Identification of Genetic Susceptibility Factors for Fibromyalgia / Identificació de factors de susceptibilitat genètica per a fibromiàlgia

• Autores: Elisa Docampo Martínez
• Directores de la Tesis: Xavier Estivill Palleja (dir. tes.), Daniel Grinberg Vaisman (dir. tes.), Raquel Rabionet (dir. tes.)
• Lectura: En la Universitat de Barcelona ( España ) en 2013
• Idioma: inglés
• Tribunal Calificador de la Tesis: Josep Blanch Rubió (presid.), Bru Cormand Rifa (secret.), Lauro Sumoy Van Dyck (voc.)
• Materias:
  • Ciencias de la vida
    • Genética
    • Biología molecular
    • Biología vegetal (botánica)
  • Ciencias médicas
    • Medicina interna
      • Reumatología
• Enlaces
  • Tesis en acceso abierto en:  TDX  Dipòsit Digital de la UB 
• Resumen

  • Fibromyalgia (FM) is a highly disabling syndrome defined by a low pain threshold and a permanent state of pain. Widespread pain is accompanied by a constellation of symptoms such as fatigue, sleep disturbances and cognitive impairment, among others. The mechanisms explaining this chronic pain remain unclear. Nowadays, the most established/ plausible hypothesis underlying FM ethiopathogenesis is the existence of a dysfunction in pain processing, as supported by alterations in neuroimaging and neurotransmitters levels. The etiology of FM involves the interaction of environmental and genetic susceptibility factors. The genetic contribution to FM has been proven by the presence of a higher concordance of monozygotic than dizygotic twins as well as family aggregation. However, the individual genetic and environmental factors involved have not been identified. The aim of this thesis was to elucidate genetic susceptibility factors for fibromyalgia. We assessed this objective through three main approaches: the identification of FM clinically homogeneous subgroups with a two step cluster analyses, a genome-wide association study in order to evaluate the possible contribution of single nucleotide polymorphisms with Illumina 1 million duo array, and array comparative genomic hybridization experiments to identify regions varying in copy number that could be involved in FM susceptibility,using Agilent 2X400K platform. 48 variables were evaluated in 1,446 Spanish FM cases fulfilling 1990 ACR FM criteria. A partitioning analysis was performed to find groups of variables similar to each other. Variables clustered into three independent dimensions: “symptomatology”, “comorbidities” and “clinical scales”. Only the two first dimensions were considered for the construction of FM subgroups, classifying FM samples into three subgroups: low symptomatology and comorbidities (Cluster 1), high symptomatology and comorbidities (Cluster 2), and high symptomatology but low comorbidities (Cluster 3). These subgroups showed differences in measures of disease severity and were further implemented in genetic analysis. Genome-wide association study was performed in 300 FM cases and 203 controls. No SNP reached GWAS association threshold, but 21 of the most associated SNPs were chosen for replication in over 900 cases and 900 pain free-controls. Four of the strongest associated SNPs selected for replication showed a nominal association in the joint analysis. In particular, rs11127292 (MYT1L) was found to be associated to FM with low comorbidities. Array comparative genomic hybridization detected 5 differentially hybridized regions. They were followed up and one of these regions was validated though a multiplex PCR experiment. An intronic deletion in NRXN3 showed to be associated to female cases of FM and in particular those with low levels of comorbidities. Replication analysis showed a stronger association when considering only female cases and controls and low comorbidities. This enhance the importance of gender in FM etiopathogenesis and could be pointing to the existence of a different genetic background for FM in males and females highlights the importance of identifying FM homogeneous subgroups for the detection of FM genetic susceptibility factors. If the proposed FM candidate genes are further validated in replication studies, this would constitute a change in the FM ethiologycal concept, as several of these candidates are known neuropsychiatric disease associated genes (autism, addiction, mental disability). This would highlight a novel neurocognitive involvement in this disorder, currently considered musculoskeletal and affective.