Skip to content
2000
image of Circulating Cytokines Mediate the Causal Relationship between Plasma Lipids and Migraine and its Subtypes: A Mediated Mendelian Randomization Study

Abstract

Introduction

Migraine, a primary headache disorder, is the third disabling disease of neurological disorders worldwide. The pathological mechanism underlying migraine remains poorly understood. Lipid metabolism may be related to migraine pathophysiology. We aimed to investigate the causal relationship between plasma lipids and migraine or its subtypes, including migraine with aura (MA) and migraine without aura (MO), and explore whether the circulating cytokines serve as mediators in the pathway from plasma lipids to migraine.

Methods

A two-step Mendelian randomization (MR) approach was used to assess the mediating effect. The summary genetic data for 179 lipid species were obtained from were derived from a genome-wide association studies (GWAS) summary dataset encompassing 7,174 individuals. The summary genetic data for 91 circulating cytokines were obtained from genome-wide pQTL mapping data. The summary genetic data of GWAS related to migraine and its subtypes were derived from the FinnGen Release 10 database. The MR Analysis methods included the inverse-variance-weighted (IVW), MR-Egger, and weighted median.

Results

The risk of migraine was reduced mediated by CD5 with phosphatidylinositol (18:1_18:2), sphingomyelin (d34:1), and sphingomyelin (d38:1). The risk of migraine and MA was reduced mediated by CD6 with sphingomyelin (d40:1) and sphingomyelin (d42:2). The risk of migraine and MA was increased mediated by CD6 with phosphatidylethanolamine (O-16:1_18:2).

Discussion

CD5 and CD6 were found to be related to migraine. CD5 and CD6 may affect migraine by immunological dysregulation-induced neuroinflammation. Six plasma lipids are associated with two cytokines, indicating that lipid metabolism participates in neuroinflammation, and T cells may be part of it. Plasma levels of lipids were associated with the risk of migraine. The circulating cytokines may serve as mediators in the pathway from plasma lipids to migraine.

Conclusions

CD5 and CD6 appeared to mediate the causal relationship between plasma lipids and migraine or MA, including four kinds of sphingomyelin, one phosphatidylinositol, and one phosphatidylethanolamine.

Loading

Article metrics loading...

/content/journals/cchts/10.2174/0113862073386181251001071432
2025-10-28
2026-01-29
Loading full text...

Full text loading...

References

  1. The international classification of headache disorders. Headache Classification Committee of the International Headache Society (IHS). Cephalalgia 2018 38 1 211 10.1177/0333102417738202
    [Google Scholar]
  2. Steinmetz J.D. Seeher K.M. Schiess N. Nichols E. Cao B. Servili C. Cavallera V. Cousin E. Hagins H. Moberg M.E. Mehlman M.L. Abate Y.H. Abbas J. Abbasi M.A. Abbasian M. Abbastabar H. Abdelmasseh M. Abdollahi M. Abdollahi M. Abdollahifar M-A. Abd-Rabu R. Abdulah D.M. Abdullahi A. Abedi A. Abedi V. Abeldańo Zuńiga R.A. Abidi H. Abiodun O. Aboagye R.G. Abolhassani H. Aboyans V. Abrha W.A. Abualhasan A. Abu-Gharbieh E. Aburuz S. Adamu L.H. Addo I.Y. Adebayo O.M. Adekanmbi V. Adekiya T.A. Adikusuma W. Adnani Q.E.S. Adra S. Afework T. Afolabi A.A. Afraz A. Afzal S. Aghamiri S. Agodi A. Agyemang-Duah W. Ahinkorah B.O. Ahmad A. Ahmad D. Ahmad S. Ahmadzade A.M. Ahmed A. Ahmed A. Ahmed H. Ahmed J.Q. Ahmed L.A. Ahmed M.B. Ahmed S.A. Ajami M. Aji B. Ajumobi O. Akade S.E. Akbari M. Akbarialiabad H. Akhlaghi S. Akinosoglou K. Akinyemi R.O. Akonde M. Al Hasan S.M. Alahdab F. AL-Ahdal, T.M.A.; Al-amer, R.M.; Albashtawy, M.; AlBataineh, M.T.; Aldawsari, K.A.; Alemi, H.; Alemi, S.; Algammal, A.M.; Al-Gheethi, A.A.S.; Alhalaiqa, F.A.N.; Alhassan, R.K.; Ali, A.; Ali, E.A.; Ali, L.; Ali, M.U.; Ali, M.M.; Ali, R.; Ali, S.; Ali, S.S.S.; Ali, Z.; Alif, S.M.; Alimohamadi, Y.; Aliyi, A.A.; Aljofan, M.; Aljunid, S.M.; Alladi, S.; Almazan, J.U.; Almustanyir, S.; Al-Omari, B.; Alqahtani, J.S.; Alqasmi, I.; Alqutaibi, A.Y.; Al-Shahi Salman, R.; Altaany, Z.; Al-Tawfiq, J.A.; Altirkawi, K.A.; Alvis-Guzman, N.; Al-Worafi, Y.M.; Aly, H.; Aly, S.; Alzoubi, K.H.; Amani, R.; Amindarolzarbi, A.; Amiri, S.; Amirzade-Iranaq, M.H.; Amu, H.; Amugsi, D.A.; Amusa, G.A.; Amzat, J.; Ancuceanu, R.; Anderlini, D.; Anderson, D.B.; Andrei, C.L.; Androudi, S.; Angappan, D.; Angesom, T.W.; Anil, A.; Ansari-Moghaddam, A.; Anwer, R.; Arafat, M.; Aravkin, A.Y.; Areda, D.; Ariffin, H.; Arifin, H.; Arkew, M.; Ärnlöv, J.; Arooj, M.; Artamonov, A.A.; Artanti, K.D.; Aruleba, R.T.; Asadi-Pooya, A.A.; Asena, T.F.; Asghari-Jafarabadi, M.; Ashraf, M.; Ashraf, T.; Atalell, K.A.; Athari, S.S.; Atinafu, B.T.T.; Atorkey, P.; Atout, M.M.W.; Atreya, A.; Aujayeb, A.; Avan, A.; Ayala Quintanilla, B.P.; Ayatollahi, H.; Ayinde, O.O.; Ayyoubzadeh, S.M.; Azadnajafabad, S.; Azizi, Z.; Azizian, K.; Azzam, A.Y.; Babaei, M.; Badar, M.; Badiye, A.D.; Baghdadi, S.; Bagherieh, S.; Bai, R.; Baig, A.A.; Balakrishnan, S.; Balalla, S.; Baltatu, O.C.; Banach, M.; Bandyopadhyay, S.; Banerjee, I.; Baran, M.F.; Barboza, M.A.; Barchitta, M.; Bardhan, M.; Barker-Collo, S.L.; Bärnighausen, T.W.; Barrow, A.; Bashash, D.; Bashiri, H.; Bashiru, H.A.; Basiru, A.; Basso, J.D.; Basu, S.; Batiha, A-M.M.; Batra, K.; Baune, B.T.; Bedi, N.; Begde, A.; Begum, T.; Behnam, B.; Behnoush, A.H.; Beiranvand, M.; Béjot, Y.; Bekele, A.; Belete, M.A.; Belgaumi, U.I.; Bemanalizadeh, M.; Bender, R.G.; Benfor, B.; Bennett, D.A.; Bensenor, I.M.; Berice, B.; Bettencourt, P.J.G.; Beyene, K.A.; Bhadra, A.; Bhagat, D.S.; Bhangdia, K.; Bhardwaj, N.; Bhardwaj, P.; Bhargava, A.; Bhaskar, S.; Bhat, A.N.; Bhat, V.; Bhatti, G.K.; Bhatti, J.S.; Bhatti, R.; Bijani, A.; Bikbov, B.; Bilalaga, M.M.; Biswas, A.; Bitaraf, S.; Bitra, V.R.; Bjørge, T.; Bodolica, V.; Bodunrin, A.O.; Boloor, A.; Braithwaite, D.; Brayne, C.; Brenner, H.; Briko, A.; Bringas Vega, M.L.; Brown, J.; Budke, C.M.; Buonsenso, D.; Burkart, K.; Burns, R.A.; Bustanji, Y.; Butt, M.H.; Butt, N.S.; Butt, Z.A.; Cabral, L.S.; Caetano dos Santos, F.L.; Calina, D.; Campos-Nonato, I.R.; Cao, C.; Carabin, H.; Cárdenas, R.; Carreras, G.; Carvalho, A.F.; Castańeda-Orjuela, C.A.; Casulli, A.; Catalá-López, F.; Catapano, A.L.; Caye, A.; Cegolon, L.; Cenderadewi, M.; Cerin, E.; Chacón-Uscamaita, P.R.; Chan, J.S.K.; Chanie, G.S.; Charan, J.; Chattu, V.K.; Chekol Abebe, E.; Chen, H.; Chen, J.; Chi, G.; Chichagi, F.; Chidambaram, S.B.; Chimoriya, R.; Ching, P.R.; Chitheer, A.; Chong, Y.Y.; Chopra, H.; Choudhari, S.G.; Chowdhury, E.K.; Chowdhury, R.; Christensen, H.; Chu, D-T.; Chukwu, I.S.; Chung, E.; Coberly, K.; Columbus, A.; Comachio, J.; Conde, J.; Cortesi, P.A.; Costa, V.M.; Couto, R.A.S.; Criqui, M.H.; Cruz-Martins, N.; Dabbagh Ohadi, M.A.; Dadana, S.; Dadras, O.; Dai, X.; Dai, Z.; D’Amico, E.; Danawi, H.A.; Dandona, L.; Dandona, R.; Darwish, A.H.; Das, S.; Das, S.; Dascalu, A.M.; Dash, N.R.; Dashti, M.; De la Hoz, F.P.; de la Torre-Luque, A.; De Leo, D.; Dean, F.E.; Dehghan, A.; Dehghan, A.; Dejene, H.; Demant, D.; Demetriades, A.K.; Demissie, S.; Deng, X.; Desai, H.D.; Devanbu, V.G.C.; Dhama, K.; Dharmaratne, S.D.; Dhimal, M.; Dias da Silva, D.; Diaz, D.; Dibas, M.; Ding, D.D.; Dinu, M.; Dirac, M.A.; Diress, M.; Do, T.C.; Do, T.H.P.; Doan, K.D.K.; Dodangeh, M.; Doheim, M.F.; Dokova, K.G.; Dongarwar, D.; Dsouza, H.L.; Dube, J.; Duraisamy, S.; Durojaiye, O.C.; Dutta, S.; Dziedzic, A.M.; Edinur, H.A.; Eissazade, N.; Ekholuenetale, M.; Ekundayo, T.C.; El Nahas, N.; El Sayed, I.; Elahi Najafi, M.A.; Elbarazi, I.; Elemam, N.M.; Elgar, F.J.; Elgendy, I.Y.; Elhabashy, H.R.; Elhadi, M.; Elilo, L.T.; Ellenbogen, R.G.; Elmeligy, O.A.A.; Elmonem, M.A.; Elshaer, M.; Elsohaby, I.; Emamverdi, M.; Emeto, T.I.; Endres, M.; Esezobor, C.I.; Eskandarieh, S.; Fadaei, A.; Fagbamigbe, A.F.; Fahim, A.; Faramarzi, A.; Fares, J.; Farjoud Kouhanjani, M.; Faro, A.; Farzadfar, F.; Fatehizadeh, A.; Fathi, M.; Fathi, S.; Fatima, S.A.F.; Feizkhah, A.; Fereshtehnejad, S-M.; Ferrari, A.J.; Ferreira, N.; Fetensa, G.; Firouraghi, N.; Fischer, F.; Fonseca, A.C.; Force, L.M.; Fornari, A.; Foroutan, B.; Fukumoto, T.; Gadanya, M.A.; Gaidhane, A.M.; Galali, Y.; Galehdar, N.; Gan, Q.; Gandhi, A.P.; Ganesan, B.; Gardner, W.M.; Garg, N.; Gau, S-Y.; Gautam, R.K.; Gebre, T.; Gebrehiwot, M.; Gebremeskel, G.G.; Gebreslassie, H.G.; Getacher, L.; Ghaderi Yazdi, B.; Ghadirian, F.; Ghaffarpasand, F.; Ghanbari, R.; Ghasemi, M.R.; Ghazy, R.M.; Ghimire, S.; Gholami, A.; Gholamrezanezhad, A.; Ghotbi, E.; Ghozy, S.; Gialluisi, A.; Gill, P.S.; Glasstetter, L.M.; Gnedovskaya, E.V.; Golchin, A.; Golechha, M.; Goleij, P.; Golinelli, D.; Gomes-Neto, M.; Goulart, A.C.; Goyal, A.; Gray, R.J.; Grivna, M.; Guadie, H.A.; Guan, B.; Guarducci, G.; Guicciardi, S.; Gunawardane, D.A.; Guo, H.; Gupta, B.; Gupta, R.; Gupta, S.; Gupta, V.B.; Gupta, V.K.; Gutiérrez, R.A.; Habibzadeh, F.; Hachinski, V.; Haddadi, R.; Hadei, M.; Hadi, N.R.; Haep, N.; Haile, T.G.; Haj-Mirzaian, A.; Hall, B.J.; Halwani, R.; Hameed, S.; Hamiduzzaman, M.; Hammoud, A.; Han, H.; Hanifi, N.; Hankey, G.J.; Hannan, M.A.; Hao, J.; Harapan, H.; Hareru, H.E.; Hargono, A.; Harlianto, N.I.; Haro, J.M.; Hartman, N.N.; Hasaballah, A.I.; Hasan, F.; Hasani, H.; Hasanian, M.; Hassan, A.; Hassan, S.; Hassanipour, S.; Hassankhani, H.; Hassen, M.B.; Haubold, J.; Hay, S.I.; Hayat, K.; Hegazy, M.I.; Heidari, G.; Heidari, M.; Heidari-Soureshjani, R.; Hesami, H.; Hezam, K.; Hiraike, Y.; Hoffman, H.J.; Holla, R.; Hopf, K.P.; Horita, N.; Hossain, M.M.; Hossain, M.B.; Hossain, S.; Hosseinzadeh, H.; Hosseinzadeh, M.; Hostiuc, S.; Hu, C.; Huang, J.; Huda, M.N.; Hussain, J.; Hussein, N.R.; Huynh, H-H.; Hwang, B-F.; Ibitoye, S.E.; Ilaghi, M.; Ilesanmi, O.S.; Ilic, I.M.; Ilic, M.D.; Immurana, M.; Iravanpour, F.; Islam, S.M.S.; Ismail, F.; Iso, H.; Isola, G.; Iwagami, M.; Iwu, C.C.D.; Iyer, M.; Jaan, A.; Jacob, L.; Jadidi-Niaragh, F.; Jafari, M.; Jafarinia, M.; Jafarzadeh, A.; Jahankhani, K.; Jahanmehr, N.; Jahrami, H.; Jaiswal, A.; Jakovljevic, M.; Jamora, R.D.G.; Jana, S.; Javadi, N.; Javed, S.; Javeed, S.; Jayapal, S.K.; Jayaram, S.; Jiang, H.; Johnson, C.O.; Johnson, W.D.; Jokar, M.; Jonas, J.B.; Joseph, A.; Joseph, N.; Joshua, C.E.; Jürisson, M.; Kabir, A.; Kabir, Z.; Kabito, G.G.; Kadashetti, V.; Kafi, F.; Kalani, R.; Kalantar, F.; Kaliyadan, F.; Kamath, A.; Kamath, S.; Kanchan, T.; Kandel, A.; Kandel, H.; Kanmodi, K.K.; Karajizadeh, M.; Karami, J.; Karanth, S.D.; Karaye, I.M.; Karch, A.; Karimi, A.; Karimi, H.; Karimi Behnagh, A.; Kasraei, H.; Kassebaum, N.J.; Kauppila, J.H.; Kaur, H.; Kaur, N.; Kayode, G.A.; Kazemi, F.; Keikavoosi-Arani, L.; Keller, C.; Keykhaei, M.; Khadembashiri, M.A.; Khader, Y.S.; Khafaie, M.A.; Khajuria, H.; Khalaji, A.; Khamesipour, F.; Khammarnia, M.; Khan, M.; Khan, M.A.B.; Khan, Y.H.; Khan Suheb, M.Z.; Khanmohammadi, S.; Khanna, T.; Khatab, K.; Khatatbeh, H.; Khatatbeh, M.M.; Khateri, S.; Khatib, M.N.; Khayat Kashani, H.R.; Khonji, M.S.; khorashadizadeh, F.; Khormali, M.; Khubchandani, J.; Kian, S.; Kim, G.; Kim, J.; Kim, M.S.; Kim, Y.J.; Kimokoti, R.W.; Kisa, A.; Kisa, S.; Kivimäki, M.; Kochhar, S.; Kolahi, A-A.; Koly, K.N.; Kompani, F.; Koroshetz, W.J.; Kosen, S.; Kourosh Arami, M.; Koyanagi, A.; Kravchenko, M.A.; Krishan, K.; Krishnamoorthy, V.; Kuate Defo, B.; Kuddus, M.A.; Kumar, A.; Kumar, G.A.; Kumar, M.; Kumar, N.; Kumsa, N.B.; Kundu, S.; Kurniasari, M.D.; Kusuma, D.; Kuttikkattu, A.; Kyu, H.H.; La Vecchia, C.; Ladan, M.A.; Lahariya, C.; Laksono, T.; Lal, D.K.; Lallukka, T.; Lám, J.; Lami, F.H.; Landires, I.; Langguth, B.; Lasrado, S.; Latief, K.; Latifinaibin, K.; Lau, K.M-M.; Laurens, M.B.; Lawal, B.K.; Le, L.K.D.; Le, T.T.T.; Ledda, C.; Lee, M.; Lee, S.; Lee, S.W.; Lee, W-C.; Lee, Y.H.; Leonardi, M.; Lerango, T.L.; Li, M-C.; Li, W.; Ligade, V.S.; Lim, S.S.; Linehan, C.; Liu, C.; Liu, J.; Liu, W.; Lo, C-H.; Lo, W.D.; Lobo, S.W.; Logroscino, G.; Lopes, G.; Lopukhov, P.D.; Lorenzovici, L.; Lorkowski, S.; Loureiro, J.A.; Lubinda, J.; Lucchetti, G.; Lutzky Saute, R.; Ma, Z.F.; Mabrok, M.; Machoy, M.; Madadizadeh, F.; Magdy Abd El Razek, M.; Maghazachi, A.A.; Maghbouli, N.; Mahjoub, S.; Mahmoudi, M.; Majeed, A.; Malagón-Rojas, J.N.; Malakan Rad, E.; Malhotra, K.; Malik, A.A.; Malik, I.; Mallhi, T.H.; Malta, D.C.; Manilal, A.; Mansouri, V.; Mansournia, M.A.; Marasini, B.P.; Marateb, H.R.; Maroufi, S.F.; Martinez-Raga, J.; Martini, S.; Martins-Melo, F.R.; Martorell, M.; März, W.; Marzo, R.R.; Massano, J.; Mathangasinghe, Y.; Mathews, E.; Maude, R.J.; Maugeri, A.; Maulik, P.K.; Mayeli, M.; Mazaheri, M.; McAlinden, C.; McGrath, J.J.; Meena, J.K.; Mehndiratta, M.M.; Mendez-Lopez, M.A.M.; Mendoza, W.; Mendoza-Cano, O.; Menezes, R.G.; Merati, M.; Meretoja, A.; Merkin, A.; Mersha, A.M.; Mestrovic, T.; Mi, T.; Miazgowski, T.; Michalek, I.M.; Mihretie, E.T.; Minh, L.H.N.; Mirfakhraie, R.; Mirica, A.; Mirrakhimov, E.M.; Mirzaei, M.; Misganaw, A.; Misra, S.; Mithra, P.; Mizana, B.A.; Mohamadkhani, A.; Mohamed, N.S.; Mohammadi, E.; Mohammadi, H.; Mohammadi, S.; Mohammadi, S.; Mohammadshahi, M.; Mohammed, M.; Mohammed, S.; Mohammed, S.; Mohan, S.; Mojiri-forushani, H.; Moka, N.; Mokdad, A.H.; Molinaro, S.; Möller, H.; Monasta, L.; Moniruzzaman, M.; Montazeri, F.; Moradi, M.; Moradi, Y.; Moradi-Lakeh, M.; Moraga, P.; Morovatdar, N.; Morrison, S.D.; Mosapour, A.; Mosser, J.F.; Mossialos, E.; Motaghinejad, M.; Mousavi, P.; Mousavi, S.E.; Mubarik, S.; Muccioli, L.; Mughal, F.; Mukoro, G.D.; Mulita, A.; Mulita, F.; Musaigwa, F.; Mustafa, A.; Mustafa, G.; Muthu, S.; Nagarajan, A.J.; Naghavi, P.; Naik, G.R.; Nainu, F.; Nair, T.S.; Najmuldeen, H.H.R.; Nakhostin Ansari, N.; Nambi, G.; Namdar Areshtanab, H.; Nargus, S.; Nascimento, B.R.; Naser, A.Y.; Nashwan, A.J.J.; Nasoori, H.; Nasreldein, A.; Natto, Z.S.; Nauman, J.; Nayak, B.P.; Nazri-Panjaki, A.; Negaresh, M.; Negash, H.; Negoi, I.; Negoi, R.I.; Negru, S.M.; Nejadghaderi, S.A.; Nematollahi, M.H.; Nesbit, O.D.; Newton, C.R.J.; Nguyen, D.H.; Nguyen, H.T.H.; Nguyen, H.Q.; Nguyen, N-T.T.; Nguyen, P.T.; Nguyen, V.T.; Niazi, R.K.; Nikolouzakis, T.K.; Niranjan, V.; Nnyanzi, L.A.; Noman, E.A.; Noroozi, N.; Norrving, B.; Noubiap, J.J.; Nri-Ezedi, C.A.; Ntaios, G.; Nuńez-Samudio, V.; Nurrika, D.; Oancea, B.; Odetokun, I.A.; O’Donnell, M.J.; Ogunsakin, R.E.; Oguta, J.O.; Oh, I-H.; Okati-Aliabad, H.; Okeke, S.R.; Okekunle, A.P.; Okonji, O.C.; Okwute, P.G.; Olagunju, A.T.; Olaiya, M.T.; Olana, M.D.; Olatubi, M.I.; Oliveira, G.M.M.; Olufadewa, I.I.; Olusanya, B.O.; Omar Bali, A.; Ong, S.; Onwujekwe, O.E.; Ordak, M.; Orji, A.U.; Ortega-Altamirano, D.V.; Osuagwu, U.L.; Otstavnov, N.; Otstavnov, S.S.; Ouyahia, A.; Owolabi, M.O.; P A, M.P.; Pacheco-Barrios, K.; Padubidri, J.R.; Pal, P.K.; Palange, P.N.; Palladino, C.; Palladino, R.; Palma-Alvarez, R.F.; Pan, F.; Panagiotakos, D.; Panda-Jonas, S.; Pandey, A.; Pandey, A.; Pandian, J.D.; Pangaribuan, H.U.; Pantazopoulos, I.; Pardhan, S.; Parija, P.P.; Parikh, R.R.; Park, S.; Parthasarathi, A.; Pashaei, A.; Patel, J.; Patil, S.; Patoulias, D.; Pawar, S.; Pedersini, P.; Pensato, U.; Pereira, D.M.; Pereira, J.; Pereira, M.O.; Peres, M.F.P.; Perico, N.; Perna, S.; Petcu, I-R.; Petermann-Rocha, F.E.; Pham, H.T.; Phillips, M.R.; Pinilla-Monsalve, G.D.; Piradov, M.A.; Plotnikov, E.; Poddighe, D.; Polat, B.; Poluru, R.; Pond, C.D.; Poudel, G.R.; Pouramini, A.; Pourbagher-Shahri, A.M.; Pourfridoni, M.; Pourtaheri, N.; Prakash, P.Y.; Prakash, S.; Prakash, V.; Prates, E.J.S.; Pritchett, N.; Purnobasuki, H.; Qasim, N.H.; Qattea, I.; Qian, G.; Radhakrishnan, V.; Raee, P.; Raeisi Shahraki, H.; Rafique, I.; Raggi, A.; Raghav, P.R.; Rahati, M.M.; Rahim, F.; Rahimi, Z.; Rahimifard, M.; Rahman, M.O.; Rahman, M.H.U.; Rahman, M.; Rahman, M.A.; Rahmani, A.M.; Rahmani, S.; Rahmani Youshanlouei, H.; Rahmati, M.; Raj Moolambally, S.; Rajabpour-Sanati, A.; Ramadan, H.; Ramasamy, S.K.; Ramasubramani, P.; Ramazanu, S.; Rancic, N.; Rao, I.R.; Rao, S.J.; Rapaka, D.; Rashedi, V.; Rashid, A.M.; Rashidi, M-M.; Rashidi Alavijeh, M.; Rasouli-Saravani, A.; Rawaf, S.; Razo, C.; Redwan, E.M.M.; Rekabi Bana, A.; Remuzzi, G.; Rezaei, N.; Rezaei, N.; Rezaei, N.; Rezaeian, M.; Rhee, T.G.; Riad, A.; Robinson, S.R.; Rodrigues, M.; Rodriguez, J.A.B.; Roever, L.; Rogowski, E.L.B.; Romoli, M.; Ronfani, L.; Roy, P.; Roy Pramanik, K.; Rubagotti, E.; Ruiz, M.A.; Russ, T.C.; S Sunnerhagen, K.; Saad, A.M.A.; Saadatian, Z.; Saber, K.; SaberiKamarposhti, M.; Sacco, S.; Saddik, B.; Sadeghi, E.; Sadeghian, S.; Saeed, U.; Saeed, U.; Safdarian, M.; Safi, S.Z.; Sagar, R.; Sagoe, D.; Saheb Sharif-Askari, F.; Saheb Sharif-Askari, N.; Sahebkar, A.; Sahoo, S.S.; Sahraian, M.A.; Sajedi, S.A.; Sakshaug, J.W.; Saleh, M.A.; Salehi Omran, H.; Salem, M.R.; Salimi, S.; Samadi Kafil, H.; Samadzadeh, S.; Samargandy, S.; Samodra, Y.L.; Samuel, V.P.; Samy, A.M.; Sanadgol, N.; Sanjeev, R.K.; Sanmarchi, F.; Santomauro, D.F.; Santri, I.N.; Santric-Milicevic, M.M.; Saravanan, A.; Sarveazad, A.; Satpathy, M.; Saylan, M.; Sayyah, M.; Scarmeas, N.; Schlaich, M.P.; Schuermans, A.; Schwarzinger, M.; Schwebel, D.C.; Selvaraj, S.; Sendekie, A.K.; Sengupta, P.; Senthilkumaran, S.; Serban, D.; Sergindo, M.T.; Sethi, Y.; SeyedAlinaghi, S.A.; Seylani, A.; Shabani, M.; Shabany, M.; Shafie, M.; Shahabi, S.; Shahbandi, A.; Shahid, S.; Shahraki-Sanavi, F.; Shahsavari, H.R.; Shahwan, M.J.; Shaikh, M.A.; Shaji, K.S.; Sham, S.; Shama, A.T.T.; Shamim, M.A.; Shams-Beyranvand, M.; Shamsi, M.A.; Shanawaz, M.; Sharath, M.; Sharfaei, S.; Sharifan, A.; Sharma, M.; Sharma, R.; Shashamo, B.B.; Shayan, M.; Sheikhi, R.A.; Shekhar, S.; Shen, J.; Shenoy, S.M.; Shetty, P.H.; Shiferaw, D.S.; Shigematsu, M.; Shiri, R.; Shittu, A.; Shivakumar, K.M.; Shokri, F.; Shool, S.; Shorofi, S.A.; Shrestha, S.; Siankam Tankwanchi, A.B.; Siddig, E.E.; Sigfusdottir, I.D.; Silva, J.P.; Silva, L.M.L.R.; Sinaei, E.; Singh, B.B.; Singh, G.; Singh, P.; Singh, S.; Sirota, S.B.; Sivakumar, S.; Sohag, A.A.M.; Solanki, R.; Soleimani, H.; Solikhah, S.; Solomon, Y.; Solomon, Y.; Song, S.; Song, Y.; Sotoudeh, H.; Spartalis, M.; Stark, B.A.; Starnes, J.R.; Starodubova, A.V.; Stein, D.J.; Steiner, T.J.; Stovner, L.J.; Suleman, M.; Suliankatchi Abdulkader, R.; Sultana, A.; Sun, J.; Sunkersing, D.; Sunny, A.; Susianti, H.; Swain, C.K.; Szeto, M.D.; Tabarés-Seisdedos, R.; Tabatabaei, S.M.; Tabatabai, S.; Tabish, M.; Taheri, M.; Tahvildari, A.; Tajbakhsh, A.; Tampa, M.; Tamuzi, J.J.L.L.; Tan, K-K.; Tang, H.; Tareke, M.; Tarigan, I.U.; Tat, N.Y.; Tat, V.Y.; Tavakoli Oliaee, R.; Tavangar, S.M.; Tavasol, A.; Tefera, Y.M.; Tehrani-Banihashemi, A.; Temesgen, W.A.; Temsah, M-H.; Teramoto, M.; Tesfaye, A.H.; Tesfaye, E.G.; Tesler, R.; Thakali, O.; Thangaraju, P.; Thapa, R.; Thapar, R.; Thomas, N.K.; Thrift, A.G.; Ticoalu, J.H.V.; Tillawi, T.; Toghroli, R.; Tonelli, M.; Tovani-Palone, M.R.; Traini, E.; Tran, N.M.; Tran, N-H.; Tran, P.V.; Tromans, S.J.; Truelsen, T.C.; Truyen, T.T.T.T.; Tsatsakis, A.; Tsegay, G.M.; Tsermpini, E.E.; Tualeka, A.R.; Tufa, D.G.; Ubah, C.S.; Udoakang, A.J.; Ulhaq, I.; Umair, M.; Umakanthan, S.; Umapathi, K.K.; Unim, B.; Unnikrishnan, B.; Vaithinathan, A.G.; Vakilian, A.; Valadan Tahbaz, S.; Valizadeh, R.; Van den Eynde, J.; Vart, P.; Varthya, S.B.; Vasankari, T.J.; Vaziri, S.; Vellingiri, B.; Venketasubramanian, N.; Verras, G-I.; Vervoort, D.; Villafańe, J.H.; Villani, L.; Vinueza Veloz, A.F.; Viskadourou, M.; Vladimirov, S.K.; Vlassov, V.; Volovat, S.R.; Vu, L.T.; Vujcic, I.S.; Wagaye, B.; Waheed, Y.; Wahood, W.; Walde, M.T.; Wang, F.; Wang, S.; Wang, Y.; Wang, Y-P.; Waqas, M.; Waris, A.; Weerakoon, K.G.; Weintraub, R.G.; Weldemariam, A.H.; Westerman, R.; Whisnant, J.L.; Wickramasinghe, D.P.; Wickramasinghe, N.D.; Willekens, B.; Wilner, L.B.; Winkler, A.S.; Wolfe, C.D.A.; Wu, A-M.; Wulf Hanson, S.; Xu, S.; Xu, X.; Yadollahpour, A.; Yaghoubi, S.; Yahya, G.; Yamagishi, K.; Yang, L.; Yano, Y.; Yao, Y.; Yehualashet, S.S.; Yeshaneh, A.; Yesiltepe, M.; Yi, S.; Yiğit, A.; Yiğit, V.; Yon, D.K.; Yonemoto, N.; You, Y.; Younis, M.Z.; Yu, C.; Yusuf, H.; Zadey, S.; Zahedi, M.; Zakham, F.; Zaki, N.; Zali, A.; Zamagni, G.; Zand, R.; Zandieh, G.G.Z.; Zangiabadian, M.; Zarghami, A.; Zastrozhin, M.S.; Zeariya, M.G.M.; Zegeye, Z.B.; Zeukeng, F.; Zhai, C.; Zhang, C.; Zhang, H.; Zhang, Y.; Zhang, Z-J.; Zhao, H.; Zhao, Y.; Zheng, P.; Zhou, H.; Zhu, B.; Zhumagaliuly, A.; Zielińska, M.; Zikarg, Y.T.; Zoladl, M.; Murray, C.J.L.; Ong, K.L.; Feigin, V.L.; Vos, T.; Dua, T. Global, regional, and national burden of disorders affecting the nervous system, 1990–2021: A systematic analysis for the Global Burden of Disease Study 2021. Lancet Neurol. 2024 23 4 344 381 10.1016/S1474‑4422(24)00038‑3 38493795
    [Google Scholar]
  3. Dodick D.W. Migraine. Lancet 2018 391 10127 1315 1330 10.1016/S0140‑6736(18)30478‑1 29523342
    [Google Scholar]
  4. Gross E.C. Lisicki M. Fischer D. Sándor P.S. Schoenen J. The metabolic face of migraine — from pathophysiology to treatment. Nat. Rev. Neurol. 2019 15 11 627 643 10.1038/s41582‑019‑0255‑4 31586135
    [Google Scholar]
  5. Cockcroft S. Mammalian lipids: Structure, synthesis and function. Essays Biochem. 2021 65 5 813 845 10.1042/EBC20200067 34415021
    [Google Scholar]
  6. Onderwater G.L.J. Ligthart L. Bot M. Demirkan A. Fu J. van der Kallen C.J.H. Vijfhuizen L.S. Pool R. Liu J. Vanmolkot F.H.M. Beekman M. Wen K. Amin N. Thesing C.S. Pijpers J.A. Kies D.A. Zielman R. de Boer I. van Greevenbroek M.M.J. Arts I.C.W. Milaneschi Y. Schram M.T. Dagnelie P.C. Franke L. Ikram M.A. Ferrari M.D. Goeman J.J. Slagboom P.E. Wijmenga C. Stehouwer C.D.A. Boomsma D.I. van Duijn C.M. Penninx B.W. ’t Hoen P.A.C. Terwindt G.M. van den Maagdenberg A.M.J.M. Large-scale plasma metabolome analysis reveals alterations in HDL metabolism in migraine. Neurology 2019 92 16 e1899 e1911 10.1212/WNL.0000000000007313 30944236
    [Google Scholar]
  7. Ren C. Liu J. Zhou J. Liang H. Wang Y. Sun Y. Ma B. Yin Y. Lipidomic analysis of serum samples from migraine patients. Lipids Health Dis. 2018 17 1 22 10.1186/s12944‑018‑0665‑0 29394939
    [Google Scholar]
  8. Leuti A. Fazio D. Fava M. Piccoli A. Oddi S. Maccarrone M. Bioactive lipids, inflammation and chronic diseases. Adv. Drug Deliv. Rev. 2020 159 133 169 10.1016/j.addr.2020.06.028 32628989
    [Google Scholar]
  9. Bogie J.F.J. Haidar M. Kooij G. Hendriks J.J.A. Fatty acid metabolism in the progression and resolution of CNS disorders. Adv. Drug Deliv. Rev. 2020 159 198 213 10.1016/j.addr.2020.01.004 31987838
    [Google Scholar]
  10. Kursun O. Yemisci M. van den Maagdenberg A.M.J.M. Karatas H. Migraine and neuroinflammation: The inflammasome perspective. J. Headache Pain 2021 22 1 55 10.1186/s10194‑021‑01271‑1 34112082
    [Google Scholar]
  11. Thuraiaiyah J. Erritzøe-Jervild M. Al-Khazali H.M. Schytz H.W. Younis S. The role of cytokines in migraine: A systematic review. Cephalalgia 2022 42 14 1565 1588 10.1177/03331024221118924 35962530
    [Google Scholar]
  12. Li R. Han J. Shao G. Liu C. Li S. Wang M. Yang D. Causality between multiple autoimmune disorders and migraine and its subtypes: A two-sample Mendelian randomization study. Front. Neurol. 2024 15 1420201 10.3389/fneur.2024.1420201 39087012
    [Google Scholar]
  13. Musubire A.K. Cheema S. Ray J.C. Hutton E.J. Matharu M. Cytokines in primary headache disorders: A systematic review and meta-analysis. J. Headache Pain 2023 24 1 36 10.1186/s10194‑023‑01572‑7 37016284
    [Google Scholar]
  14. Davies N.M. Holmes M.V. Davey Smith G. Reading Mendelian randomisation studies: A guide, glossary, and checklist for clinicians. BMJ 2018 362 k601 10.1136/bmj.k601 30002074
    [Google Scholar]
  15. Lin S.C. Lin S.H. Ge T. Chen C.Y. Lin Y.F. Causal mediation analysis: A summary‐data mendelian randomization approach. Stat. Med. 2025 44 5 10317 10.1002/sim.10317 39910926
    [Google Scholar]
  16. Sekula P. Del Greco M.F. Pattaro C. Köttgen A. Mendelian randomization as an approach to assess causality using observational data. J. Am. Soc. Nephrol. 2016 27 11 3253 3265 10.1681/ASN.2016010098 27486138
    [Google Scholar]
  17. Au Yeung S.L. Gill D. Standardizing the reporting of Mendelian randomization studies. BMC Med. 2023 21 1 187 10.1186/s12916‑023‑02894‑8 37198682
    [Google Scholar]
  18. Liu B. Lyu L. Zhou W. Song J. Ye D. Mao Y. Chen G.B. Sun X. Associations of the circulating levels of cytokines with risk of amyotrophic lateral sclerosis: A Mendelian randomization study. BMC Med. 2023 21 1 39 10.1186/s12916‑023‑02736‑7 36737740
    [Google Scholar]
  19. Zheng T. Zeng N. Li G. Lin S. Yu B. Yuan J. Duan S. Wang G. Liu Z. Causal relationship between primary headache mediated by circulating cytokines and cerebral cortex structure: A mediation Mendelian randomization study. Cereb. Cortex 2024 34 9 bhae349 10.1093/cercor/bhae349 39264754
    [Google Scholar]
  20. Ottensmann L. Tabassum R. Ruotsalainen S.E. Gerl M.J. Klose C. Widén E. Simons K. Ripatti S. Pirinen M. Genome-wide association analysis of plasma lipidome identifies 495 genetic associations. Nat. Commun. 2023 14 1 6934 10.1038/s41467‑023‑42532‑8 37907536
    [Google Scholar]
  21. Zhao J.H. Stacey D. Eriksson N. Macdonald-Dunlop E. Hedman Å.K. Kalnapenkis A. Enroth S. Cozzetto D. Digby-Bell J. Marten J. Folkersen L. Herder C. Jonsson L. Bergen S.E. Gieger C. Needham E.J. Surendran P. Metspalu A. Milani L. Mägi R. Nelis M. Hudjašov G. Paul D.S. Polasek O. Thorand B. Grallert H. Roden M. Võsa U. Esko T. Hayward C. Johansson Å. Gyllensten U. Powell N. Hansson O. Mattsson-Carlgren N. Joshi P.K. Danesh J. Padyukov L. Klareskog L. Landén M. Wilson J.F. Siegbahn A. Wallentin L. Mälarstig A. Butterworth A.S. Peters J.E. Genetics of circulating inflammatory proteins identifies drivers of immune-mediated disease risk and therapeutic targets. Nat. Immunol. 2023 24 9 1540 1551 10.1038/s41590‑023‑01588‑w 37563310
    [Google Scholar]
  22. Li J. Tang M. Gao X. Tian S. Liu W. Mendelian randomization analyses explore the relationship between cathepsins and lung cancer. Commun. Biol. 2023 6 1 1019 10.1038/s42003‑023‑05408‑7 37805623
    [Google Scholar]
  23. Martin L. Boutwell B.B. Messerlian C. Adams C.D. Mendelian randomization reveals apolipoprotein B shortens healthspan and possibly increases risk for Alzheimer’s disease. Commun. Biol. 2024 7 1 230 10.1038/s42003‑024‑05887‑2 38402277
    [Google Scholar]
  24. Ji D. Chen W.Z. Zhang L. Zhang Z.H. Chen L.J. Gut microbiota, circulating cytokines and dementia: A Mendelian randomization study. J. Neuroinflammation 2024 21 1 2 10.1186/s12974‑023‑02999‑0 38178103
    [Google Scholar]
  25. Hartwig F.P. Davies N.M. Hemani G. Davey Smith G. Two-sample Mendelian randomization: Avoiding the downsides of a powerful, widely applicable but potentially fallible technique. Int. J. Epidemiol. 2016 45 6 1717 1726 10.1093/ije/dyx028 28338968
    [Google Scholar]
  26. Boehm F.J. Zhou X. Statistical methods for Mendelian randomization in genome-wide association studies: A review. Comput. Struct. Biotechnol. J. 2022 20 2338 2351 10.1016/j.csbj.2022.05.015 35615025
    [Google Scholar]
  27. Greco M. F.D.; Minelli, C.; Sheehan, N.A.; Thompson, J.R. Detecting pleiotropy in Mendelian randomisation studies with summary data and a continuous outcome. Stat. Med. 2015 34 21 2926 2940 10.1002/sim.6522 25950993
    [Google Scholar]
  28. Bowden J. Davey Smith G. Burgess S. Mendelian randomization with invalid instruments: Effect estimation and bias detection through Egger regression. Int. J. Epidemiol. 2015 44 2 512 525 10.1093/ije/dyv080 26050253
    [Google Scholar]
  29. Yamanaka G. Hayashi K. Morishita N. Takeshita M. Ishii C. Suzuki S. Ishimine R. Kasuga A. Nakazawa H. Takamatsu T. Watanabe Y. Morichi S. Ishida Y. Yamazaki T. Go S. Experimental and clinical investigation of cytokines in migraine: A narrative review. Int. J. Mol. Sci. 2023 24 9 8343 10.3390/ijms24098343 37176049
    [Google Scholar]
  30. Sun H. Lv X. Zhang D. Shen Y. Lu H. The 1400 metabolite‐mediated relationship between 91 inflammatory cytokines and migraine: An exploratory two‐step Mendelian randomization study. Eur. J. Clin. Invest. 2024 54 12 14316 10.1111/eci.14316 39279254
    [Google Scholar]
  31. Velasco-de Andrés M. Casadó-Llombart S. Català C. Leyton-Pereira A. Lozano F. Aranda F. Soluble CD5 and CD6: Lymphocytic class I scavenger receptors as immunotherapeutic agents. Cells 2020 9 12 2589 10.3390/cells9122589 33287301
    [Google Scholar]
  32. Consuegra-Fernández M. Lin F. Fox D.A. Lozano F. Clinical and experimental evidence for targeting CD6 in immune-based disorders. Autoimmun. Rev. 2018 17 5 493 503 10.1016/j.autrev.2017.12.004 29526637
    [Google Scholar]
  33. Mix E. Olsson T. Correale J. Baig S. Kostulas V. Olsson O. Link H. B cells expressing CD5 are increased in cerebrospinal fluidof patients with multiple sclerosis. Clin. Exp. Immunol. 2008 79 1 21 27 10.1111/j.1365‑2249.1990.tb05121.x 1689227
    [Google Scholar]
  34. Huang J. Khademi M. Fugger L. Lindhe Ö. Novakova L. Axelsson M. Malmeström C. Constantinescu C. Lycke J. Piehl F. Olsson T. Kockum I. Inflammation-related plasma and CSF biomarkers for multiple sclerosis. Proc. Natl. Acad. Sci. USA 2020 117 23 12952 12960 10.1073/pnas.1912839117 32457139
    [Google Scholar]
  35. Kofler D.M. Farkas A. von Bergwelt-Baildon M. Hafler D.A. The link between CD6 and autoimmunity: Genetic and cellular associations. Curr. Drug Targets 2016 17 6 651 665 10.2174/1389450117666160201105934 26844569
    [Google Scholar]
  36. Li Y. Singer N.G. Whitbred J. Bowen M.A. Fox D.A. Lin F. CD6 as a potential target for treating multiple sclerosis. Proc. Natl. Acad. Sci. USA 2017 114 10 2687 2692 10.1073/pnas.1615253114 28209777
    [Google Scholar]
  37. Biscetti L. De Vanna G. Cresta E. Bellotti A. Corbelli I. Letizia Cupini M. Calabresi P. Sarchielli P. Immunological findings in patients with migraine and other primary headaches: A narrative review. Clin. Exp. Immunol. 2022 207 1 11 26 10.1093/cei/uxab025 35020858
    [Google Scholar]
  38. Chapman N.M. Chi H. Metabolic adaptation of lymphocytes in immunity and disease. Immunity 2022 55 1 14 30 10.1016/j.immuni.2021.12.012 35021054
    [Google Scholar]
  39. Lim S.A. Su W. Chapman N.M. Chi H. Lipid metabolism in T cell signaling and function. Nat. Chem. Biol. 2022 18 5 470 481 10.1038/s41589‑022‑01017‑3 35484263
    [Google Scholar]
  40. Liu M.K. Cheng L.L. Yi H.M. He Y. Li X. Fu D. Dai Y.T. Fang H. Cheng S. Xu P.P. Qian Y. Feng Y. Liu Q. Wang L. Zhao W.L. Enhanced lipid metabolism confers the immunosuppressive tumor microenvironment in CD5-positive non-MYC/BCL2 double expressor lymphoma. Front. Oncol. 2022 12 885011 10.3389/fonc.2022.885011 36276140
    [Google Scholar]
  41. Liampas I. Mylonas K.S. Brotis A. Dervenis P. Serum lipid abnormalities in migraine: A meta-analysis of observational studies. Headache 2021 61 1 44 59 10.1111/head.14039
    [Google Scholar]
  42. Hong P. Han L. Wan Y. Mendelian randomization study of lipid metabolism characteristics and migraine risk. Eur. J. Pain 2024 28 6 978 986 10.1002/ejp.2235 38183343
    [Google Scholar]
  43. van der Veen J.N. Kennelly J.P. Wan S. Vance J.E. Vance D.E. Jacobs R.L. The critical role of phosphatidylcholine and phosphatidylethanolamine metabolism in health and disease. Biochim. Biophys. Acta Biomembr. 2017 1859 9 1558 1572 10.1016/j.bbamem.2017.04.006 28411170
    [Google Scholar]
  44. Treede I. Braun A. Sparla R. Kühnel M. Giese T. Turner J.R. Anes E. Kulaksiz H. Füllekrug J. Stremmel W. Griffiths G. Ehehalt R. Anti-inflammatory effects of phosphatidylcholine. J. Biol. Chem. 2007 282 37 27155 27164 10.1074/jbc.M704408200 17636253
    [Google Scholar]
  45. Hui L. Wu Y. Jiang S. Plasma metabonomic analysis of migraine in rats. Chin J. Clin. Res. 2016 29 1716 1719 10.13429/j.cnki.cjcr.2016.12.040
    [Google Scholar]
  46. Cantley L.C. The phosphoinositide 3-kinase pathway. Science 2002 296 5573 1655 1657 10.1126/science.296.5573.1655 12040186
    [Google Scholar]
  47. Zhang W. Lei M. Wen Q. Zhang D. Qin G. Zhou J. Chen L. Dopamine receptor D2 regulates GLUA1-containing AMPA receptor trafficking and central sensitization through the PI3K signaling pathway in a male rat model of chronic migraine. J. Headache Pain 2022 23 1 98 10.1186/s10194‑022‑01469‑x 35948867
    [Google Scholar]
  48. Hose M. Günther A. Naser E. Schumacher F. Schönberger T. Falkenstein J. Papadamakis A. Kleuser B. Becker K.A. Gulbins E. Haimovitz-Friedman A. Buer J. Westendorf A.M. Hansen W. Cell-intrinsic ceramides determine T cell function during melanoma progression. eLife 2022 11 83073 10.7554/eLife.83073 36426850
    [Google Scholar]
  49. Adada M. Luberto C. Canals D. Inhibitors of the sphingomyelin cycle: Sphingomyelin synthases and sphingomyelinases. Chem. Phys. Lipids 2016 197 45 59 10.1016/j.chemphyslip.2015.07.008 26200918
    [Google Scholar]
  50. Cartier A. Hla T. Sphingosine 1-phosphate: Lipid signaling in pathology and therapy. Science 2019 366 6463 eaar5551 10.1126/science.aar5551 31624181
    [Google Scholar]
  51. Mielke M.M. Bandaru V.V.R. Haughey N.J. Xia J. Fried L.P. Yasar S. Albert M. Varma V. Harris G. Schneider E.B. Rabins P.V. Bandeen-Roche K. Lyketsos C.G. Carlson M.C. Serum ceramides increase the risk of Alzheimer disease. Neurology 2012 79 7 633 641 10.1212/WNL.0b013e318264e380 22815558
    [Google Scholar]
  52. Peterlin B.L. Mielke M.M. Dickens A.M. Chatterjee S. Dash P. Alexander G. Vieira R.V.A. Bandaru V.V.R. Dorskind J.M. Tietjen G.E. Haughey N.H. Interictal, circulating sphingolipids in women with episodic migraine. Neurology 2015 85 14 1214 1223 10.1212/WNL.0000000000002004 26354990
    [Google Scholar]
/content/journals/cchts/10.2174/0113862073386181251001071432
Loading
/content/journals/cchts/10.2174/0113862073386181251001071432
Loading

Data & Media loading...


  • Article Type:
    Research Article
Keywords: mediation mendelian randomization study ; migraine ; CD6 ; cytokine ; CD5 ; plasma lipids
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test