Group name: Genetics of Complex Diseases

    Group leader
  • Marta Alarcón Riquelme
  • Senior Researcher
  • María Morell Hita
  • Concepción Marañón Lizana
  • Postdoctorals
  • Guillermo Barturen Briñas
  • María Teruel Artacho
  • Manuel Martínez Bueno
  • Ina Georg
  • PHD Students
  • Daniel Toro Domínguez
  • Paulina Rybakowska
  • Technicians
  • Nieves Varela Hernández
  • Project Coordinator
  • Tania Gomes Anjos

Presentation Video


In recent years science has experienced an explosion in the number of genetic findings, due to the advance of faster, more efficient and lower cost new genotyping and sequencing technologies. Through expression studies it has been found that the level of expression of many genes is altered in comparison with healthy subjects. Fine mapping techniques and genetic association studies can inquire about what genes, and more specifically what changes within a gene, are related to the disease. Although the human genome is essentially the same among individuals, every human being is unique based on their SNPs (single nucleotide polymorphisms). New methods of genomic DNA sequencing have allowed to discover the genotypic differences among individuals, and according to "the 1000 Genomes Project", it is estimated that there are around 15 million SNPs in the human genome. SNPs, as well as other genetic variants, are associated with the predisposition to certain complex diseases, which are influenced by intrincate interactions among multiple genes and between these and environmental factors. Complex diseases are those in which susceptibility genes interact with the environment in a manner still unknown, resulting in the clinical expression of the disease. It has been identified the main genes responsible for several of these complex diseases such as systemic lupus erythematosus, rheumatoid arthritis, Crohn's disease, etc. In the identification of susceptibility genes to complex diseases, the bottleneck is not the technology available (very advanced and ever-progressing), but the sampling problem, in other words, to get a sufficient number of clinical samples properly characterized clinically


  • Study of the genetic basis of systemic lupus erythematosus (SLE): SLE is a complex autoimmune disease whose etiology is still unknown. It is characterized by inflammation and tissue damage mediated by the immune system. There is substantial evidence to argue that genetic factors in SLE are of great importance, and that combined with environmental factors interact in the development of the disease.

    SLE has a strong genetic component: more than 8% of women with SLE have a first or second degree relative who also suffers from the disease. The first published genetic association studies were about diseases treated with a genetic component much smaller than that of SLE (e.g. diabetes mellitus type 1 and type 2), or in which the prevalence of the disease in the population was higher (as in rheumatoid arthritis). In studies of patients with SLE families, particularly in monozygotic twins, it is revealed a higher incidence than that expected only by chance. That is, it is described a significant familial aggregation, where over 10% of patients has an affected relative.

    The first identified genetic association to SLE was found in the genes of human leukocyte antigen (HLA) and briefly, also in 2 or 3 haplotypes that included widespread complement genes and the class III region. These haplotypes were identified and were subsequently confirmed in European populations. Most previous studies of candidate genes associated with lupus have been based on biological hypotheses. A notable example of a family of genes identified in this way is the receptor cluster FCG. Moreover, the recent identification of gene “interferon regulatory factor 5” (IRF5) was the result of a biological hypothesis on the role of type I interferon pathway.

    We have identified the first gene for SLE, called PDCD1, as the gene that contributes to the linkage on chromosome 2q37, this gene encodes the immunoreceptor PD-1. We identified a susceptibility variant in the fourth intron of PDCD1 affecting the transcription of this gene through the deletion of a site for RUNX1 muffler. In addition, we found that this variant implicated in susceptibility is also involved in rheumatoid arthritis in two populations, is highly expressed in Sjögren syndrome and particularly important in lupus renal disease. Also, it has been found a relationship with myocardial infarction. In SLE, the identification of susceptibility genes has been more likely than in the case of rheumatoid arthritis. We also identified BANK1 as a candidate gene, which encodes a molecule scaffold, which participates in the movement of other molecules within the cell cytoplasm, and defines its location within the cell.

    The aim of our research is to describe new genetic associations that will be confirmed in new groups of patients and healthy controls, and fine mapping of specific gene regions to identify functional polymorphisms and their effects on function and gene expression. We also intend to identify interactions between genes and their effect on the genetic contribution of the disease. This last point is important to clarify new pathways of disease pathogenesis and lead to the identification of new pathogenic mechanisms of SLE, which will enable the potential development of new therapies against this disease.

    Study of the molecular basis of other diseases: The human DNA variability area has as an objective to study diseases important at the level of the Andalusian health system. As so, we are initiating projects in collaboration with established consortia such as the DRECA, a longitudinal study analyzing the advent of cardiovascular complications in the Andalusian population. In this study, genes will be analyzed as to their role to predict the development of such complications, including also diabetes and obesity.
  • Other projects are the analysis of genes for autoimmune diseases in Meniere disease or hypoacusia, as well as in the primary antiphospholipid syndrome.
    Any complex disease can result from a combination of mutations inherited in more than one gene as well as exposure to environmental factors, which together modulate susceptibility, severity and clinical manifestations of the disease. In other words, it is not absolutely necessary or sufficient for a single mutation to cause a particular complex disease, but rather individual mutations could trigger a particular disease only in a given genetic background (with other mutations present) or after exposure to certain environmental factors such as infections, drugs, pollutants, UV radiation, etc


  • The SOLiD™ System: Next-Generation Sequencing from Applied Biosystems
  • The iScan System from Illumina Real
  • Time PCR System (Applied Biosystems 7900 and 7500).
  • Confocal microscopy


  • European Science Foundation financiada por fondos de FMR (Austria), FNRS (Bélgica), FWO (Bélgica), RPF (Chipre), Danish Medical Research Council, DFG (Alemania), FCT (Portugal), CSIC (España), MICINN (España), Swedish Research Council, SNF (Suiza), MRC (Reino Unido). (2009-2014)
  • Instituto de Salud Carlos III (FIS, Miguel Servet, Rio Hortega and Sara Borrell programs) (2009-actualidad)
  • Swedish Research Council (2009-2013)
  • Fundación Ramón Areces (2011-2015)
  • Innovative Medicines Initiative Program of the European Unión (2014-2018): special funding of the project PRECISESADS


Prokunina, L., Castillejo-López, C., Öberg, F., Gunnarsson, I., Berg,L., Magnusson, V., Brookes, A.J., Tentler, D., Kristjansdottir, H., Gröndal, G., Bolstad, A.I., Svenungsson, E., Lundberg, I., Sturfelt, G., Jönssen, A., Truedsson, L., Lima, G., Alcocer-Varela, J., Jonsson, R.,Gyllensten, U., Harley, J.B., Alarcón-Segovia, D., Steinsson K., and Alarcón-Riquelme, M.E. A regulatory polymorphism within the PDCD1gene is associated with susceptibility to systemic lupus erythematosus in humans. Nat Genetics 32:666-669, 2002.

Graham, R.R., Kozyrev, S.V., Baechler, E.C., Linga Reddy, P.M.V., Plenge, R.M., Bauer, J.W., Ortmann, W.A., Koeuth, T., Gonzalez-Escribano, M.F., Pons-Estel,B., Petri, M., Daly, M., Gregersen, P.K., Martin, J., Altshuler, D., Behrens, T.W., and Alarcón-Riquelme, M.E. A Common Haplotype of Interferon Regulatory Factor 5 (IRF5) Regulates Splicing and Expression and is Associated with Increased Risk of Systemic Lupus Erythematosus. Nat Genetics 38(5):550-5, 2006.

SLEGEN* (*Members: John B. Harley, Carl D. Langefeld, Marta E. Alarcón-Riquelme, Lindsey A. Criswell, Chaim O. Jacob, Robert P. Kimberly, Kathy L. Moser, Betty P. Tsao and Timothy J. Vyse). A genome wide association scan in women with systemic lupus erythematosus (SLE) identifies ITGAM, PXK, KIAA1542 and rs10798268 and other loci. Nat Genet 40(2):204-10, 2008.

Kozyrev, S.V., Abelson, A.K., Wojcik, J., Zaghlool, A., Linga Reddy, P.M.V., Sanchez, E., Yin, H., Gunnarsson, I., Svenungsson, E., Sturfelt, G., Jönsen, A., Truedsson, L., Pons-Estel, B., Witte, T., D’Alfonso, S., Momigliano-Richiardi, P., Danieli, M.G., Gutierrez, C., Suárez, A., Junker, P., Laustrup, H., González-Escribano, M.F., Martin, J., Abderrahim, H., and Alarcón-Riquelme, M.E. The B Cell Gene BANK1 is Associated with Systemic Lupus Erythematosus Through the Effect of Several Functional Variants. Nat Genet 40(2):211-6, 2008.

Delgado-Vega, A.M., Dozmorov, M.G., Bernal Quirós, M., Wu, Y.Y., Martínez-García, B., Frostegård, J., Truedsson, L., De Ramón, E., González-Escribano, M.F., Ortego-Centeno, N., Pons-Estel, B.A., D’Alfonso, S., Sebastiani, G.D., Witte, T., Lauwerys, B.R., Endreffy, E., Kovacs, L., Vasconcelos, C., Martins Da Silva, B., Wren, J.D., Martin, J., Castillejo-López, C., and Alarcón-Riquelme, M.E. Fine Mapping and Conditional Analysis Identify a New Mutation in the Autoimmunity Susceptibility Gene BLK that Leads to Reduced Half-Life of the BLK Protein. Ann Rheum Dis 71(7):1219-26, 2012.

Sánchez E, Rasmussen A, Riba L, Acevedo E, Kelly JA, Langefeld CD, García-De La Torre I, Maradiaga-Ceceña MA, Cardiel MH, Esquivel-Valerio JA, Rodriguez-Amado J, Moctezuma JF, Miranda P, Perandones C, Castel C, Laborde HA, Alba P, Musuruana J, Goecke A, Anaya JM, Kaufman KM, Adler A, Brown EE, Alarcón GS, Kimberly RP, Edberg JC, Criswell LA, Gilkeson GS, Niewold TB, Martin J, Vyse TJ, Ramsey-Goldman R, Petri M, Merrill JT, Reveille JD, Tsao BP, Orozco L, Baca V, James JA, Harley JB, Tusié-Luna T, Pons-Estel BA, Jacob CO, Alarcón-Riquelme ME. Impact of genetic ancestry and socio-demographic status on the clinical expression of systemic lupus erythematosus in Amerindian-European populations. Arthritis Rheum 64(11):3687-94, 2012

López Herráez D, Martínez-Bueno M, Riba L, García de la Torre I, Sacnún M, Goñi M, Berbotto G, Paira S, Musuruana JL, Graf C, Alvarellos A, Messina OD, Babini A, Strusberg I, Marcos JC, Scherbarth H, Spindler A, Quinteros A, Toloza S, Moreno JLC, Catoggio LJ, Tate G, Eimon A, Citera G, Catalán Pellet A, Nasswetter G, Cardiel MH, Miranda P, Ballesteros F, Esquivel-Valerio JA, Maradiaga-Ceceña MA, Acevedo-Vásquez EM, García García C, GENAR, Tusié-Luna T, Pons-Estel BA, and Alarcón-Riquelme ME. Rheumatoid Arthritis in Latin Americans Enriched for Amerindian Ancestry is Associated with Loci in Chromosomes 1, 12, 13, and HLA Class II Region. Arthritis Rheum 65(6):1457-67, 2013.

Bernal-Quirós M, Wu, YY, Alarcón-Riquelme ME, and Castillejo-López C. BANK1 and BLK act through phospholipase C gamma 2 in B-cell signaling. 2013. PlosOne 01/2013 8(3):e59842.

Wu, Y.Y., Kumar, R., Haque, S.M., Castillejo-López, C., and Alarcón-Riquelme, M.E. BANK1 Controls CpG-induced IL-6 Secretion Via a p38 and MNK1/2-eIF4E Translation Initiation Pathway. J Immunol (In Press).

Dozmorov, M.G., Wren, J.D., and Alarcón-Riquelme, M.E. Epigenomic Elements Enriched in the Promoters of Autoimmunity Susceptibility Genes. Epigenetics Nov 8;9(2), 2013.


Título: Interacting Genes of BANK1
Autores (1er Apellido, Iniciales): Castillejo C, Delgado A, Alarcón M, Wojcik J
Solicitante: Merck Serono S.A.
Fecha Prioridad: 19/01/2012

Título: Un Método para la detección de la Interacción entre BANK1 y PLCG2 en la señalización celular
Autores (1er Apellido, Iniciales): Castillejo C, Bernal, M. Alarcón M
Solicitante: Consejería de Salud de Andalucía


International Collaborations: We have a large number of clinical samples to identify the genetic basis of these diseases in multiple populations, and our group participates in numerous collaborative projects with many other centers. Specifically, GENLES and GENAR, projects in Latin America. Our group is also a member of SLEGEN Consortium, funded by the Alliance for Lupus Research: and coordinates BIOLUPUS, the European consortium that works towards understanding of the SLE genetics and its translation to the clinic: Dr Alarcón-Riquelme heads the Managing Entity of the IMI funded project PRECISESADS, on the “Molecular Re-classification of Systemic Autoimmune Diseases” which joins 21 European academic groups, 2 SMEs and 5 Big Pharma.