RA patients with serum ACPA have a strong and specific genetic background. The objective of the s... more RA patients with serum ACPA have a strong and specific genetic background. The objective of the study was to identify new susceptibility genes for ACPA-positive RA using a genome-wide association approach. A total of 924 ACPA-positive RA patients with joint damage in hands and/or feet, and 1524 healthy controls were genotyped in 582 591 single-nucleotide polymorphisms (SNPs) in the discovery phase. In the validation phase, the most significant SNPs in the genome-wide association study representing new candidate loci for RA were tested in an independent cohort of 863 ACPA-positive patients with joint damage and 1152 healthy controls. All individuals from the discovery and validation cohorts were Caucasian and of Southern European ancestry. In the discovery phase, 60 loci not previously associated with RA risk showed evidence for association at P < 5×10(-4) and were tested for replication in the validation cohort. A total of 12 loci were replicated at the nominal level (P < 0.05, same direction of effect as in the discovery phase). When combining the discovery and validation cohorts, an intronic SNP in the Solute Carrier family 8 gene (SLC8A3) was found to be associated with ACPA-positive RA at a genome-wide level of significance RA [odds ratio (95% CI): 1.42 (1.25, 1.6), Pcombined = 3.19×10(-8)]. SLC8A3 was identified as a new risk locus for ACPA-positive RA. This study demonstrates the advantage of analysing relevant subsets of RA patients to identify new genetic risk variants.
Visual rhodopsins are membrane proteins that function as light photoreceptors in the vertebrate r... more Visual rhodopsins are membrane proteins that function as light photoreceptors in the vertebrate retina. Specific amino acids have been positively selected in visual pigments during mammal evolution, which, as products of adaptive selection, would be at the base of important functional innovations. We have analyzed the top candidates for positive selection at the specific amino acids and the corresponding reverse changes (F13M, Q225R and A346S) in order to unravel the structural and functional consequences of these important sites in rhodopsin evolution. We have constructed, expressed and immunopurified the corresponding mutated pigments and analyzed their molecular phenotypes. We find that position 13 is very important for the folding of the receptor and also for proper protein glycosylation. Position 225 appears to be important for the function of the protein affecting the G-protein activation process, and position 346 would also regulate functionality of the receptor by enhancing G-protein activation and presumably affecting protein phosphorylation by rhodopsin kinase. Our results represent a link between the evolutionary analysis, which pinpoints the specific amino acid positions in the adaptive process, and the structural and functional analysis, closer to the phenotype, making biochemical sense of specific selected genetic sequences in rhodopsin evolution.
Rheumatoid Factor (RF) is a well established diagnostic and prognostic biomarker in Rheumatoid Ar... more Rheumatoid Factor (RF) is a well established diagnostic and prognostic biomarker in Rheumatoid Arthritis (RA). However, approximately 20% of RA patients do not express this anti-IgG antibody. To date, only variation at HLA-DRB1 gene has been associated with the presence of RF. The objective of the study was to identify additional genetic variation associated with RF positivity. A genome-wide association study (GWAS) for RF-positivity was performed using the Illumina Quad610 genotyping platform. A total of 937 RF-positive and 323 RF-negative RA patients were genotyped for >550,000 single nucleotide polymorphisms (SNPs). Association testing was performing using the allelic chi-square test implemented in PLINK software. An independent cohort of 472 RF-positive and 190 RF-negative RA patients was used to validate the most significant findings. In the GWAS stage, a SNP in Iroquois homeobox 1 gene (IRX1) locus on chromosome 5p15.3 showed a genome-wide significant association with RF-positivity (SNP rs1502644, P = 4.13 x 10(-8) , OR(95% CI) = 0.37 (0.26-0.53)). In the validation stage, IRX1 association with RF was replicated in the independent group of RA patients (P = 0.034, OR(95% CI) = 0.58 (0.35-0.97), combined P = 1.14 x 10(-8) , OR(95% CI) = 0.43 (0.32-0.58)). To our knowledge, this is the first GWAS for RF positivity in RA. Variation at IRX1 locus on chromosome 5p15.3 is associated with the presence of RF. This study shows that IRX1 and HLA-DRB1 are the strongest genetic factors for RF production in RA. This article is protected by copyright. All rights reserved.
The Journal of investigative dermatology, Jan 29, 2015
Psoriasis is a chronic inflammatory disease with a complex genetic architecture. To date, the pso... more Psoriasis is a chronic inflammatory disease with a complex genetic architecture. To date, the psoriasis heritability is only partially explained. However, there is increasing evidence that the missing heritability in psoriasis could be explained by multiple genetic variants of low effect size from common genetic pathways. The objective of the present study was to identify new genetic variation associated with psoriasis risk at the pathway level. We genotyped 598,258 SNPs in a discovery cohort of 2,281 case-control individuals from Spain. We performed a genome-wide pathway analysis using 1,053 reference biological pathways. A total of 14 genetic pathways (PFDR≤2.55e-2) were found to be significantly associated with psoriasis risk. Using an independent validation cohort of 7,353 individuals from the UK, a total of 6 genetic pathways were significantly replicated (PFDR≤3.46e-2). We found genetic pathways that had not been previously associated with psoriasis risk like retinol metabolis...
... Interesarse por la evoluci6n huma-na, como el autor nos demuestra que lo hace con profundidad... more ... Interesarse por la evoluci6n huma-na, como el autor nos demuestra que lo hace con profundidad y ... Me ima-gino a la posible esposa de Jos6 Luis Sanz escribiendo Me casd con un di ... Mercedes de la Merced Monge, Jose Maria de la Riva Amez, Ignacio del Rio Garcia de Sola ...
El descubrimiento fortuito en 1994 de un llamativo conjunto de fósiles humanos en la Cueva de El ... more El descubrimiento fortuito en 1994 de un llamativo conjunto de fósiles humanos en la Cueva de El Sidrón (Asturias), despertó el interés de la comunidad científica y dio lugar a la intervención arqueológica multidisciplinar del yacimiento (1) (ver figura 1). Como resultado de estos ...
RA patients with serum ACPA have a strong and specific genetic background. The objective of the s... more RA patients with serum ACPA have a strong and specific genetic background. The objective of the study was to identify new susceptibility genes for ACPA-positive RA using a genome-wide association approach. A total of 924 ACPA-positive RA patients with joint damage in hands and/or feet, and 1524 healthy controls were genotyped in 582 591 single-nucleotide polymorphisms (SNPs) in the discovery phase. In the validation phase, the most significant SNPs in the genome-wide association study representing new candidate loci for RA were tested in an independent cohort of 863 ACPA-positive patients with joint damage and 1152 healthy controls. All individuals from the discovery and validation cohorts were Caucasian and of Southern European ancestry. In the discovery phase, 60 loci not previously associated with RA risk showed evidence for association at P < 5×10(-4) and were tested for replication in the validation cohort. A total of 12 loci were replicated at the nominal level (P < 0.05, same direction of effect as in the discovery phase). When combining the discovery and validation cohorts, an intronic SNP in the Solute Carrier family 8 gene (SLC8A3) was found to be associated with ACPA-positive RA at a genome-wide level of significance RA [odds ratio (95% CI): 1.42 (1.25, 1.6), Pcombined = 3.19×10(-8)]. SLC8A3 was identified as a new risk locus for ACPA-positive RA. This study demonstrates the advantage of analysing relevant subsets of RA patients to identify new genetic risk variants.
Visual rhodopsins are membrane proteins that function as light photoreceptors in the vertebrate r... more Visual rhodopsins are membrane proteins that function as light photoreceptors in the vertebrate retina. Specific amino acids have been positively selected in visual pigments during mammal evolution, which, as products of adaptive selection, would be at the base of important functional innovations. We have analyzed the top candidates for positive selection at the specific amino acids and the corresponding reverse changes (F13M, Q225R and A346S) in order to unravel the structural and functional consequences of these important sites in rhodopsin evolution. We have constructed, expressed and immunopurified the corresponding mutated pigments and analyzed their molecular phenotypes. We find that position 13 is very important for the folding of the receptor and also for proper protein glycosylation. Position 225 appears to be important for the function of the protein affecting the G-protein activation process, and position 346 would also regulate functionality of the receptor by enhancing G-protein activation and presumably affecting protein phosphorylation by rhodopsin kinase. Our results represent a link between the evolutionary analysis, which pinpoints the specific amino acid positions in the adaptive process, and the structural and functional analysis, closer to the phenotype, making biochemical sense of specific selected genetic sequences in rhodopsin evolution.
Rheumatoid Factor (RF) is a well established diagnostic and prognostic biomarker in Rheumatoid Ar... more Rheumatoid Factor (RF) is a well established diagnostic and prognostic biomarker in Rheumatoid Arthritis (RA). However, approximately 20% of RA patients do not express this anti-IgG antibody. To date, only variation at HLA-DRB1 gene has been associated with the presence of RF. The objective of the study was to identify additional genetic variation associated with RF positivity. A genome-wide association study (GWAS) for RF-positivity was performed using the Illumina Quad610 genotyping platform. A total of 937 RF-positive and 323 RF-negative RA patients were genotyped for >550,000 single nucleotide polymorphisms (SNPs). Association testing was performing using the allelic chi-square test implemented in PLINK software. An independent cohort of 472 RF-positive and 190 RF-negative RA patients was used to validate the most significant findings. In the GWAS stage, a SNP in Iroquois homeobox 1 gene (IRX1) locus on chromosome 5p15.3 showed a genome-wide significant association with RF-positivity (SNP rs1502644, P = 4.13 x 10(-8) , OR(95% CI) = 0.37 (0.26-0.53)). In the validation stage, IRX1 association with RF was replicated in the independent group of RA patients (P = 0.034, OR(95% CI) = 0.58 (0.35-0.97), combined P = 1.14 x 10(-8) , OR(95% CI) = 0.43 (0.32-0.58)). To our knowledge, this is the first GWAS for RF positivity in RA. Variation at IRX1 locus on chromosome 5p15.3 is associated with the presence of RF. This study shows that IRX1 and HLA-DRB1 are the strongest genetic factors for RF production in RA. This article is protected by copyright. All rights reserved.
The Journal of investigative dermatology, Jan 29, 2015
Psoriasis is a chronic inflammatory disease with a complex genetic architecture. To date, the pso... more Psoriasis is a chronic inflammatory disease with a complex genetic architecture. To date, the psoriasis heritability is only partially explained. However, there is increasing evidence that the missing heritability in psoriasis could be explained by multiple genetic variants of low effect size from common genetic pathways. The objective of the present study was to identify new genetic variation associated with psoriasis risk at the pathway level. We genotyped 598,258 SNPs in a discovery cohort of 2,281 case-control individuals from Spain. We performed a genome-wide pathway analysis using 1,053 reference biological pathways. A total of 14 genetic pathways (PFDR≤2.55e-2) were found to be significantly associated with psoriasis risk. Using an independent validation cohort of 7,353 individuals from the UK, a total of 6 genetic pathways were significantly replicated (PFDR≤3.46e-2). We found genetic pathways that had not been previously associated with psoriasis risk like retinol metabolis...
... Interesarse por la evoluci6n huma-na, como el autor nos demuestra que lo hace con profundidad... more ... Interesarse por la evoluci6n huma-na, como el autor nos demuestra que lo hace con profundidad y ... Me ima-gino a la posible esposa de Jos6 Luis Sanz escribiendo Me casd con un di ... Mercedes de la Merced Monge, Jose Maria de la Riva Amez, Ignacio del Rio Garcia de Sola ...
El descubrimiento fortuito en 1994 de un llamativo conjunto de fósiles humanos en la Cueva de El ... more El descubrimiento fortuito en 1994 de un llamativo conjunto de fósiles humanos en la Cueva de El Sidrón (Asturias), despertó el interés de la comunidad científica y dio lugar a la intervención arqueológica multidisciplinar del yacimiento (1) (ver figura 1). Como resultado de estos ...
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