulllistofauthorinformationisavailableattheendofthearticle
©2012Qinetal;licenseeBioMedCentralLtd.ThisisanOpenAccessarticledistributedunderthetermsoftheCreativeCommons
AttributionLicense(http://creativecommons.org/licenses/by/2.0),whichpermitsunrestricteduse,distribution,andreproductionin
anymedium,providedtheoriginalworkisproperlycited.
Qinetal.NutritionJournal2012,11:2 Page2of7
http://www.nutritionj.com/content/11/1/2
(RR:0.85;95CI:0.76-0.96,P=0.009),particularlyintrials examined at baseline and at 4 and 8 weeks of the trial.
withnoorpartialFAfortification(RR:0.80;95%CI:0.65- MTHFR C677T and MTR A2756G genotypes were
0.99;p=0.04)[5].Thesefindingsunderscoretheimpor- determined for each study subject.
tanceof effectivelyloweringhomocysteineconcentration Allanalyses were performedaccording to theprinciple
inthepreventionofCVD,particularlyinpopulationswith ofintentiontotreat.Homocysteineandfolateconcentra-
a highprevalence ofhypertensionandhyperhomocystie- tions in the natural logarithms (due to their positively
nemiabutwithoutFAfortification. skewed distributions) were analyzed as continuous vari-
Methylenetetrahydrofolate reductase (MTHFR) and ables.Therelativechangeofhomocysteineisexpressedas
methionine synthase (MTR) are the main regulatory thechangeofhomocysteineafterFAtreatmentrelativeto
enzymesforhomocysteinemetabolism.MTHFRconverts baseline concentration [(homocysteine after treatment-
5,10-methylene-THFinto5-methyl-THF. Polymorphism homocysteine at baseline)/(homocysteine at baseline)],
ofMTHFRC677Tleadstoareductioninenzymeactivity, whichwasappliedastheprimaryoutcome.Multivariable
whichmay lead to an increased concentration of plasma regression models were applied to compare the relative
homocysteineandlowerlevelsofserumfolate,particularly change of homocysteine among different groups. The
in those with low folate intake [6]. MTR catalyzes the additive modelswere used to testthe gene-gene interac-
demethylationof5-methyl-THFtoTHFandtheremethy- tive effect between the MTHFR C677T and the MTR
lation(usingthemethylgroupdonatedby5-methyl-THF) A2756G polymorphisms on the homocysteine-lowering
of homocysteine to methionine. A common polymorph- efficacy of FA supplementationwithand without adjust-
ism in the MTR gene (A2756G) also seems to influence mentsforthe potentialnon-geneticconfoundingfactors.
plasmahomocysteine[7]. StatisticalanalysiswasperformedusingSASsoftwarever-
Toourknowledge,nopublishedtrialhasinvestigatedif sion6.12(SASInstitute,Cary,NC,USA).
the homocysteine-lowering efficacy of two commonly
useddoses(0.4mg/dand0.8mg/d)ofFAcanbemodified Results
by individual MTHFR C677T and MTG A2756G poly- Atotalof480patientswererecruitedforthisstudy.This
morphismsinhypertensiveadultswithoutFAfortification. analysisexcluded35subjectswhowereineligibletoparti-
In this report, we analyzed the data from a randomized, cipateinthetrial(7incontrolgroup:9inlowFAgroup;8
double-blind,controlledtrialthatincludedthreeinterven- inhighFAgroup)orwithoutdataofMTHFRgenotype(2
tion groups: 1) enalapril only (10 mg, control group); 2) inhighFAgroup)orMTRA2756G(1incontrolgroup;4
enalapril-FAtablet(10mgenalaprilcombinedwith0.4mg inlowFAgroup;4inhighFAgroup).Accordingly,atotal
of FA, low FA group); and 3) enalapril-FA tablet (10 mg of445subjectswereincludedinourfinalanalysis.
enalapril combined with 0.8 mg of FA, high FA group), The prevalence of MTHFRC677Tpolymorphisms677
oncedailyfor8weeks.WesoughttoassessifMTHFRor CC, 677 CT, and 677TT were 0.256, 0.497, and 0.247,
MTRgenotypescaninfluenceachangeinplasma homo- respectively.Theprevalenceofthe2756AA,2756AG,and
cysteineconcentrationinresponsetoeachofthetwodif- 2756GGgenotypeswere0.820,0.171,and0.009,respec-
ferentdosagesofFAsupplementation. tively. This population had no significant deviations in
genotype distributions from expected Hardy-Weinberg
Methods equilibrium.Becausetherewereonlyfoursubjectshomo-
This was a multicenter, randomized, double-blind con- zygous for the G2756 allele, the genotypes AG and GG
trolled trial in hypertensive Chinese adults(clinicaltrials. werecombinedforstatisticalanalyses.
gov; identifier: NCT00520247) [8]. The details regarding Table1showsthebaselinecharacteristicsofthesubjects
“Subjects”,“Interventionanddatacollection”,“Laboratory accordingto MTHFRandMTRgenotypes.Subjectswith
methods”,and“Statistical Analysis”havebeenpreviously MTHFR677TTgenotypehadsignificantlyhigherhomo-
described[9].Briefly,480patientswithmildormoderate cysteine concentrations (median: 17.5 μmol/L) than did
hypertensionwererecruitedfromsixhospitalsindifferent those withCT (11.5 μmol/L) or CC (11.1 μmol/L) geno-
Chinese regions (Ha’erbin, Shanghai, Shenyang, Beijing, type (P < 0.01 for either of these genotypes). However,
Xi’an,andNanjing)fromSeptember-December2005.Eli- homocysteine concentrations did not differ among sub-
giblesubjectswererandomlyanddouble-blindlyassigned jectswithdifferentgenotypesoftheMTRgene.Therewas
to one of the three treatment groups: 1) enalapril tablet no significant interactive effect between MTHFR C677T
(10mg,controlgroup);2)enalapril-FAtablet(10mgena- andMTRA2756Gpolymorphismsonhomocysteinecon-
lapril combined with 0.4 mg ofFA, low FA group); or 3) centrationsatbaseline.
enalapril-FAtablet(10mgenalaprilcombinedwith0.8mg Compared to baseline, after 4 or 8 weeks of FA treat-
ofFA,highFAgroup),oncedailyfor8weeks. ment decreases in plasma homocysteine concentrations
Demographic and clinical information were obtained were seen across all MTHFR C677T genotypes and FA
at baseline. Blood homocysteine concentrations were dosage groups (Table 2). Even after the treatment,
Qinetal.NutritionJournal2012,11:2 Page3of7
http://www.nutritionj.com/content/11/1/2
Table 1Baseline characteristics ofparticipants by MTHFR C677Tor MTRA2756Gpolymorphism1
MTHFRC677T MTRA2756G
All CC CT TT P AA AG/GG P
N 445 114 221 110 365 80
Sex(Male),no.(%) 191(42.9) 51(44.7) 91(41.2) 49(44.5) 0.761 155(42.5) 36(45.0) 0.678
Age,yrs 57.0(9.8) 57.0(9.5) 56.4(9.6) 58.2(10.4) 0.284 57.0(9.8) 57.0(9.9) 0.971
BMI,kg/m2 25.7(3.5) 25.5(3.9) 25.8(3.3) 25.7(3.3) 0.758 25.8(3.5) 25.2(3.5) 0.137
SBP,mmHg 154.0(11.2) 154.0(11.5) 153.8(11.4) 154.5(10.5) 0.863 153.8(11.2) 155.1(11.2) 0.324
DBP,mmHg 93.0(8.3) 92.4(8.5) 93.4(7.8) 92.8(9.0) 0.530 93.3(8.0) 91.4(9.4) 0.052
FPG,mmol/L 5.5(1.3) 5.5(1.5) 5.4(1.2) 5.7(1.2) 0.312 5.5(1.3) 5.5(1.2) 0.865
TC,mmol/L 5.0(1.1) 5.0(1.4) 4.9(1.0) 5.1(1.0) 0.555 5.0(1.1) 4.9(1.1) 0.259
HDL-C,mmol/L 1.3(0.4) 1.3(0.4) 1.3(0.4) 1.3(0.4) 0.479 1.3(0.4) 1.3(0.3) 0.542
TG,mmol/L 1.7(1.2) 1.7(1.0) 1.8(1.2) 1.7(1.5) 0.970 1.8(1.3) 1.6(0.8) 0.252
Creatinine,μmol/L 69.5(17.5) 68.0(17.5) 69.2(17.3) 71.9(17.9) 0.233 69.2(17.9) 71.3(15.6) 0.334
Folate,nmol/L2 12.6(1.5)[12.3] 13.7(1.4)[13.4] 13.0(1.5)[12.6] 11.0(1.4)[10.8]* <0.001 12.8(1.5)[12.5] 11.9(1.5)[11.6] 0.107
Homocysteine,μmol/L2 13.2(1.6)[12.1] 11.2(1.4)[11.1] 12.0(1.4)[11.5] 18.8(1.8)[17.5]* <0.001 13.1(1.6)[12.1] 13.3(1.6)[12.6] 0.794
BMI=bodymassindex,SBP=systolicbloodpressure,DBP=diastolicbloodpressure,FPG=fastingplasmaglucose,
TC=totalcholesterol,HDL-C=high-densitylipoproteincholesterol,TG=triglyceride;
1Means(SD);2geometricmean(anti-logSD),medianinbrackets;*SignificantlydifferentfromtheCTorCCgenotype,P<0.001.
homocysteine concentrations in subjects with TT and were seen in all MTR A2756G genotypes and FA dosage
CT genotypes remained significantly higher at week 4 or groups, except in subjects with AG/GG genotype in the
week 8 (P < 0.05 for either of these genotypes) com- low FA group at week 4. However, neither the homocys-
pared to those with CC genotype in the low FA group. teine concentration post-FA treatment nor the homo-
In contrast, only subjects with TT genotype had higher cysteine-lowering response of FA supplementation was
homocysteine concentrations compared to CC genotype affected by MTR A2756G polymorphism (Table 3).
(P < 0.05) at week 4 or week 8 in the high FA group There was no significant interactive effect between
(Table 2). MTHFR C677T and MTR A2756G polymorphisms on
Furthermore, in the high FA group subjects with TT the homocysteine-lowering efficacy of different doses of
genotypeshowedasignificantlygreaterhomocysteine-low- FA supplementation with or without adjustments for
ering response than did subjects with CC genotype at potential non-genetic confounding factors.
week 4 or week 8, with or without adjustments for the We obtained similar results when we restricted our
relevantdemographicandclinicalcharacteristicsatbase- analysestosubjectswhofullycompliedwiththeprotocol
line(mean percentreductionofhomocysteineat week4: (consuming at least 80% of all of the prescribed drugs)
CC5.9%vs.TT:20.3%,P<0.001;meanpercentreduction during the treatment periods (per protocol set, n = 381)
of homocysteine at week 8: CC 10.8% vs.TT: 22.0%, P = (datanotshown).
0.005). This heightened level of response was not shown
inthelowFAgroup(meanpercentreductionofhomocys- Discussion
teine at week 4: CC 8.8% vs. TT 10.6%, P = 0.769; mean Both a previous dose-finding trial [10] and a dose-
percentreductionofhomocysteineatweek8:CC9.9%vs. responsetrial[11]havediscussedtherelationshipbetween
TT11.2%,P=0.989)(Table2). homocysteine-lowering efficacy and optimal dose of FA
The change in homocysteine was positively related to supplementation, but without considering the possible
the baseline homocysteine concentrations in all geno- modifying effect of MTHFR C677T polymorphism. A
types and FA dosage groups. When baseline homocys- more recent study [12] evaluated the effect of MTHFR
teine also was adjusted, subjects with TT genotype C677Tpolymorphismonthe response to differentdoses
seemed to have an attenuated homocysteine lowering ofFAsupplementation(0.1mg/d,0.4mg/d,4mg/dand4
response compared to subjects with CC genotype (P = mg/week)innorthernChinesewomenofchildbearingage
0.036 at week 4, P = 0.002 at week 8) in the low FA and reported that the MTHFR 677 TT genotype was an
group, but not in the high FA group (P = 0.449 at week independentpredictorofplasmahomocysteineconcentra-
4, P = 0.414 at week 8). Our results did not substantially tions,irrespective ofFA dose, which was consistentwith
alter with further adjustment for baseline folate concen- our results. However, the study population consisted of
tration and folate change after treatment. young womenand the FA dosage category wasnot opti-
Compared to baseline, after 4 or 8 weeks of FA treat- mal,beingeithertoolow(0.1mg/d)ortoohigh(4mg/d).
ment, decreases in plasma homocysteine concentrations Furthermore, plasma homocysteine concentrations
Qinetal.NutritionJournal2012,11:2 Page4of7
http://www.nutritionj.com/content/11/1/2
Table 2Responseofplasma homocysteine to different doses andduration offolicacid supplementation by MTHFR
C677Tgenotypes
N Homocysteine,μmol/L1 Differenceinchangeof Differenceinchangeof
Percentrelativechangeofhomocysteine2 Homocysteineat4weeksby Homocysteineat8weeksby
genotypes3 genotypes3
baseline 4weeks 8weeks b SE P b SE P
Control
CC 41 11.6(1.4)[11.3] 11.9(1.3)[11.8] 11.8(1.4)[11.3]
3.35(13.7) 2.2(14.0) ref ref .
CT 73 11.0(1.4)[11.1] 11.2(1.4)[11.3] 11.3(1.4)[11.1]
2.25(13.2) 3.1(14.0) -3.69 2.94 0.209 -1.80 3.45 0.601
TT 38 18.1(1.9)[14.7]# 18.0(1.9)[15.6]# 18.1(1.8)[16.5]#
1.19(19.7) 3.3(27.0) -4.05 3.33 0.225 -0.52 3.91 0.895
Total 152 12.7(1.6)[12.0] 12.8(1.6)[11.7] 12.8(1.6)[12.0]
2.3(15.1) 2.9(18.0)
LowFA
CC 34 11.0(1.3)[11.0] 9.9(1.3)[9.4]* 9.8(1.3)[9.5]*
-8.8(13.0) -9.9(14.9) ref ref
CT 79 12.6(1.5)[11.4] 11.5(1.4)[11.1]*# 11.2(1.4)[10.7]*#$
-7.6(15.4) -9.7(16.8) 2.14 3.35 0.523 2.52 3.88 0.516
TT 34 17.5(1.8)[17.2]# 15.2(1.7)[14.2]*# 14.8(1.6)[14.2]*#
-10.6(21.3) -11.2(27.1) -1.16 3.95 0.769 0.06 4.58 0.989
Total 147 13.2(1.6)[11.6] 11.8(1.5)[11.3]* 11.6(1.5)[10.8]*$%
-8.6(16.4)% -10.1(19.1)%
HighFA
CC 39 11.0(1.4)[10.8] 10.2(1.4)[10.1]* 9.7(1.4)[9.8]*$
-5.9(14.2) -10.8(11.1) ref ref
CT 69 12.3(1.3)[12.0] 10.8(1.3)[11.0]* 10.7(1.3)[10.5]*
-11.2(14.5) -11.2(16.5) -6.21 3.19 0.052 -0.47 3.39 0.890
TT 38 20.8(1.8)[19.6]# 15.8(1.6)[14.2]*# 15.4(1.6)[14.1]*#
-20.3(22.2)# -22.0(23.8)# -15.51 3.72 <0.001 -11.12 3.95 0.005
Total 146 13.7(1.6)[12.7] 11.7(1.5)[11.4]* 11.5(1.5)[10.8]*%
-12.1(17.5)% -13.9(18.1)%
1Geometricmean(anti-logSD),medianinbrackets;
2[(Homocysteineaftertreatment-homocysteineatbaseline)/(homocysteineatbaseline)]*100,Mean(SD);
3Regressionmodelwasadjustedforage,sex,BMI,baselineSBP,DBP,creatinine,TG,HDL-C,TC,FPG,folate,folatechange,MTRA2756Gpolymorphismandstudy
centers;
*Significantlydifferentfrombaseline,P<0.05;$Significantlydifferentfromweek4,P<0.05;
#SignificantlydifferentfromtheCCgenotype,P<0.05;%Significantlydifferentfromcontrolgroup,P<0.05.
(7.2μmol/L)inthestudypopulation(withoutFAfortifica- homocysteine-lowering effect in all genotypes and FA
tion)werelowerthanthoseobservedinaU.S.population dosagegroups.Subsequently,inthepresentstudy,after4
[13]andaChinesepopulation[14],whichmeansthatthis or 8 weeks of treatment, subjects with MTHFR 677 TT
Chinesepopulationwasnotarepresentativepopulationin genotypehadasignificantlygreaterhomocysteine-lower-
whichtoevaluatethehomocysteineloweringeffectofFA. ing response than did subjects with CC genotype in the
In our study, we investigated if the change in plasma highFAgroup.However,suchaheightenedresponsewas
homocysteineconcentrationinresponsetotwocommonly not shown in the low FA group. Furthermore, when we
used physiological doses (0.4 mg/d and 0.8 mg/d) of FA furtheradjustedbaselinehomocysteine,subjectswithTT
supplementationcouldbemodifiedbyindividualMTHFR genotype seemed to have a more attenuated homocys-
C677TandMTGA2756Gpolymorphismsinamulticen- teine-loweringresponsethandid subjects withCCgeno-
ter,randomized,double-blind,controlledtrialinhyperten- type in the low FA group but not in the high FA group.
sive Chinese adults, whose homocysteine concentrations Themolecularmechanismsthatunderlieclinicalremedia-
werecomparabletothegeneralChinesepopulation[14]. tionofenzymevariantsaretheabilityofelevatedlevelsof
Consistentwithapreviousstudy[15],baselinehomocys- thecofactororsubstratetoovercomethebindingdefects
teine concentration was the major determinant of the of Km mutants or to serve as a chemical chaperone to
Qinetal.NutritionJournal2012,11:2 Page5of7
http://www.nutritionj.com/content/11/1/2
Table 3Responseofplasma Homocysteine to differentdoses andduration offolic acid supplementation by MTR
A2756Ggenotypes
N Homocysteine,μmol/L1 Differenceinchangeof Differenceinchangeof
Percentrelativechangeofhomocysteine2 Homocysteineat4weeksby Homocysteineat8weeksby
genotypes3 genotypes3
baseline 4weeks 8weeks b SE P b SE P
Control
AA 130 12.8(1.6)[12.0] 12.9(1.6)[11.7] 12.9(1.6)[12.0]
1.7(15.1) 2.33(17.7) ref ref .
AG/GG 22 12.1(1.5)[11.7] 12.6(6.8)[1.6] 12.6(1.5)[12.2]
5.8(15.2) 6.32(20.1) 5.17 3.50 0.139 6.08 4.10 0.138
Total 152 12.7(1.6)[12.0] 12.8(1.6)[11.7] 12.8(1.6)[12.0]
2.3(15.1) 2.9(18.0)
LowFA
AA 116 12.9(1.6)[11.5] 11.5(1.5)[11.1]* 11.3(1.5)[10.6]*
-9.4(16.5) -10.2(19.4) ref ref
AG/GG 31 14.1(1.5)[14.5] 13.1(1.5)[12.3] 12.5(1.5)[12.3]*$
-5.4(15.9) -9.6(18.3) 3.73 3.33 0.262 -0.06 3.86 0.989
Total 147 13.2(1.6)[11.6] 11.8(1.5)[11.3]* 11.6(1.5)[10.8]*$%
-8.6(16.4)% -10.1(19.1)%
HighFA
AA 119 13.7(1.6)[12.7] 11.8(1.5)[11.4]* 11.5(1.4)[10.8]*$
-12.3(16.2) -14.4(17.3) ref ref
AG/GG 27 13.5(1.8)[12.9] 11.6(1.5)[11.4]* 11.5(1.5)[10.7]*
-11.5(22.7) -11.9(21.5) 1.30 3.39 0.700 2.72 3.60 0.450
Total 146 13.7(1.6)[12.7] 11.7(1.5)[11.4]* 11.5(1.5)[10.8]*%
-12.1(17.5)% -13.9(18.1)%
1Geometricmean(anti-logSD),medianinbrackets;
2[(Homocysteineaftertreatment-homocysteineatbaseline)/(homocysteineatbaseline)]*100,Mean(SD);
3Regressionmodelwasadjustedforage,sex,BMI,baselineSBP,DBP,creatinine,TG,HDL,TC,FPG,MTHFRC677Tpolymorphismandstudycenters;
*Significantlydifferentfrombaseline,P<0.05;$Significantlydifferentfromweek4,P<0.05;
%Significantlydifferentfromcontrolgroup,P<0.05.
improve the stability of mutant enzyme variants [16,17]. 2mg/dfor3weeksthandidCCsubjects.Amongsubjects
Our results further suggest that daily 0.4 mg FA supple- who were not previously taking multivitamins, the mean
mentationmaybeinsufficient,andthatadailydoseof0.8 reductions in plasma total homocysteine concentrations
mgFAmayberequiredtolowerhomocysteineconcentra- were -20.9%, -13.1%, and -7.1% in persons with the TT,
tioninsubjectswithTTgenotype. CT,andCCgenotypes,respectively(P=0.019forTTver-
Furthermore,afterthetreatment,subjectswithCTgen- susCC).Asimilarresultalsohasbeenreportedinastudy
otype had significantly higher homocysteine concentra- inTaiwan,inwhich5mgofFAdailyweresupplemented
tions than those with CC genotype in the low FA group, for 8 wks [19]. Our results appear to be consistent with
andhadsimilarhomocysteineconcentrationsasCCsub- thesestudies. However,the studyofWoodside etal.[20]
jects in the high FA group. These results indicate that showedthatTTsubjectsarelessresponsivetotheeffects
daily0.8mgFAalsomaybenecessaryforloweringhomo- ofFAandB-vitaminsupplementation(daily1mgFA,7.2
cysteine concentration in subjects with CT genotypes. mgVitaminB6,and0.02mgVitaminB12for8wks.)than
However, although they showed a greater homocysteine CC subjects. And Ho GY et al. [21] also reported that
lowering effectthansubjects with CC genotype,subjects MTHFR C677T did not impact the total homocysteine-
withTTgenotypestillhadthehighesthomocysteinecon- loweringeffectofvitamins(daily2.5mg FA,25mgVita-
centrations even after 8 weeks of high FA treatment. minB6,and0.5mgVitaminB12for1year)inastudyper-
Therefore, other therapeutic strategies need to be devel- formed in Singapore. The reasons for the disparities
opedtoreducetheriskassociatedwithhyperhomocystei- amongtheresultsofthesestudiesareunknown.Additional
nemiainTTsubjects. largedose-findingstudiesarerequiredtofurtherelucidate
Infact,Malinowetal.[18]firstreportedthatTTsubjects thepossiblecontributoryfactors,suchasfolatestatus,eth-
experiencedmuchgreaterdecreasesinplasmatotalhomo- nicity of the participants, and in particular the possible
cysteineconcentrationsafterreceivingFAatadoseof1or effectsofconcomitantvitaminB6and/orB12.
Qinetal.NutritionJournal2012,11:2 Page6of7
http://www.nutritionj.com/content/11/1/2
Our study showed that neither homocysteine concen- andalargersamplesizeareneededtoconfirmourresults.
tration at baseline or post-FA treatment nor the homo- The association between angiotensin-converting enzyme
cysteine lowering response of FA supplementation was inhibitortreatment and the change of homocysteine was
affected by MTR A2756G polymorphism. However, controversial [28,29]. We did not observe a significant
there was a significant homocysteine reduction in MTR relationship between enalapril treatment and homocys-
2756 AG/GG genotype after 4 weeks of FA supplemen- teinechangeinourstudy..Additionallargesamplestudies
tation in the high FA (0.8 mg/d) group, but not in the alsoareneededtofurtherexaminetherelationshipofena-
low FA (0.4 mg/d) group, which means that we cannot lapriltreatmentwithhomocysteinechangeandthepossi-
exclude the possible role of MTR A2756G polymorph- ble interactiveeffects between enalaprilandfolic acidon
ism in the homocysteine metabolic pathway. thechangeinhomocysteine.
Overall,ourresultssuggestthatdaily0.8mgFAmaybe
necessary to lower homocysteine concentration for Chi- Conclusions
nese hypertensive subjects with CT or TT genotype, We demonstrated that MTHFR C677T polymorphisms
which have important clinical and publichealthimplica- can not only affect plasma homocysteine levels at base-
tions. Increased homocysteine concentration has been line and post-FA treatment, but also modify therapeutic
implicatedasariskfactorforneuraltubedefects(NTDs) response to various dosages of FA supplementation.
and Downs syndrome [22,23]. A study by Wilcken et al. These findings, if confirmed by additional studies, may
reported that the frequency of CT and TT genotypes in enable medical providers to offer more personalized
Hungarywasabout45%and11.1%,respectively[24].Two care and advice on FA supplementation for a given
Hungarianinterventiontrials[25,26],whichusedamulti- individual.
vitamin containing 0.8 mg folic acid, found a significant
reductioninthefirstoccurrenceofurinarytractandcar-
Listofabbreviations
diovascular abnormalities beyond the 90% reduction of
CI:ConfidenceInterval;CVD:cardiovasculardisease;FA:folicacid;MTHFR:
NTDs. There is no evidence that 0.4 mg folic acid has a methylenetetrahydrofolatereductase;MTR:methioninesynthase;RR:Relative
similar preventive effect on defects beyond NTDs. Our Risk.
results further suggest that there may be an additional
Acknowledgements
benefit if a daily dose of 0.8 mg, but not 0.4 mg, of folic ThestudywassupportedbyBeijingHuaanfoBiomedicalResearchCenter
acidcouldbeusedinwomen, particularly inpopulations Inc.,Beijing,ChinaandinpartbyagrantfromAnhuiProvincialMinistryof
Education(No.2002kj174ZC),AnhuiProvincialMinistryofScienceand
withahighfrequencyofTallele(suchastheChinese)and
Technology,AnhuiMedicalUniversityBiomedicalInstitute.Thesponsorsdid
without folic acid fortification. Furthermore, identifying notparticipateinthedesignorconductofthestudy;collection,
TT or CT subjects and providing them with an optimal management,analysis,andinterpretationofthedata;orpreparation,review,
andapprovalofthemanuscript.Wegratefullyacknowledgetheassistance
dose of folic acid also may be very important in the pre-
andcooperationofthefacultyandstaffoftheAnhuiMedicalUniversityand
vention of CVD [4,27] in populations without folic acid thankalloftheparticipantsinourstudy.Thisstudywasconductedin
fortification. accordancewiththecurrentregulationsofthePeople’sRepublicofChina.
Ourstudyhasthefollowingstrengths.Thiswasarando-
Authordetails
mized, multicenter and double blind trial. This study 1InstituteofBiomedicine,AnhuiMedicalUniversity,Hefei,China.
simultaneouslyassessedtheeffectofFAdosagesandgene 2DepartmentofCardiologyandHeartCenter,PekingUniversityFirstHospital,
Beijing,China.3DepartmentofPharmacy,PekingUniversityFirstHospital,
polymorphisms on homocysteine-lowering efficacy. Our
Beijing,China.4DepartmentofPharmacy,FirstAffiliatedHospitalofAcademy
trial studied two commonly used doses of FA, which are ofMilitaryMedical,SciencesofChina,Beijing,China.5Departmentof
of important clinical and public health relevance. How- Pharmacy,BeijingTiantanHospital,CapitalMedicalUniversity,Beijing,China.
6DepartmentofCardiology,ZhongshanHospitalFudanUniversity,Shanghai,
ever, cautionis needed ingeneralizing ourfindings from
China.7DepartmentofCardiology,FirstClinicalMedicalCollegeofHarbin
thishypertensiveChinesepopulationtootherpopulations. MedicalUniversity,Harbin,China.8DepartmentofCardiology,FirstAffiliated
Furthermore, though similar resultswere obtained when HospitalofChinaMedicalUniversity,Shenyang,China.9Departmentof
Cardiology,FirstAffiliatedHospitaloftheSchoolofMedicine,Xi’anJiaotong
we restrictedouranalysestosubjectswhofullycomplied
University,Xi’an,China.10DepartmentofCardiology,FirstAffiliatedHospital
with the protocol during the treatment periods, we still ofNanjingMedicalUniversity,Nanjing,China.11GuangdongInstituteof
couldnotfullyexcludetheeffectofnon-compliancepro- Nephrology,SouthernMedicalUniversity,Guangzhou,China.12MaryAnn
andJ.MilburnSmithChildHealthResearchProgram,Children’sMemorial
blemonourresults. Also,itshouldbenoted that wedid
HospitalandChildren’sMemorialResearchCenter,DepartmentofPediatrics,
notmeasure other polymorphismsin the folate pathway, NorthwesternUniversityFeinbergSchoolofMedicine,Chicago,USA.
such as the MTHFR A1298C variant. Furthermore, the
Authors’contributions
treatmentperiodwithFAwasonly8weeksandthesam-
QX,LJ,CY,LZ,ZZ,GJ,GD,HJ,WY,ZF,XX,WX,XXandHYparticipatedinthe
ple size was rather small when sub-grouped into various designofthestudy;LJ,CY,LZ,GJ,GD,HJ,WY,ZF,HYconductedthestudy;
groups(control,lowFAandhighFA)forgeneticassocia- QX,LJ,XXu,WX,XXuandYHanalyzeddata;QX,LJ,CY,LZ,ZZ,GJ,GD,HJ,
WY,ZF,XX,WX,XXandHYwrotethepaper;allauthorsreadandapproved
tionstudies.Futurestudieswithlongertreatmentduration
thefinalmanuscript.
Qinetal.NutritionJournal2012,11:2 Page7of7
http://www.nutritionj.com/content/11/1/2
Competinginterests 17. AmesBN,Elson-SchwabI,SilverEA:High-dosevitamintherapystimulates
Theauthorsdeclarethattheyhavenocompetinginterests. variantenzymeswithdecreasedcoenzymebindingaffinity(increasedK
(m)):relevancetogeneticdiseaseandpolymorphisms.AmJClinNutr
Received:26August2011 Accepted:10January2012 2002,75:616-658.
Published:10January2012 18. MalinowMR,NietoFJ,KrugerWD,DuellPB,HessDL,GluckmanRA,
BlockPC,HolzgangCR,AndersonPH,SeltzerD,UpsonB,LinQR:The
effectsoffolicacidsupplementationonplasmatotalhomocysteineare
References
modulatedbymultivitaminuseandmethylenetetrahydrofolate
1. TolonenH,MähönenM,AsplundK,RastenyteD,KuulasmaaK,VanuzzoD,
reductasegenotypes.ArteriosclerThrombVascBiol1997,17:1157-1162.
TuomilehtoJ:Dotrendsinpopulationlevelsofbloodpressureandother
19. LiuCS,ChiangHC,ChenHW:Methylenetetrahydrofolatereductase
cardiovascularriskfactorsexplaintrendsinstrokeeventrates?
polymorphismdeterminestheplasmahomocysteine-loweringeffectof
Comparisonsof15populationsin9countrieswithintheWHOMONICA
large-dosefolicacidsupplementationinpatientswithcardiovascular
StrokeProject.WorldHealthOrganizationMonitoringofTrendsand
disease.Nutrition2004,20:974-978.
DeterminantsinCardiovascularDisease.Stroke2002,33:2367-2375.
20. WoodsideJV,YarnellJW,McMasterD,YoungIS,HarmonDL,McCrumEE,
2. WaldDS,LawM,MorrisJK:Homocysteineandcardiovasculardisease:
PattersonCC,GeyKF,WhiteheadAS,EvansA:EffectofB-groupvitamins
evidenceoncausalityfromameta-analysis.BMJ2003,325:1202-1206.
andantioxidantvitaminsonhyperhomocysteinemia:adouble-blind,
3. TowfighiA,MarkovicD,OvbiageleB:Pronouncedassociationofelevated
randomized,factorial-design,controlledtrial.AmJClinNutr1998,
serumhomocysteinewithstrokeinsubgroupsofindividuals:a
6:858-866.
nationwidestudy.JNeurolSci2010,298:153-157.
21. HoGY,EikelboomJW,HankeyGJ,WongCR,TanSL,ChanJB,ChenCP:
4. WangX,QinX,DemirtasH,LiJ,MaoG,HuoY,SunN,LiuL,XuX:Efficacy
Methylenetetrahydrofolatereductasepolymorphismsandhomocysteine-
offolicacidsupplementationinstrokeprevention:ameta-analysis.
loweringeffectofvitamintherapyinSingaporeanstrokepatients.Stroke
Lancet2007,369:1876-1882.
2006,37:456-460.
5. QinX,HuoY,LangmanCB,HouF,ChenY,MatossianD,XuX,WangX:
22. MillsJL,McPartlinJM,KirkePN,LeeYJ,ConleyMR,WeirDG,ScottJM:
FolicacidtherapyandcardiovasculardiseaseinESRDorAdvanced
Homocysteinemetabolisminpregnanciescomplicatedbyneural-tube
ChronicKidneyDisease:AMeta-Analysis.ClinJAmSocNephrol2011,
defects.Lancet1995,345:149-151.
6:482-488.
23. BoscoP,Guéant-RodriguezRM,AnelloG,BaroneC,NamourF,CaraciF,
6. HustadS,MidttunØ,SchneedeJ,VollsetSE,GrotmolT,UelandPM:The
methylenetetrahydrofolatereductase677C–>Tpolymorphismasa RomanoA,RomanoC,GuéantJL:Methioninesynthase(MTR)2756(A–>
G)polymorphism,doubleheterozygositymethioninesynthase2756AG/
modulatorofaBvitaminnetworkwithmajoreffectsonhomocysteine
methioninesynthasereductase(MTRR)66AG,andelevated
metabolism.AmJHumGenet2007,80:846-855.
homocysteinemiaarethreeriskfactorsforhavingachildwithDown
7. BarbosaPR,StablerSP,MachadoAL,BragaRC,HirataRD,HirataMH,
syndrome.AmJMedGenetA2003,121:219-224.
Sampaio-NetoLF,AllenRH,Guerra-ShinoharaEM:Associationbetween
24. WilckenB,BamforthF,LiZ,ZhuH,RitvanenA,RenlundM,StollC,
decreasedvitaminlevelsandMTHFR,MTRandMTRRgene
AlembikY,DottB,CzeizelAE,Gelman-KohanZ,ScaranoG,BiancaS,
polymorphismsasdeterminantsforelevatedtotalhomocysteine
EttoreG,TenconiR,BellatoS,ScalaI,MutchinickOM,LopezMA,de
concentrationsinpregnantwomen.EurJClinNutr2008,62:1010-1021.
WalleH,HofstraR,JoutchenkoL,KavteladzeL,BermejoE,Martinez-
8. MaoG,HongX,XingH,LiuP,LiuH,YuY,ZhangS,JiangS,WangX,XuX:
FriasML,GallagherM,EricksonJD,VollsetSE,MastroiacovoP,AndriaG,
Efficacyoffolicacidandenalaprilcombinedtherapyonreductionof
BottoLD:Geographicalandethnicvariationofthe677C>Talleleof
bloodpressureandplasmaglucose:amulticenter,randomized,double-
5,10methylenetetrahydrofolatereductase(MTHFR):findingsfromover
blind,parallel-controlled,clinicaltrial.Nutrition2008,24:1088-1096.
7000newbornsfrom16areasworldwide.JMedGenet2003,40:619-625.
9. QinX,LiJ,CuiY,LiuZ,ZhaoZ,GeJ,GuanD,HuJ,WangY,ZhangF,XuX,
25. CzeizelAE,DudásI:Preventionofthefirstoccurrenceofneural-tube
WangX,XuX,HuoY:Effectoffolicacidinterventiononthechangeof
defectsbypericonceptionalvitaminsupplementation.NEnglJMed1992,
serumfolatelevelinhypertensiveChineseadults:do
327:1832-1835.
methylenetetrahydrofolatereductaseandmethioninesynthasegene
26. CzeizelAE,DoboM,VarghaP:Hungariancohort-controlledtrialof
polymorphismsaffecttherapeuticresponses?PharmacogenetGenomics
periconceptionalmultivitaminsupplementationshowsareductionin
2011.
certaincongenitalabnormalities.BirthDefectsResAClinMolTeratol2004,
10. TigheP,WardM,McNultyH,FinneganO,DunneA,StrainJ,MolloyAM,
70:853-861.
DuffyM,PentievaK,ScottJM:Adose-findingtrialoftheeffectoflong-
27. WaldDS,WaldNJ,MorrisJK,LawM:Folicacid,homocysteine,and
termfolicacidintervention:implicationsforfoodfortificationpolicy.Am
cardiovasculardisease:judgingcausalityinthefaceofinconclusivetrial
JClinNutr2011,93:11-18.
evidence.BMJ2006,333:1114-1117.
11. AndersonCA,JeeSH,CharlestonJ,NarrettM,AppelLJ:Effectsoffolicacid
28. PoduriA,KaurJ,ThakurJS,KumariS,JainS,KhullarM:EffectofACE
supplementationonserumfolateandplasmahomocysteine
inhibitorsandbeta-blockersonhomocysteinelevelsinessential
concentrationsinolderadults:adose-responsetrial.AmJEpidemiol
hypertension.JHumHypertens2008,22:289-294.
2010,172:932-941.
29. WestphalS,RadingA,LuleyC,DierkesJ:Antihypertensivetreatmentand
12. CriderKS,ZhuJH,HaoL,YangQH,YangTP,GindlerJ,ManevalDR,
homocysteineconcentrations.Metabolism2003,52:261-263.
QuinlivanEP,LiZ,BaileyLB,BerryRJ:MTHFR677C->Tgenotypeis
associatedwithfolateandhomocysteineconcentrationsinalarge,
doi:10.1186/1475-2891-11-2
population-based,double-blindtrialoffolicacidsupplementation.AmJ
Citethisarticleas:Qinetal.:MTHFRC677TandMTRA2756G
ClinNutr2011,93:1365-1372.
polymorphismsandthehomocysteineloweringefficacyofdifferent
13. JacquesPF,RosenbergIH,RogersG,SelhubJ,BowmanBA,GunterEW, dosesoffolicacidinhypertensiveChineseadults.NutritionJournal2012
WrightJD,JohnsonCL:Serumtotalhomocysteineconcentrationsin 11:2.
adolescentandadultAmericans:resultsfromthethirdNationalHealth
andNutritionExaminationSurvey.AmJClinNutr1999,69:482-489.
14. HaoL,MaJ,ZhuJ,StampferMJ,TianY,WillettWC,LiZ:Highprevalence
ofhyperhomocysteinemiainChineseadultsisassociatedwithlow
folate,vitaminB-12,andvitaminB-6status.JNutr2007,137:407-413.
15. HomocysteineLoweringTrialists’Collaboration:Loweringblood
homocysteinewithfolicacidbasedsupplements:meta-analysisof
randomisedtrials.BMJ1998,316:894-898.
16. MariniNJ,GinJ,ZiegleJ,KehoKH,GinzingerD,GilbertDA,RineJ:The
prevalenceoffolate-remedialMTHFRenzymevariantsinhumans.Proc
NatlAcadSciUSA2008,105:8055-8060.