Folate, Vitamin B6, and B12 Intakes in Relation to Risk of Stroke Among Men Ka He, MD;Anwar DMD; Eric B;. Rimm, ScD;Bernard A. Rosner, PhD; Meir J. Stempfer, MD;Walter C. Willett, MD; Alberto Ascherio, MD Stroke. 2004;35:169-174 Folate

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Folate, Vitamin B6, and B12 Intakes in Relation
to Risk of Stroke Among Men Ka He,
MDAnwar DMD Eric B. Rimm, ScDBernard A.
Rosner, PhD Meir J. Stempfer, MDWalter C.
Willett, MD Alberto Ascherio, MDStroke.
200435169-174Folate Intake and Risk of Stroke
Among Wemen Wael K. Al-Delaimy, MD,
PhDKathryn M. Rrxrode, MD, MPH Frank B. HU, MD,
PhD Christine M. Albert, MD, MPH Meir J.
Stampfer, MD, DrPHWalter C. Willett, MD, DrPH
John E. Manson, MD, DrTHStroke.
2004351259-1263

• ???

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Introduction
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Folate (Folic acid)

• Water Soluble
• Functions i. Red blood cell formation
• ii. New cell division
• iii. Protein metabolism
• Deficiencies Anemia, diarrhea, depression,
  heartburn
• Toxicity Insomnia, irritability, diarrhea, may
  mask B12 deficiency
• Recommended Intakes (RDA) 400 µg/day for
  adults
• Food Sources Green leafy vegetables, liver,
  legumes, seeds, and enriched breads, cereals,
  rice, and pasta.

http//nutrition.about.com/cs/supplements/l/blvitb
folate.htm
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Homocysteine

• Homocysteine CVD
• Homocysteine level stroke
  (Brattstrom, et al.1992 )
• Elevated homocysteine level
• Genetic defects (Brattstrom, et al.1998)
• Low intake of folate, vitamin B6 vitamin
  B12 (Verhoef, et al.1996)

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Folate metabolism
http//www.snof.org/maladies/homocystinurie.html
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Study 1
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• Examining the relationship between prospectively
  intakes of folate and vitamin B6 and vitamin B12
  and incidence of ischemic and hemorrhagic stroke
  in a large cohort of US men with an average 14
  years of follow-up.

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Subjects and Methods
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The Health Professional Follow-up Study

• Established in 1986
• 51529 male US health professionals
• 40-75 years old
• Questionnaire on medical history, lifestyle and
  diet
• Mailed questionnaire in every other year
• Potential risk factors and
• Identify new cases of diseases
• Excluded
• Have a history of CVD and DM
• Inadequate dietary data
• lt800kcal/day, gt4200kcal/day, or ?70 blank
  items

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Dietary Assessment

• Assessed in 1986, 1990, and 1994
• Semiquantitative food frequency questionnaires
  (FFQ)
• Commenly used portion size
• Never orlt1/month to ?6/day
• Nutrition intakes
• average nutrient content
  frequency
• Harvard University food composition Database

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Outcome Assessment

• End point
• Incident of stroke occurred during 1986 Jan,
  1, 2000
• Incident strokes
• Reviewed medical records by physcians
• Fatal strokes
• Kin, colleagues
  medical records
• Postal authorities gt
  autopsy reports
• A search of National Death Index death
  certificates
• Subcategorized by National Survey of Stroke
• Ischemic ( embolism or thrombosis) stroke
• Hemorrhagic (subarachnoid and
  intracerebral) stroke
• Unknown type of stroke

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Statistical Analyses

• Divided into quintiles according to intakes of B
  vitamins
• Incident rate
• Case number person time (follow-up in
  each quintile)
• Relative Risk (RR)
• The incident of stroke in a particular
  quintile compare
• with the lowest one
• Cumulative average of nutrient intakes
• Represent long-term dietary intake
• Reduce within-subject variation

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Statistical Analyses (cont.)

• The different effect between long-term and
  short-term diet intake
• Baseline diet and the most recent diet
• Stop updating
• DM, CHD, TIA, peripheral arterial disease
• Incident rates and 95 CI ( Mantel-Haenszel
  methods)
• Adjusted covariate
• Stratify age(5-year categories) and
  cigarette smoking status
• Relative Risk( COX proportional hazards models)
• (i) Cigarette smoking body mass index
  physical activity history
• of hypertention and
  hypercholesterolemia aspirin use
• (ii) Intake of alcohol, fiber, potassium,
  vitamin E
• All nutrition intakes were energy-adjusted, and
  total energy intake was included in all
  regression models.

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Results
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725 incident cases 455 ischemic stroke 125
hemorrhagic stroke 145 unknown type stroke
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• No significantly association between Dietary or
  supplemental folate and ischemic stroke
• No apparent jointly relation of alcohol
  consumption and folate intake to risk of ischemic
  or hemorragic stroke

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Discussion
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In this large prospective follow-up study

• Inversely related to risk of ischemic stroke
• Folate intake (30 )
• Vitamin B12
• But not Vitamin B6
• No significant associations with risk of
  hemorrhagic stroke were observed.

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• Other health-related factors
• Healthier lifestyle of higher folate intake
• Source of folate
• Other constituents of the supplement
• Inaccurate dietary assessment
• Inverse association between intakes of folate,
  vitamin B6, B12 and risk of CHD
• Repeated measurements
• Excluded participants with intermediate
  diseases
• Cumulative average diet
• The amount of vitamin B6 in the ref. group
• 1.8mg/d in ref. group 2mg/d of RDA

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Previous Study

• Inverse relation between folate intake and risk
  of stroke in
• the NHANE I
• RR0.79 may be diluted by cases of hemorragic
  stroke (Salhub et al)
• Inversely associated with blood homocysteine
• Toxic accumulate in endothelial
  vascular damage
• Generation of free radical
  (Verhoef et al Harker et al.)
• Regular intake 100µg folic acid/d lower
  homocysteine
• 
  (Salhub et al)
• In the Framingham Heart Study (Salhub et al)
• Homocysteine plasma folate
• plasma B12
  pyridoxal 5-phosphate

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Conclusion

• In this large cohort of US men without history
  of cardiovascular diseases and diabetes, we found
  that increased folate and vitamin B12 intakes
  were associated with decrease risk of ischemic
  stroke

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Study 2
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• Prospectively examining the association
  between folate intake and the risk of stroke
  among 83896 women participating in the Nurses
  Health study who were follow-up for 18 years

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Subjects and Methods
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Nurses Health Study

• Established in 1976
• 121700 female nurses
• 30-55 years old
• Mailed questionnaire on medical history and
  lifestyle
• Updated information every 2 years
• Potential risk factors
• Identify new cases of CVD and other
  diseases

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Seminquantitative Food Frequency Questionnaire

• In 1980, collected data by FFQ with 61 items
• In 1986, 1990, and 1994, colleted data by FFQ
  with 116 items
• Average daily intake of nutrition
• S (the frequency of each item nutrient
  content)
• Nutrient intake was adjusted for total energy
  intake using the residual approach.
• Harvard University food composition Database

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Population

• 98462 women returned the 1980 diet questionnaire
• Excluded
• I. lt500kcal/day, gt3500kcal/day, or ?10 blank
  items
• II. Women with cancers( excluding nonmelanoma
  skin
• cancer)
• III. Cardiovascular diseases diagnosed at
  baseline or
• before the development of stroke(
  during
• follow-up )
• Final population gt 83896 women

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Ascertainment of Stroke

• Incident of stroke
• Occurred during 1980 June, 1, 1998
• Nonfatal strokes
• Medical records
• Fatal strokes
• Relatives
  medical records
• Postal authorities
  gt
• A search of National Death Index
  death certificates
• Subcategorized by National Survey of Stroke
• Subarachnoid hemorrhages
• Intraparenchymal hemorrhages
• Thrombotic
• Embolic
• Ischemic (includes thrombotic, embolic, and
  non-hemorragic strokes )

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Data analysis

• Person-time of follow-up
• Return date of 1980stroke, death, or 1998
• Incident rate
• The number of case person-time of
  follow-up
• Total and dietary folate intake
• Energy-adjusted
• Quintile
• Folate supplement
• No energy-adjusted
• 4 categories
• Adjusted covariates pooled logistic regression

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Data analysis( cont.)

• Updated exposure information every 2 years
• Age, Time period, Smoking history, Body mass
  index (BMI),
• Hormone use and menopausal status, Currently
  taking aspirin,
• Vitamin E supplements, Physical activity,
  Alcohol use,
• History of high blood pressure, diabetes,
  hypercholesterolemia, Parental history of
  myocardial infarction at or before the age of 65
  years, Total caloric intake
• Stroke risk factors specific fatty acid,
  protein, cereal fiber
• Updated dietary variables
• 1980, 1984, 1986, 1990, 1994
• Cumulative average
• Reduce with-person variation
• Better present long-term intake
• Secondary analyses
• Recently intake of folate to assess
  short-term exposure
• Stop updating
• Intermediate diseases
  hypercholesterolemia and DM

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Results
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TABLE I. Age-Adjusted Characteristics of Women
According to Energy-Adjusted Total Folate Intake
Quintiles in 1980
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TABLE I. Age-Adjusted Characteristics of Women
According to Energy-Adjusted Total Folate Intake
Quintiles in 1980 (cont.)
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1140 incident cases during 1379614 preson-years
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TABLE II. Multivariable-Adjusted Relative Risks
of Developing Stroke According to the Categories
of Dietary and Supplemental Folate Intake
Type of Stroke Dietary Folate Intake Quintiles (Excluding Supplements) and Their Range (µg/d) Dietary Folate Intake Quintiles (Excluding Supplements) and Their Range (µg/d) Dietary Folate Intake Quintiles (Excluding Supplements) and Their Range (µg/d) Dietary Folate Intake Quintiles (Excluding Supplements) and Their Range (µg/d) Dietary Folate Intake Quintiles (Excluding Supplements) and Their Range (µg/d) P for trend
Cases 1 37194 2 195235 3 236273 4 274325 5 gt325
(Total stroke) RR 1140 1.00 1.03 (0.851.25) 1.08 (0.891.31) 1.01 (0.821.24) 1.06 (0.851.32) P 0.7
(Ischemic) RR 601 1.00 0.91 (0.701.18) 1.03 (0.791.35) 0.85 (0.631.13) 0.93 (0.691.25) P 0.6
(Thrombotic) RR 323 1.00 1.17 (0.811.69) 1.43 (1.002.06) 0.96 (0.641.46) 1.19 (0.781.81) P 0.8
(Embolic) RR 110 1.00 0.79 (0.421.49) 1.00 (0.541.86) 0.77 (0.391.52) 0.71 (0.341.52) P 0.4
(Subarachnoid) RR 166 1.00 1.05 (0.641.72) 1.26 (0.772.07) 1.00 (0.581.72) 0.82 (0.451.49) P 0.4
(Hemorrhagic) RR 114 1.00 1.98 (1.073.66) 1.65 (0.853.18) 1.49 (0.743.02) 1.44 (0.692.99) P 0.8
Type of Stroke Supplement Folate Intake Categories Supplement Folate Intake Categories Supplement Folate Intake Categories Supplement Folate Intake Categories Supplement Folate Intake Categories Supplement Folate Intake Categories
Cases Nonusers 0.1149 µg/d 150249 µg/d 250399 µg/d 400 µg/d
(Total stroke) RR 1140 1.00 1.17 (0.951.45) 0.93 (0.721.21) 1.02 (0.751.37) 1.02 (0.821.27) P 0.9
(Ischemic) RR 601 1.00 1.30 (0.981.74) 0.93 (0.651.33) 1.08 (0.721.63) 1.08 (0.801.48) P 0.8
(Thrombotic) RR 323 1.00 1.38 (0.961.99) 0.75 (0.451.24) 0.69 (0.371.30) 1.01 (0.661.53) P 0.5
(Embolic) RR 110 1.00 1.23 (0.642.37) 1.16 (0.562.43) 1.36 (0.593.09) 0.82 (0.381.76) P 0.8
(Subarachnoid) RR 166 1.00 1.59 (0.942.68) 1.06 (0.562.01) 1.37 (0.682.74) 0.99 (0.561.76) P 1.0
(Hemorrhagic) RR 114 1.00 0.94 (0.412.15) 2.53 (1.255.11) 2.16 (0.865.41) 1.30 (0.592.85) P 0.2
Covariates are the same as in Table 1. Covariates are the same as in Table 1. Covariates are the same as in Table 1. Covariates are the same as in Table 1. Covariates are the same as in Table 1. Covariates are the same as in Table 1. Covariates are the same as in Table 1. Covariates are the same as in Table 1.
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Discussion
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In this prospective cohort study

• Total, dietary, and supplement folate intake were
  not associated with total stroke or its subtypes
• This finding is consistent when using different
  definition of folate intake during 5 years

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• Inaccurate dietary assessment
• Good validity
• Folate associated with CHD
• Folate fortification cannot account
• Residual or unmeasured confounding
• Have no power
• Extreme value of folate intake in relation
  to risk of stroke
• Nonlinear relation between folate and stroke
• Fewer women intake very low folate

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Previous study

• Folate supplement lows homosysteine levels (Kang,
  et al Diaz-Arrastia, et al.)
• Homocysteine levels and stroke
• Risk reduced 19 24 when homocysteine
  were lower by 3µmol/L (Wald, et al)
• High homocysteine RR1.37 of ischemic
  stroke (Bautista, et al)
• However
• 4 cohort dont find the positive
  association
• (Stehouwer, et al Fallon, et al Verhoef,
  et al Alfthan, et al)
• A randomized controlled trial failed to find
  the difference between
• high and low-dose homocysteine in recurrence
  of stroke through
• lowing homocysteine levels (Toole, et al)

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Previous study (cont.)

• In NHANE I (Bazzano et al)
• Small and nonsignificant elevation the risk of
  stroke
• Folate serum level ?9.2nmol compare with
  gt9.2nmol
• The NHANE I (Bazzano et al)
• RR 0.79
• Baseline folate intake
• 24-hour recall questionnaire
• Age
• Gender

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Conclusion

• Folate intake does not have an important
  relation to the risk of stroke in women

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My comment
Gender Age Exclusion
Health Professional follow-up Study (HPFS) Men 4075 lt800 kcal/day gt4200 kcal/day ?70 blank items in 131items History of CVD or DM
Nurses Health Study (NHS) Women 3055 lt500 kcal/day gt3500 kcal/day ?10 blank items History of Cancer or CVD
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My comment
Stroke subtypes Different risk factor Result
NPFS Ischemic(embolism or thrombosis) stroke Hemorrhagic (subarachnoid and intracerebral) stroke Unknown type of stroke Intake of fiber, potassium, vit.E RR of ischemic stroke 0.71(folate) RR of ischemic stroke 0.73 (vitamin B12)
NHS Subarachnoid hemorrhages Intraparanchymal hemorrhages Thrombotic stroke Embolic stroke Ischemic stroke (embolism,thrombolism or unknown type) FA, protein, cereal fiber, History of DM Parental history of MI at or before 65 yrs old, Time period, Hormone use and menopausal status Null result in total stroke or subtypes stroke risk with high folate intake
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Thank you