SUMMARY OF RESEARCH

Research line 1

Identification of causal genes (not only associated with) of Multiple Sclerosis (MS), relevance to disease, interaction with environmental factors. Although GWAS studies (Genome-Wide Association Studies) and candidate genes have identified about a hundred loci associated with MS, for most of them there are no functional evidence that are causal genes and variants. The identification of the causal variants and genes and disease-related dysfunction is essential for the establishment of molecular pathways and mechanisms of disease, for the rational design of therapies and diagnostic systems and prognostic step.

Research line 2

Genetic and molecular factors that affect vitamin D system in Multiple Sclerosis (MS). One of the environmental factors considered most important in the predisposition to MS is the deficiency of vitamin D (VitD), which is supported by the association to MS of CYP27B1 gene, for activation VitD, and CYP24A1, for degradation. The large number of genes regulating VitD along with its anti-inflammatory role, show the therapeutic and preventive potential impact this factor in MS and many other diseases. Vitamin D, after interaction with its receptor VDR, is a direct regulator of the expression of more than 300 genes, and indirectly affects more than 2000 genes. In this line of research is to identify variants that may affect the genes that are regulated by the VitD, their genetic-molecular mechanisms and the pathogenic relevance in MS. This information may be valuable not only for MS but for many other diseases for which we have demonstrated the involvement of vitamin D deficiency in both predisposition and severity of the pathology.

Metabolism and mechanism of action of Vitamin D. Vitamin D3 synthesized in the skin when the sun ultraviolet B radiation (UVB, wavelength 290?315 nm) interacts with 7-dehydroxycholesterol. Vitamin D3 is transported in the blood by the vitamin D binding protein (DBP known as GC) to the liver where is transformed to 25(OH)D, (calcifediol) by CYP2R1 (Jones, 2008). 25(OH)D, the major circulating form of vitamin D, is carried by the GC to the kidney. In the kidney, another cytochrome P450 enzyme, 1?-hydroxylase (CYP27B1), converts 25(OH)D to the biologically active form of vitamin D, 1,25-dihydroxy vitamin D (1,25(OH)2D) also called calcitriol (Omdahl, 2002; Holick, 2007). Calcitriol binds to VDR forming an heterodimer with RXR. These heterodimers bind to VDREs (vitamin D responsive DNA elements) and start regulating different genes expression (activation, suppression) (Bikle, 2010). CYP24A1 hydroxylase converts the active form of vitamin D to its inactive form. DHCR7, the 7-dehydrocholesterol reductase, converts 7-dehydrocholesterol to cholesterol, thereby reducing availability for vitamin D synthesis in the skin.

FUNDING AGENCIES LAST 5 YEARS

- GENES CAUSALES DE ESCLEROSIS MULTIPLE DE GWAS INTERNACIONAL DE NEURODEGENERACION. PROYECTO, PN2016 - PROY I+D - S. E. G. C. - P. EXCELENCIA, Ref: SAF2016-80595-C2-1-P, (2016 - 2020).

PUBLICATIONS LAST 5 YEARS

-Antonio Alcina; Maria Fedetz; Isabel Vidal-Cobo; Eduardo Andrés-León; Maria-Isabel García-Sánchez; Alicia Barroso-Del-Jesus; Sara Eichau; Elia Gil-Varea; Luisa-Maria Villar; Albert Saiz; Laura Leyva; Koen Vandenbroeck; David Otaegui; Guillermo Izquierdo; Manuel Comabella; Elena Urcelay; Fuencisla Matesanz, Identification of the genetic mechanism that associates L3MBTL3 to multiple sclerosis, Human Molecular Genetics, 2022, Vol. 31: 2155-2163, ARTÍCULO, Id:887580

-Gil-Varea E; Fedetz M; Eixarch H; Spataro N; Villar LM; Urcelay E; Saiz A; Fernández Ó; Leyva L; Ramió-Torrentà L; Vandenbroeck K; Otaegui D; Castillo-Triviño T; Izquierdo G; Malhotra S; Bosch E; Navarro A; Alcina A; Montalban X; Matesanz F; Comabella M., A New Risk Variant for Multiple Sclerosis at 11q23.3 Locus Is Associated with Expansion of CXCR5+ Circulating Regulatory T Cells, Journal of Clinical Medicine, 2020, Vol. 9: 6253-625, ARTÍCULO, Id:819279

-Vilariño-Güell, C.; Zimprich, A.; Martinelli-Boneschi, F.; Herculano, B.; Wang, Z.; Matesanz, F.; Urcelay, E.; Vandenbroeck, K.; Leyva, L.; Gris, D.; Massaad, C.; Quandt, J.A.; Traboulsee, A.L.; Encarnacion, M.; Bernales, C.Q.; Follett, J.; Yee, I.M.; Criscuoli, M.G.; Deutschländer, A.; Reinthaler, E.M.; Zrzavy, T.; Mascia, E.; Zauli, A.; Esposito, F.; Alcina, A.; Izquierdo, G.; Espino-Paisán, L.; Mena, J.; Antigüedad, A.; Urbaneja-Romero, P.; Ortega-Pinazo, J.; Song, W.; Sadovnick, A.D., Exome sequencing in multiple sclerosis families identifies 12 candidate genes and nominates biological pathways for the genesis of disease, PLoS Genetics, 2019, Vol. 15: , ARTÍCULO, Id:766650

-Pérez-Núñez, I.; Karaky, M.; Fedetz, M.; Barrionuevo, C.; Izquierdo, G.; Matesanz, F.; Alcina, A., Splice-site variant in ACSL5: a marker promoting opposing effect on cell viability and protein expression, European Journal of Human Genetics, 2019, Vol. : , ARTÍCULO, Id:763391

-Karaky, M.; Fedetz, M.; Potenciano, V.; Andrés-León, E.; Codina, A.E.; Barrionuevo, C.; Alcina, A.; Matesanz, F., SP140 regulates the expression of immune-related genes associated with multiple sclerosis and other autoimmune diseases by NF-κB inhibition, Human Molecular Genetics, 2018, Vol. 27: 4012-4023, ARTÍCULO, Id:735380

DOCTORAL THESES LAST 5 YEARS