{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,2]],"date-time":"2025-11-02T04:48:46Z","timestamp":1762058926308,"version":"build-2065373602"},"reference-count":28,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2022,7,19]],"date-time":"2022-07-19T00:00:00Z","timestamp":1658188800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004587","name":"ISCIII and European Regional Development Fund (ERDF)","doi-asserted-by":"publisher","award":["PI16\/01259","PI20\/01634","FPU20\/03387"],"award-info":[{"award-number":["PI16\/01259","PI20\/01634","FPU20\/03387"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004837","name":"Ministerio de Ciencia e Innovaci\u00f3n","doi-asserted-by":"publisher","award":["PI16\/01259","PI20\/01634","FPU20\/03387"],"award-info":[{"award-number":["PI16\/01259","PI20\/01634","FPU20\/03387"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>One of the multiple sclerosis (MS) risk polymorphisms, rs7923837, maps near the HHEX (hematopoietically-expressed homeobox) gene. This variant has also been associated with type 2 diabetes susceptibility and with triglyceride levels, suggesting its metabolic involvement. HHEX plays a relevant role as a negative regulator of inflammatory genes in microglia. A reciprocal repression was reported between HHEX and BCL6, another putative risk factor in MS. The present study evidenced statistically significant lower HHEX mRNA levels in lymphocytes of MS patients compared to those of controls, showing a similar trend in MS patients to the already described eQTL effect in blood from healthy individuals. Even though no differences were found in protein expression according to HHEX genotypes, statistically significant divergent subcellular distributions of HHEX appeared in patients and controls. The epistatic interaction detected between BCL6 and HHEX MS-risk variants in healthy individuals was absent in patients, indicative of a perturbed reciprocal regulation in the latter. Lymphocytes from MS carriers of the homozygous mutant genotype exhibited a distinctive, more energetic profile, both in resting and activated conditions, and significantly increased glycolytic rates in resting conditions when compared to controls sharing the HHEX genotype. In contrast, significantly higher mitochondrial mass was evidenced in homozygous mutant controls.<\/jats:p>","DOI":"10.3390\/ijms23147956","type":"journal-article","created":{"date-parts":[[2022,7,19]],"date-time":"2022-07-19T08:28:25Z","timestamp":1658219305000},"page":"7956","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Unraveling the Influence of HHEX Risk Polymorphism rs7923837 on Multiple Sclerosis Pathogenesis"],"prefix":"10.3390","volume":"23","author":[{"given":"Adela","family":"Gonz\u00e1lez-Jim\u00e9nez","sequence":"first","affiliation":[{"name":"Laboratorio de Gen\u00e9tica de Enfermedades Complejas, Instituto de Investigaci\u00f3n Sanitaria del Hospital Cl\u00ednico San Carlos (IdISSC), 28040 Madrid, Spain"},{"name":"Redes de Investigaci\u00f3n Cooperativa Orientada a Resultados en Salud (RICORS), 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pilar","family":"L\u00f3pez-Cotarelo","sequence":"additional","affiliation":[{"name":"Laboratorio de Gen\u00e9tica de Enfermedades Complejas, Instituto de Investigaci\u00f3n Sanitaria del Hospital Cl\u00ednico San Carlos (IdISSC), 28040 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Teresa","family":"Agudo-Jim\u00e9nez","sequence":"additional","affiliation":[{"name":"Laboratorio de Gen\u00e9tica de Enfermedades Complejas, Instituto de Investigaci\u00f3n Sanitaria del Hospital Cl\u00ednico San Carlos (IdISSC), 28040 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marisa","family":"Mart\u00ednez-Gin\u00e9s","sequence":"additional","affiliation":[{"name":"Servicio de Neurolog\u00eda, Hospital General Universitario Gregorio Mara\u00f1\u00f3n, 28007 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5205-3652","authenticated-orcid":false,"given":"Jose Manuel","family":"Garc\u00eda-Dom\u00ednguez","sequence":"additional","affiliation":[{"name":"Servicio de Neurolog\u00eda, Hospital General Universitario Gregorio Mara\u00f1\u00f3n, 28007 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elena","family":"Urcelay","sequence":"additional","affiliation":[{"name":"Laboratorio de Gen\u00e9tica de Enfermedades Complejas, Instituto de Investigaci\u00f3n Sanitaria del Hospital Cl\u00ednico San Carlos (IdISSC), 28040 Madrid, Spain"},{"name":"Redes de Investigaci\u00f3n Cooperativa Orientada a Resultados en Salud (RICORS), 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"Espino-Pais\u00e1n","sequence":"additional","affiliation":[{"name":"Laboratorio de Gen\u00e9tica de Enfermedades Complejas, Instituto de Investigaci\u00f3n Sanitaria del Hospital Cl\u00ednico San Carlos (IdISSC), 28040 Madrid, Spain"},{"name":"Redes de Investigaci\u00f3n Cooperativa Orientada a Resultados en Salud (RICORS), 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1056\/NEJMra1401483","article-title":"Multiple Sclerosis","volume":"378","author":"Reich","year":"2018","journal-title":"N. 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