title: Lack of association between the MTHFR C677T variant and migraine with aura in an older population: could selective survival play a role?
abstract: BACKGROUND
  Several studies, but not all, of primarily middle-aged or younger adults have suggested that the common MTHFR C677T variant is a genetic risk factor for migraine with aura (MA). Here, we consider whether this variant is associated with MA risk in an older non-clinical population (AGES-Reykjavik cohort).
  
  
  METHODS
  Participants are a sub-sample ( N  = 1976) of subjects from the Reykjavik Study (RS; mean age 50) and its continuation, AGES-RS (mean age 76). We estimated the relative odds of MA in TT versus CC carriers using multinomial logistic regression. As both MA and the TT genotype may be linked with modestly reduced longevity, we performed a simple simulation to illustrate the effect that selective survival may have had on our observed gene-disease association.
  
  
  RESULTS
  TT versus CC carriers were at marginally reduced odds of MA (ORTT 0.55 (0.3-1.0), P  = 0.07), significantly for women (ORTT 0.45 (0.2-0.9), P  = 0.03). Assuming the 'true' (e.g. mid-life) effect of the TT genotype is ORTT 1.26, from a recent meta-analysis, our simulation suggested that if 25-year mortality had been (hypothetically) 13% higher in MA subjects with the TT versus CC genotype, the measured effect of the TT genotype on MA would have been attenuated to non-significance (e.g. ORTT 1.00). Our observed protective effect was consistent with the most extreme selective mortality scenario, in which essentially all of the previously reported increased mortality in MA subjects was (hypothetically) found in CT or TT carriers.
  
  
  CONCLUSIONS
  The MTHFR 677TT genotype was associated with marginally reduced risk of MA in our older population. Our simulation illustrated how even modest selective survival might obscure the apparent effect of a genetic or other risk factor in older populations. We speculate that some of the heterogeneity previously observed for this particular genetic variant may be due to age range differences in the studied populations.
authors.affiliation: Department of Preventive Medicine and Biometrics, Uniformed Services University, 4301 Jones Bridge Road, Bethesda, MD 20814, USA. ann.scher@usuhs.edu
authors.forename: Ann I
authors.initials: AI
authors.lastname: Scher
authors.forename: Gudny
authors.initials: G
authors.lastname: Eiriksdottir
authors.forename: Melissa
authors.initials: M
authors.lastname: Garcia
authors.forename: Preethy
authors.initials: P
authors.lastname: Feit
authors.forename: Albert V
authors.initials: AV
authors.lastname: Smith
authors.forename: Tamara B
authors.initials: TB
authors.lastname: Harris
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Roecklein
authors.forename: Larus S
authors.initials: LS
authors.lastname: Gudmundsson
authors.forename: Vilmundur
authors.initials: V
authors.lastname: Gudnason
authors.forename: Lenore J
authors.initials: LJ
authors.lastname: Launer
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D020325:Migraine with Aura / Q000235:genetics* / Q000401:mortality*; D009154:Mutation; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide
chemical_list: C573423:MTHFR protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2)