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Genotype-phenotype correlations add value to the management of families with hereditary hearing loss (HL), where age-related typical audiograms (ARTAs) are generated from cross-sectional regression equations and used to predict the audiogram phenotype across the lifespan. A seven-generation kindred with autosomal dominant sensorineural HL (ADSNHL) was recruited and a novel pathogenic variant in POU4F3 (c.37del) was identified by combining linkage analysis with whole exome sequencing (WES). POU4F3 is noted for large intrafamilial variation including the age of onset of HL, audiogram configuration and presence of vestibular impairment. Sequential audiograms and longitudinal analyses reveal highly variable audiogram features among POU4F3 (c.37del) carriers, limiting the utility of ARTAs for clinical prognosis and management of HL. Furthermore, a comparison of ARTAs against three previously published families (1 Israeli Jewish, 2 Dutch) reveals significant interfamilial differences, with earlier onset and slower deterioration. This is the first published report of a North American family with ADSNHL due to POU4F3, the first report of the pathogenic c.37del variant, and the first study to conduct longitudinal analysis, extending the phenotypic spectrum of DFNA15.
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Sordera , Pérdida Auditiva Sensorineural , Pérdida Auditiva , Humanos , Estudios Transversales , Proteínas de Homeodominio/genética , Pérdida Auditiva/genética , Pérdida Auditiva Sensorineural/diagnóstico , Pérdida Auditiva Sensorineural/genética , Pérdida Auditiva Sensorineural/patología , Linaje , Factor de Transcripción Brn-3C/genéticaRESUMEN
The purpose of this document is to provide pre-analytical, analytical and post-analytical considerations and recommendations to Canadian clinical laboratories developing, validating and offering next-generation sequencing (NGS)-based BRCA1 and BRCA2 (BRCA1/2) tumour testing in ovarian cancers. This document was drafted by the members of the Canadian College of Medical Geneticists (CCMG) somatic BRCA Ad Hoc Working Group, and representatives from the Canadian Association of Pathologists. The document was circulated to the CCMG members for comment. Following incorporation of feedback, this document has been approved by the CCMG board of directors. The CCMG is a Canadian organisation responsible for certifying medical geneticists and clinical laboratory geneticists, and for establishing professional and ethical standards for clinical genetics services in Canada. The current CCMG Practice Guidelines were developed as a resource for clinical laboratories in Canada; however, they are not inclusive of all information laboratories should consider in the validation and use of NGS for BRCA1/2 tumour testing in ovarian cancers.
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Servicios de Laboratorio Clínico , Neoplasias Ováricas , Proteína BRCA1/genética , Proteína BRCA2/genética , Canadá , Carcinoma Epitelial de Ovario , Femenino , Pruebas Genéticas , Mutación de Línea Germinal , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/genéticaRESUMEN
Sequencing exomes/genomes have been successful for identifying recessive genes; however, discovery of dominant genes including deafness genes (DFNA) remains challenging. We report a new DFNA gene, ATP11A, in a Newfoundland family with a variable form of bilateral sensorineural hearing loss (SNHL). Genome-wide SNP genotyping linked SNHL to DFNA33 (LOD = 4.77), a locus on 13q34 previously mapped in a German family with variable SNHL. Whole-genome sequencing identified 51 unremarkable positional variants on 13q34. Continuous clinical ascertainment identified several key recombination events and reduced the disease interval to 769 kb, excluding all but one variant. ATP11A (NC_000013.11: chr13:113534963G>A) is a novel variant predicted to be a cryptic donor splice site. RNA studies verified in silico predictions, revealing the retention of 153 bp of intron in the 3' UTR of several ATP11A isoforms. Two unresolved families from Israel were subsequently identified with a similar, variable form of SNHL and a novel duplication (NM_032189.3:c.3322_3327+2dupGTCCAGGT) in exon 28 of ATP11A extended exon 28 by 8 bp, leading to a frameshift and premature stop codon (p.Asn1110Valfs43Ter). ATP11A is a type of P4-ATPase that transports (flip) phospholipids from the outer to inner leaflet of cell membranes to maintain asymmetry. Haploinsufficiency of ATP11A, the phospholipid flippase that specially transports phosphatidylserine (PS) and phosphatidylethanolamine (PE), could leave cells with PS/PE at the extracellular side vulnerable to phagocytic degradation. Given that surface PS can be pharmaceutically targeted, hearing loss due to ATP11A could potentially be treated. It is also likely that ATP11A is the gene underlying DFNA33.
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Transportadoras de Casetes de Unión a ATP , Sordera , Pérdida Auditiva Sensorineural , Pérdida Auditiva , Humanos , Regiones no Traducidas 3' , Transportadoras de Casetes de Unión a ATP/genética , Sordera/genética , Pérdida Auditiva/genética , Pérdida Auditiva Sensorineural/genética , Mutación , Linaje , Fosfolípidos/metabolismo , Sitios de Empalme de ARNRESUMEN
Rare post-zygotic mutations in the brain are now known to contribute to several neurodevelopmental disorders, including autism spectrum disorder (ASD). However, due to the limited availability of brain tissue, most studies rely on estimates of mosaicism from peripheral samples. In this study, we undertook whole exome sequencing on brain tissue from 26 ASD brain donors from the Harvard Brain Tissue Resource Center (HBTRC) and ascertained the presence of post-zygotic and germline mutations categorized as pathological, including those impacting known ASD-implicated genes. Although quantification did not reveal enrichment for post-zygotic mutations compared with the controls (n = 15), a small number of pathogenic, potentially ASD-implicated mutations were identified, notably in TRAK1 and CLSTN3. Furthermore, germline mutations were identified in the same tissue samples in several key ASD genes, including PTEN, SC1A, CDH13, and CACNA1C. The establishment of tissue resources that are available to the scientific community will facilitate the discovery of new mutations for ASD and other neurodevelopmental disorders.
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Trastorno del Espectro Autista , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/patología , Encéfalo/patología , Proteínas de Unión al Calcio/genética , Predisposición Genética a la Enfermedad , Humanos , Proteínas de la Membrana/genética , Mutación , Secuenciación del ExomaRESUMEN
Otosclerosis is a bone disorder of the otic capsule and common form of late-onset hearing impairment. Considered a complex disease, little is known about its pathogenesis. Over the past 20 years, ten autosomal dominant loci (OTSC1-10) have been mapped but no genes identified. Herein, we map a new OTSC locus to a 9.96 Mb region within the FOX gene cluster on 16q24.1 and identify a 15 bp coding deletion in Forkhead Box L1 co-segregating with otosclerosis in a Caucasian family. Pre-operative phenotype ranges from moderate to severe hearing loss to profound sensorineural loss requiring a cochlear implant. Mutant FOXL1 is both transcribed and translated and correctly locates to the cell nucleus. However, the deletion of 5 residues in the C-terminus of mutant FOXL1 causes a complete loss of transcriptional activity due to loss of secondary (alpha helix) structure. FOXL1 (rs764026385) was identified in a second unrelated case on a shared background. We conclude that FOXL1 (rs764026385) is pathogenic and causes autosomal dominant otosclerosis and propose a key inhibitory role for wildtype Foxl1 in bone remodelling in the otic capsule. New insights into the molecular pathology of otosclerosis from this study provide molecular targets for non-invasive therapeutic interventions.
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Otosclerosis , Factores de Transcripción Forkhead/genética , Humanos , Otosclerosis/genéticaRESUMEN
Psoriatic arthritis (PsA) is caused by a combination of environmental and multiple genetic factors, with clear evidence for a strong genetic basis. The remarkable accumulation of knowledge gained from genetic, pharmacogenetic, and therapeutic response of biologic agents in PsA has fundamentally changed and advanced our understanding of disease pathogenesis and has identified key signalling pathways. However, only one-quarter of the genetic contribution of PsA has been accounted for; and dissecting the genetic contributors of the cutaneous disease from those that would identify joint disease has been challenging. More importantly, the clinical utility of multiple proposed loci is unclear. In this review, we summarize the potential clinical relevance from established genetic associations and provide insight on the proposed molecular pathways that arise from these associations.
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Artritis Psoriásica , Artritis Psoriásica/tratamiento farmacológico , Artritis Psoriásica/genética , Factores Biológicos , Sitios Genéticos , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , HumanosRESUMEN
Genetic and environmental factors are critical elements in most common complex disease. Genetics is increasingly being recognized to play a substantive role in the susceptibility, prognosis, and treatment of common diseases. Due to recent and rapid advancements in characterization of genetic variants and large-scale genotyping platforms, multiple genes and genetic variants have now been identified for common, complex diseases. The most efficient method for gene identification at present appears to be large-scale association-based studies, which integrate genetic and epidemiological principles. As the strategy for gene identification studies has shifted toward genetic association-based methods rather than traditional linkage analysis, epidemiological methods are increasingly being integrated into genetic investigations and in public health research. Consequently, the disciplines of genetics and epidemiology, which historically have functioned separately, have been integrated into a hybrid discipline referred to as genetic epidemiology. In this chapter, we review methods for establishing the genetic burden of complex genetic disease, followed by methods for gene and/or genetic variant identification. When appropriate, we will highlight the epidemiological issues and clinical applications that guide these methods.
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Predisposición Genética a la Enfermedad/genética , Variación Genética , Estudio de Asociación del Genoma Completo/métodos , Ligamiento Genético , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Epidemiología Molecular , Fenotipo , Análisis de Secuencia de ADNRESUMEN
Collectively, rare genetic diseases affect a significant number of individuals worldwide. In this study, we have conducted whole-exome sequencing (WES) and identified underlying pathogenic or likely pathogenic variants in five children with rare genetic diseases. We present evidence for disease-causing autosomal recessive variants in a range of disease-associated genes such as DHH-associated 46,XY gonadal dysgenesis (GD) or 46,XY sex reversal 7, GNPTAB-associated mucolipidosis II alpha/beta (ML II), BBS1-associated Bardet-Biedl Syndrome (BBS), SURF1-associated Leigh Syndrome (LS) and AP4B1-associated spastic paraplegia-47 (SPG47) in unrelated affected members from Bangladesh. Our analysis pipeline detected three homozygous mutations, including a novel c. 863 G > C (p.Pro288Arg) variant in DHH, and two compound heterozygous variants, including two novel variants: c.2972dupT (p.Met991Ilefs*) in GNPTAB and c.229 G > C (p.Gly77Arg) in SURF1. All mutations were validated by Sanger sequencing. Collectively, this study adds to the genetic heterogeneity of rare genetic diseases and is the first report elucidating the genetic profile of (consanguineous and nonconsanguineous) rare genetic diseases in the Bangladesh population.
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This study explored the physical and clinical phenotype of Bangladeshi children with autism spectrum disorder (ASD). A totally of 283 children who were referred for screening and administered Module 1 of the Autism Diagnostic Observation Schedule (ADOS) were included. Overall, 209 met the ADOS algorithmic cutoff for ASD. A trend for greater weight and head circumference was observed in children with ASD versus non-ASD. Head circumference was significantly (p < 0.03) larger in ASD males compared with non-ASD males. A trend was also observed for symptom severity, higher in females than males (p = 0.068), with further analyses demonstrating that social reciprocity (p < 0.014) and functional play (p < 0.03) were significantly more impaired in ASD females than males. The findings help understand sex differences in ASD.
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Trastorno del Espectro Autista/etnología , Trastorno del Espectro Autista/patología , Factores Sexuales , Adolescente , Bangladesh/etnología , Peso Corporal , Cefalometría , Niño , Preescolar , Femenino , Cabeza/patología , Humanos , Masculino , Fenotipo , Examen Físico , Índice de Severidad de la Enfermedad , Conducta SocialRESUMEN
Biological therapies have dramatically improved the therapeutic landscape of psoriatic arthritis (PsA); however, 40-50% of patients are primary non-responders with response rates declining significantly with each successive biological therapy. Therefore, there is a pressing need to develop a coherent strategy for effective initial and subsequent selection of biologic agents. We interrogated 40 PsA patients initiating either tumour necrosis factor inhibitors (TNFi) or interleukin-17A inhibitors (17Ai) for active PsA. Patients achieving low disease activity according to the Disease Activity Index for PsA (DAPSA) at 3 months were classified as responders. Baseline and 3-month CD4+ transcript profiling were performed, and novel signaling pathways were identified using a multi-omics profiling and integrative computational analysis approach. Using transcriptomic data at initiation of therapy, we identified over 100 differentially expressed genes (DEGs) that differentiated IL-17Ai response from non-response and TNFi response from non-response. Integration of cell-type-specific DEGs with protein-protein interactions and further comprehensive pathway enrichment analysis revealed several pathways. Rho GTPase signaling pathway exhibited a strong signal specific to IL-17Ai response and the genes, RAC1 and ROCKs, are supported by results from prior research. Our detailed network and pathway analyses have identified the rewiring of Rho GTPase pathways as potential markers of response to IL17Ai but not TNFi. These results need further verification.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Antirreumáticos/uso terapéutico , Artritis Psoriásica/tratamiento farmacológico , Artritis Psoriásica/genética , Terapia Biológica/métodos , Interleucina-17/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Proteínas de Unión al GTP rho/metabolismo , Adalimumab , Anticuerpos Monoclonales , Anticuerpos Monoclonales Humanizados/farmacología , Antirreumáticos/farmacología , Artritis Psoriásica/diagnóstico , Transducción de Señal/fisiología , Resultado del Tratamiento , Proteína de Unión al GTP rac1RESUMEN
Stargardt disease (STGD1) is a form of inherited retinal dystrophy attributed to variants affecting function of the large ABCA4 gene and is arguably the most complex monogenic disease. Therapeutic trials in patients depend on identifying causal ABCA4 variants in trans, which is complicated by extreme allelic and clinical heterogeneity. We report the genetic architecture of STGD1 in the young genetically isolated population of Newfoundland, Canada. Population-based clinical recruitment over several decades yielded 29 STGD1 and STGD1-like families (15 multiplex, 14 singleton). Family interviews and public archival records reveal the vast majority of pedigree founders to be of English extraction. Full gene sequencing and haplotype analysis yielded a high solve rate (38/41 cases; 92.7%) for STGD1 and identified 16 causative STGD1 alleles, including a novel deletion (NM_000350.3: ABCA4 c.67-1delG). Several STGD1 alleles of European origin (including NM_000350.3: ABCA4 c.5714 + 5G>A and NM_000350.3: ABCA4 c.5461-10T>C) have drifted to a relatively high population frequency due to founder effect. We report on retinal disease progression in homozygous patients, providing valuable allele-specific insights. The least involved retinal disease is seen in patients homozygous for c.5714 + 5G>A variant, a so-called "mild" variant which is sufficient to precipitate a STGD1 phenotype in the absence of other pathogenic variants in the coding region and intron/exon boundaries of ABCA4. The most severe retinal disease is observed in cases with ABCA4 c.[5461-10T>C;5603A>T] complex allele. We discuss the advantages of determining genetic architecture in genetic isolates in order to begin to meet the grand challenge of human genetics.
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Transportadoras de Casetes de Unión a ATP/genética , Frecuencia de los Genes , Enfermedad de Stargardt/genética , Femenino , Efecto Fundador , Homocigoto , Humanos , Masculino , Mutación , LinajeRESUMEN
PURPOSE OF THE REVIEW: To provide a general overview and current challenges regarding the genetics of psoriatic disease. With the use of integrative medicine, multiple candidate loci identified to date in psoriatic disease will be annotated, summarized, and visualized. Recent studies reporting differences in genetic architecture between psoriatic arthritis and cutaneous-only psoriasis will be highlighted. RECENT FINDINGS: Focusing on functional pathways that connect previously identified genetic variants can increase our understanding of psoriatic diseases. The genetic architecture differs between psoriatic arthritis and cutaneous-only psoriasis with arthritis-specific signals in linkage disequilibrium independent of the published psoriasis signals. Integrative medicine is helpful in understanding cellular mechanisms of psoriatic diseases. Careful selection of the psoriatic disease cohort has translated into mechanistic differences among psoriatic arthritis and cutaneous psoriasis.
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Artritis Psoriásica/genética , Interacción Gen-Ambiente , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo , Humanos , Fenotipo , Polimorfismo de Nucleótido SimpleRESUMEN
Chronic plaque psoriasis and psoriatic arthritis are multifactorial inter-related diseases with strong genetic contributions. Better elucidation of the heritability of psoriatic disease subsets is important for identifying novel genes, risk stratification and potential clinical applications. In this study, we used two mixed-effect modelling methodologies to assess the additive contribution of common single nucleotide polymorphisms from genome-wide association studies to estimate the heritability of cutaneous psoriasis, psoriasis vulgaris and psoriatic arthritis. We found that cutaneous psoriasis and psoriatic arthritis both exhibit considerable heritability, with a greater contribution coming from cutaneous psoriasis.
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Artritis Psoriásica/diagnóstico , Artritis Psoriásica/genética , Patrón de Herencia , Psoriasis/diagnóstico , Psoriasis/genética , Enfermedades Cutáneas Papuloescamosas/diagnóstico , Enfermedades Cutáneas Papuloescamosas/genética , Edad de Inicio , Alelos , Estudios de Casos y Controles , Diagnóstico Diferencial , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Masculino , Polimorfismo de Nucleótido SimpleRESUMEN
BACKGROUND: RAD51C is important in DNA repair and individuals with pathogenic RAD51C variants have increased risk of hereditary breast and ovarian cancer syndrome (HBOC), an autosomal dominant genetic predisposition to early onset breast and/or ovarian cancer. METHODS: Five female HBOC probands sequenced negative for moderate- and high-risk genes but shared a recurrent variant of uncertain significance in RAD51C (NM_058216.3: c.571 + 4A > G). Participant recruitment was followed by haplotype and case/control analyses, RNA splicing analysis, gene and protein expression assays, and Sanger sequencing of tumors. RESULTS: The RAD51C c.571 + 4A > G variant segregates with HBOC, with heterozygotes sharing a 5.07 Mbp haplotype. RAD51C c.571 + 4A > G is increased ~52-fold in the Newfoundland population compared with the general Caucasian population and positive population controls share disease-associated alleles, providing evidence of a founder effect. Splicing analysis confirmed in silico predictions that RAD51C c.571 + 4A > G causes exon 3 skipping, creating an immediate premature termination codon. Gene and protein expression were significantly reduced in a RAD51C c.571 + 4G > A heterozygote compared with a wild-type relative. Sanger sequencing of tumors from two probands indicates loss-of-heterozygosity, suggesting loss of function. CONCLUSION: The RAD51C c.571 + 4A > G variant affects mRNA splicing and should be re-classified as pathogenic according to American College of Medical Genetics and Genomics guidelines.
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Proteínas de Unión al ADN/genética , Efecto Fundador , Síndrome de Cáncer de Mama y Ovario Hereditario/genética , Población/genética , Anciano , Anciano de 80 o más Años , Femenino , Genes Dominantes , Haplotipos , Humanos , Masculino , Persona de Mediana Edad , Mutación , Terranova y Labrador , Empalme del ARNRESUMEN
Psoriatic arthritis (PsA) is an inflammatory arthritis that manifests in 20-30% of patients diagnosed with psoriasis. Epidemiologic studies suggest a substantial genetic contribution to PsA. There is a strong need for genome-wide association studies on patients with PsA, including PsA-weighted or specific variants, and a need for a better understanding of the relevance of HLA alleles in disease expression. Interferon signaling and the nuclear factor-κB cascade are involved in PsA, and there are genetic differences between purely cutaneous psoriasis (PsC) and PsA. Psoriasis susceptibility genes for which putative functional coding variants in TYK2 and TRAF3IP2 are strongly associated with PsC and PsA, and neutrophil extracellular traps promote Th17 induction in an Act1 D10N-dependent fashion. Genomics and serological factors may also predict treatment response in tumor necrosis factor inhibitors (TNFi) in PsA, and genetics may play a role in treatment response to TNFi. Collaborations through the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) are essential to increase study population size, which will enhance the ability to detect the genetic variants that create a predisposition to psoriatic disease and to predict response to biological therapy.
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Artritis Psoriásica/genética , Predisposición Genética a la Enfermedad , Antígenos HLA-C/genética , Polimorfismo de Nucleótido Simple , Psoriasis/genética , Alelos , Estudio de Asociación del Genoma Completo , Genotipo , HumanosRESUMEN
BACKGROUND: Usher syndrome, the most common form of inherited deaf-blindness, is unlike many other forms of syndromic hereditary hearing loss in that the extra aural clinical manifestations are also detrimental to communication. Usher syndrome patients with early onset deafness also experience vision loss due to progressive retinitis pigmentosa that can lead to legal blindness in their third or fourth decade. METHODS: Using a multi-omic approach, we identified three novel pathogenic variants in two Usher syndrome genes (USH2A and ADGRV1) in cases initially referred for isolated vision or hearing loss. RESULTS: In a multiplex hearing loss family, two affected sisters, the product of a second cousin union, are homozygous for a novel nonsense pathogenic variant in ADGRV1 (c.17062C > T, p.Arg5688*), predicted to create a premature stop codon near the N-terminus of ADGRV1. Ophthalmological examination of the sisters confirmed typical retinitis pigmentosa and prompted a corrected Usher syndrome diagnosis. In an unrelated clinical case, a child with hearing loss tested positive for two novel USH2A splicing variants (c.5777-1G > A, p. Glu1926_Ala1952del and c.10388-2A > G, p.Asp3463Alafs*6) and RNA studies confirmed that both pathogenic variants cause splicing errors. Interestingly, these same USH2A variants are also identified in another family with vision loss where subsequent clinical follow-up confirmed pre-existing hearing loss since early childhood, eventually resulting in a reassigned diagnosis of Usher syndrome. CONCLUSION: These findings provide empirical evidence to increase Usher syndrome surveillance of at-risk children. Given that novel antisense oligonucleotide therapies have been shown to rescue retinal degeneration caused by USH2A splicing pathogenic variants, these solved USH2A patients may now be eligible to be enrolled in therapeutic trials.
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Trastornos Sordoceguera/genética , Síndromes de Usher/genética , Niño , Preescolar , Femenino , Genotipo , Humanos , Masculino , Linaje , FenotipoRESUMEN
INTRODUCTION: Psoriatic arthritis (PsA) is a heterogeneous inflammatory disorder with articular, peri-articular, and extra-articular features along with selected co-morbidities as a sequela to chronic inflammation. There is accumulating evidence that the Th-17 signaling pathway is of critical importance in PsA pathogenesis. Areas covered: Ixekizumab (IXE) is a humanized immunoglobulin G subclass 4 (IgG4) monoclonal antibody directed against IL-17A. Two phase III randomized clinical trials, SPIRIT-P1 and SPIRIT-P2, unequivocally demonstrated superiority of IXE (80 mg every two or 4 weeks) dosing over placebo in moderate-to-severe PsA patients that failed either NSAIDs, conventional disease-modifying anti-rheumatic drugs (csDMARDs), or tumor necrosis factor-α inhibitors (TNFi) for numerous articular and cutaneous parameters. IXE also delayed structural progression of PsA. No new safety signals were identified as compared with chronic plaque psoriasis studies which included many more patients. Expert opinion: IXE is a highly effective treatment for moderate to severe PsA patients, including those that have been previously exposed to csDMARD and TNFi. Most domains of PsA significantly improved with IXE treatment and disease modification was achieved.
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Anticuerpos Monoclonales Humanizados/administración & dosificación , Antirreumáticos/administración & dosificación , Artritis Psoriásica/tratamiento farmacológico , Células Th17/efectos de los fármacos , Animales , Anticuerpos Monoclonales Humanizados/efectos adversos , Antirreumáticos/efectos adversos , Artritis Psoriásica/diagnóstico , Artritis Psoriásica/inmunología , Humanos , Inducción de Remisión , Índice de Severidad de la Enfermedad , Transducción de Señal/efectos de los fármacos , Células Th17/inmunología , Resultado del TratamientoRESUMEN
Psoriatic arthritis (PsA) is an inflammatory arthritis that commonly occurs with psoriasis and is attributed to genetic, immunologic and environmental factors. The T-helper (Th)-17 pathway and the interleukin (IL)-23/IL-17 axis have become prominent players in PsA and considerably increased our understanding of disease pathogenesis. In this review article, we will focus on the emerging role of IL-12/23 and its blockade, in the pathogenesis and management of PsA as well as of psoriasis and inflammatory bowel disease. Ustekinumab, is a fully human monoclonal immunoglobulin (Ig)G1 antibody that binds specifically to the p40 subunit of IL-12 and IL-23, primarily inhibiting downstream Th-17 signalling pathways. Ustekinumab produced consistent and sustained clinical efficacy in two phase III clinical trials in PsA, PSUMMIT-1 and PSUMMIT-2, with data out to 52 weeks, and no new safety signals. PSUMMIT-1 included patients with active PsA despite conventional therapy who were all naïve to anti-tumour necrosis factor (TNF) agents, whereas PSUMMIT-2 also included anti-TNF experienced patients. Similarly, ustekinumab produced consistent clinical efficacy in two phase III clinical trials in psoriasis, PHOENIX-1 and PHOENIX-2, and in both induction and maintenance of moderate-to-severe Crohn's disease, UNITI-1, UNITI-2 and IM-UNITI, without an increased safety signal. Currently, ustekinumab is used in the treatment of PsA following the failure of nonsteroidal anti-inflammatory drugs (NSAIDs) and conventional disease-modifying antirheumatic drugs (DMARDs), and as an alternative to, or after failure of an anti-TNF agent.
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PURPOSE OF REVIEW: The purpose of this review is to highlight recent evidence with respect to expression and metabolomic profiling in axial spondyloarthritis (axSpA) that included ankylosing spondylitis (AS). RECENT FINDINGS: AxSpA is not only characterized by the strongest genetic contribution for any complex rheumatic disease but is also influenced by environmental and immunological factors. Large-scale association-based studies have identified over 100 genetic variants contributing to 30% of the genetic risk of ankylosing spondylitis. Recent studies in global expression and metabolomic profiling appear to highlight common themes despite differences in tissues, populations, techniques, and relative paucity of patients in many of these studies. Expression studies support a role for immunomodulation and bone remodeling in the pathogenesis and progression of axSpA/AS, while metabolomic studies implicate the importance of the intestinal microbial metabolism as well as fat and choline metabolic pathways in AS.