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.
Methods_e-1_Cohort_background
Methods e-1 Cohort background, migraine assessment method, and sampling procedure.
Figure_e-1_Influence_of_Heritability
Figure e-1: Influence of heritability on metabolite estimates and log p-values in ERF and NTR.
Figure_e-2_Ratio_stratification_plots_migraine_smoking
Figure e-2: ApoA1 and S-HDL-FC ratio stratification plots for migraine and smoking in NESDA and LUMINA.
Figure_e-3_Ratio_stratification_plots_migraine_lipid_lowering_medication
Figure e-3: ApoA1 and S-HDL-FC ratio stratification plots for migraine and lipid lowering medication usage in NESDA and LUMINA.
Figure_e-4_Ratio_stratification_plots_migraine_fasting
Figure e-4: ApoA1 and S-HDL-FC ratio stratification plots for migraine and fasting in NESDA and LUMINA.
Figure_e-5_Ratio_stratification_plots_migraine_depression
Figure e-5: ApoA1 and S-HDL-FC ratio stratification plots for migraine and depression in NESDA and LUMINA.
Figure_e-6_Ratio_stratification_plots_migraine_body_mass_index
Figure e-6: ApoA1 and S-HDL-FC ratio stratification plots for migraine and body mass index in NESDA and LUMINA.
Figure_e-7_Metabolite_correlation_between_measurements_and_over_time
Figure e-7: Metabolite correlations between measurements and over time for apoA1 and the S-HDL-FC ratio.
Figure_e-8_HDL_feature_plots_for_all_individual_cohorts
Figure e-8: HDL feature plots for all individual cohorts.
Table_e-1_Included_metabolites_in_pathways
Table e-1: Included metabolites in (sub-)pathways
Table_e-2_Included_metabolite_ratios
Table e-2: Included metabolite ratio’s
Table_e-3_Results_from_logistic_regression_sex_age_migraine
Table e-3: Results from logistic regression with metabolite concentrations, sex, and age as independent variables and migraine status as dependent variable.
Table_e-4_Meta_analysis_results_of_the_logistic_regression
Table e-4: Meta-analysis results of the logistic regressions with sex, age, and metabolite concentrations as independent variables and migraine status as dependent variable.
Table_e-5_Results_logistic_regression_LLM_BMI_sex_age_migraine
Table e-5: Results logistic regression with metabolite concentrations, lipid lowering medication usage, body mass index, sex, and age as independent variables and migraine status as dependent variable.
