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 vs. 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 vs. 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 vs. 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.

Haplotype analysis of the folate-related genes MTHFR, MTRR, and MTR and migraine with aura

“…The effect this may have on our observed association between MA and C677T is to attenuate a ‘real’ deleterious effect of the genotype, and essential reveal a protective effect of individuals with this genotype. In the simulation by Scher et al (24), the authors demonstrate that even small effects on survival of this allele might obscure a genetic risk factor, and even suggest a protective factor in a population comprised of older individuals as is the case in this study.…”

“…The selective mortality effect on this region is tested and described further in a recent paper. (24) Specifically, the TT and CT genotypes at C677T in MTHFR may be linked with somewhat reduced longevity. The effect this may have on our observed association between MA and C677T is to attenuate a ‘real’ deleterious effect of the genotype, and essential reveal a protective effect of individuals with this genotype.…”

Effects of MTHFR C677T and A1298C Polymorphisms on Migraine Susceptibility: A Meta‐Analysis of 26 Studies

“…Studies.-After retrieving the electronic databases, we initially identified 653 articles. Six hundred twentysix articles were excluded for various reasons and 26 studies (23 case-control studies and 3 cross-sectional studies) with 10,228 migraineurs and 28,608 controls were deemed eligible according to the inclusion and exclusion criteria [10][11][12][13][14][18][19][20][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45] (Fig. 1 shows the selection process).…”

Methylenetetrahydrofolate reductase polymorphism (MTHFR C677T) and headache in children: a retrospective study from a tertiary level outpatient service

“…So we compared the headache patients with patients referring to our clinic for other problems not related to headache, who did the MTHFR C677T genotyping for other reasons [4–7, 12]. …”