Large-scale plasma metabolome analysis reveals alterations in HDL metabolism in migraine

Abstract

Objective: To identify a plasma metabolomic biomarker signature for migraine.

Methods: Plasma samples from 8 Dutch cohorts (n = 10,153: 2,800 migraine patients and 7,353 controls) were profiled on a ¹H-NMR-based metabolomics platform, to quantify 146 individual metabolites (e.g., lipids, fatty acids, and lipoproteins) and 79 metabolite ratios. Metabolite measures associated with migraine were obtained after single-metabolite logistic regression combined with a random-effects meta-analysis performed in a nonstratified and sex-stratified manner. Next, a global test analysis was performed to identify sets of related metabolites associated with migraine. The Holm procedure was applied to control the family-wise error rate at 5% in single-metabolite and global test analyses.

Results: Decreases in the level of apolipoprotein A1 (β -0.10; 95% confidence interval [CI] -0.16, -0.05; adjusted p = 0.029) and free cholesterol to total lipid ratio present in small high-density lipoprotein subspecies (HDL) (β -0.10; 95% CI -0.15, -0.05; adjusted p = 0.029) were associated with migraine status. In addition, only in male participants, a decreased level of omega-3 fatty acids (β -0.24; 95% CI -0.36, -0.12; adjusted p = 0.033) was associated with migraine. Global test analysis further supported that HDL traits (but not other lipoproteins) were associated with migraine status.

Conclusions: Metabolic profiling of plasma yielded alterations in HDL metabolism in migraine patients and decreased omega-3 fatty acids only in male migraineurs.

Figure 1. Study flowchart

Determination of the sample set used for data analysis and the different data analysis approaches performed in the current study. ¹H-NMR = proton nuclear magnetic resonance.

Figure 2. Forest plots of candidate migraine biomarkers apolipoprotein A1 (apoA1) and the free cholesterol to total lipid ratio in small high-density lipoprotein ratio (S-HDL-FC)

Associations with migraine in random-effects meta-analyses. The effect sizes and 95% confidence intervals (CIs) for apoA1 and S-HDL-FC are presented per cohort and in a random-effects meta-analysis. Values from logistic regression with metabolite levels, sex, and age as independent variables and migraine status as dependent variable. Error bars denote 95% CIs. To facilitate the interpretation of the effect sizes (β coefficients), we calculated the odds ratio (OR) for having migraine for a typical low metabolite score (z score = −1, 1 SD below average) and a typical high metabolite score: β −0.10, OR 1.22; β −0.20, OR 1.49; β −0.30, OR 1.82; β −0.40, OR 2.22; β −0.50, OR 2.72. *p Values after Holm-Bonferroni (p < 0.0002) multiple testing correction. ERF = Erasmus Rucphen Family study; I² = measure of heterogeneity; LUMINA = Leiden University Migraine Neuro-Analysis; NESDA = Netherlands Study of Depression and Anxiety 1 and 2; NTR = Netherlands Twin Registry; RS = Rotterdam Study.

Figure 3. Sex-stratified metabolite associations with migraine

Metabolite associations with migraine in male (blue squares) and female (red circles) participants in a random-effects meta-analysis comprised of 8 cohorts. The effect sizes and 95% confidence intervals (CIs) are shown. Values are from logistic regression with metabolite levels, sex, age, body mass index, and lipid-lowering medication usage as independent variables and migraine status as dependent variable. Error bars denote 95% CIs, filled squares (male participants ) or circles (female participants ) indicate significance after Holm-Bonferroni (p < 0.0002) multiple testing correction. All other metabolite classes without significant metabolites after Holm-Bonferroni correction as well as I² values can be found in table e-5 (doi.org/10.5061/dryad.p698mn7). To facilitate the interpretation of the effect sizes (β coefficients), we calculated the odds ratio (OR) for having migraine for a typical low metabolite score (z score = −1, 1 SD below average) and a typical high metabolite score: β −0.10, OR 1.22; β −0.20, OR 1.49; β −0.30, OR 1.82; β −0.40, OR 2.22; β −0.50, OR 2.72. All metabolite abbreviations can be found in tables e-1 and e-2 (doi.org/10.5061/dryad.p698mn7).

Figure 4. Global test analysis

Meta-analysis of the results of the 23 sets of (functionally) related metabolites tested in 8 cohorts for their association with migraine. The analysis using the global test framework has been adjusted for a sex, age, body mass index, and lipid-lowering medication usage. Glutamate metabolism does not include results from the Netherlands Twin Registry as glutamine levels could not be determined in this cohort. Bars denote −log¹⁰ of the p value (Fisher combination of global test p values for the individual cohorts) per pathway, where only the black bars remain significant after multiple testing correction using Holm-Bonferroni. The threshold for withstanding multiple testing correction is indicated by a dotted line. IDL = intermediate-density lipoprotein; LDL = low-density lipoprotein; VLDL = very low-density lipoprotein.