TY - JOUR
T1 - Lack of association between the MTHFR C677T variant and migraine with aura in an older population
T2 - Could selective survival play a role?
AU - Scher, Ann I.
AU - Eiriksdottir, Gudny
AU - Garcia, Melissa
AU - Feit, Preethy
AU - Smith, Albert V.
AU - Harris, Tamara B.
AU - Roecklein, Kathryn A.
AU - Gudmundsson, Larus S.
AU - Gudnason, Vilmundur
AU - Launer, Lenore J.
N1 - Funding Information:
This study was supported by a grant from the National Institutes of Health (N01-AG-1-2100), National Institute on Aging Intramural Research Program, the Hjartavernd (the Icelandic Heart Association) and the Althingi (the Icelandic Parliament).
PY - 2013/4
Y1 - 2013/4
N2 - 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 genedisease association. Results: TT versus CC carriers were at marginally reduced odds of MA (ORTT 0.55 (0.31.0), p=0.07), significantly for women (ORTT 0.45 (0.20.9), p=0.03). Assuming the true (e.g. mid-life) effect of the TT genotype is OR TT 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. Conclusion: 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.
AB - 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 genedisease association. Results: TT versus CC carriers were at marginally reduced odds of MA (ORTT 0.55 (0.31.0), p=0.07), significantly for women (ORTT 0.45 (0.20.9), p=0.03). Assuming the true (e.g. mid-life) effect of the TT genotype is OR TT 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. Conclusion: 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.
KW - MTHFR
KW - Migraine
KW - association studies in genetics
KW - folate
KW - selection bias
KW - selective survival
UR - http://www.scopus.com/inward/record.url?scp=84875480532&partnerID=8YFLogxK
U2 - 10.1177/0333102412469739
DO - 10.1177/0333102412469739
M3 - Article
C2 - 23230240
AN - SCOPUS:84875480532
SN - 0333-1024
VL - 33
SP - 308
EP - 315
JO - Cephalalgia
JF - Cephalalgia
IS - 5
ER -