LogoCab
LogoIPBLN
Instituto de Parasitología y Biomedicina
"López - Neyra"
Logotipo del Consejo Superior de Investigaciones Científicas
Imagen de Santiago Ramon y Cajal

Non-additive and interaction effects within HLA loci modulate the risk of autoimmune diseases


Genetic variation within the HLA region (human leukocyte antigen), which encodes the antigen-presenting molecules of the adaptive immune system, represents the main risk factor for most autoimmune diseases, explaining a substantial proportion of their genetic component. In recent years, high throughput genotyping studies have define very precisely the specific HLA alleles influencing different autoimmune diseases. Traditionally, it has been considered that the association between certain HLA alleles and these pathologies fits an additive genetic model, under which, for a given allele, the disease risk of heterozygotes in comparison to non-carriers of the allele should be half that of homozygotes. However, a study recently published in "Nature Genetics", conducted in collaboration with a research group from the Institute of Parasitology and Biomedicine López-Neyra (IPBLN), led by Professor Javier Martin, has revealed the existence of a non-additive component for four autoimmune diseases, specifically, rheumatoid arthritis (RA), celiac disease (CD), type I diabetes (T1D) and psoriasis. Through bioinformatic analyses was shown that, for most alleles, heterozygosity confers a higher risk of autoimmunity than expected from homozygote disease risk, which is called dominance effect. Further analyses revealed that, for RA, CD and T1D, these non-additive dominance effects were at least partially explained by interactions between HLA alleles, that is the disease risk of a specific genotype combination of two alleles deviates from the disease risk expected from both alleles alone. The addition of dominance and interaction terms to the model explained significant fractions of phenotypic variance beyond a simple additive model.

 

 

Imagen

 

Figure 1. Phenotypic variance explained by the additive, dominance and interaction effects of HLA alleles for each disease.

 

 

 

This study, conducted thanks to the collaboration of numerous research centers worldwide, represents a breakthrough in understanding the role of HLA molecules in the pathogenesis of autoimmune diseases, demonstrating that their pathogenic role seems to be mediated through their ability to self-antigens presentation. Because both alleles at a given HLA locus are expressed, heterozygous genotypes might confer expanded antigen-binding properties, which may lead to increased presentation of self-components and, consequently, a higher risk of developing autoimmunity.

 

Widespread non-additive and interaction effects within HLA loci modulate the risk of autoimmune diseases.

Lenz TL, Deutsch AJ, Han B, Hu X, Okada Y, Eyre S, Knapp M, Zhernakova A, Huizinga TW, Abecasis G, Becker J, Boeckxstaens GE, Chen WM, Franke A, Gladman DD, Gockel I, Gutierrez-Achury J, Martin J, Nair RP, Nöthen MM, Onengut-Gumuscu S, Rahman P, Rantapää-Dahlqvist S, Stuart PE, Tsoi LC, van Heel DA, Worthington J, Wouters MM, Klareskog L, Elder JT, Gregersen PK, Schumacher J, Rich SS, Wijmenga C, Sunyaev SR, de Bakker PI, Raychaudhuri S.

Nat Genet. 2015 Sep;47(9):1085-90. doi: 10.1038/ng.3379. Epub 2015 Aug 10.

Sede: Parque Tecnológico de Ciencias de la Salud, Avda. del Conocimiento, 17. 18016 Armilla (Granada)(ESPAÑA). TEL:+34 958181621. FAX:+34 958181633

world
    Resolución mínima: 1024 x 768   Navegadores:Internet Explorer 6.0 / Netscape 7.01 / Mozilla 1.3a / Opera 7.54   Imagen sustitutiva del texto de correo electrnico para webmasterarrobacsic.es