The <i>SEM6A6</i> Locus Is Not Associated With Granulomatosis With Polyangiitis or Other Forms of Antineutrophil Cytoplasmic Antibody–Associated Vasculitides in Europeans: Comment on the Article by Xie et al

Wieczorek, Stefan; Holle, Julia; Tervaert, Jan Willem Cohen; Harper, Lorraine; Moosig, Frank; Gross, Wolfgang L.; Epplen, Jörg T.

doi:10.1002/art.38367

Cited by 12 publications

(3 citation statements)

References 5 publications

(7 reference statements)

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“…The protein encoded by SEMA6A has been characterized as a critical regulator of angiogenesis by modulating VEGF signaling (85). Nevertheless, it should be considered that, although polymorphisms within this locus showed genome-wide significance (13), this association was not subsequently validated in a replication study performed in a well-powered cohort of European AAV patients (including GPA, MPA, and EGPA cases) (86) or in the subsequent GWAS carried out by the same group (10). Therefore, further genetic association studies are needed to confirm the role of SEMA6A in AAV.…”

Section: Contribution Of Genetics To New Therapeutic Approaches In Vamentioning

confidence: 99%

Leveraging Genetic Findings for Precision Medicine in Vasculitis

2019

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Vasculitides are a heterogeneous group of low frequent disorders, mainly characterized by the inflammation of blood vessels that narrows or occlude the lumen and limits the blood flow, leading eventually to significant tissue and organ damage. These disorders are classified depending on the size of the affected blood vessels in large, medium, and small vessel vasculitis. Currently, it is known that these syndromes show a complex etiology in which both environmental and genetic factors play a major role in their development. So far, these conditions are not curable and the therapeutic approaches are mainly symptomatic. Moreover, a percentage of the patients do not adequately respond to standard treatments. Over the last years, numerous genetic studies have been carried out to identify susceptibility loci and biological pathways involved in vasculitis pathogenesis as well as potential genetic predictors of treatment response. The ultimate goal of these studies is to identify new therapeutic targets and to improve the use of existing drugs to achieve more effective treatments. This review will focus on the main advances made in the field of genetics and pharmacogenetics of vasculitis and their potential application for ameliorating long-term outcomes in patient management and in the development of precision medicine.

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Section: Contribution Of Genetics To New Therapeutic Approaches In Vamentioning

confidence: 99%

Leveraging Genetic Findings for Precision Medicine in Vasculitis

2019

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“…The function of the proteins belonging to this family is unclear, but it has been proposed that they may be involved in immune regulation [57]. The association between the rs26595 SNP of the SEM6A gene and GPA was recently investigated also in a different cohort of Northern European patients, including 879 GPA, 150 MPA and 191 EGPA [58]. No statistically significant difference in allele frequencies was observed in this group, suggesting the necessity of further studies to better clarify the role of this region in AAV.…”

Section: Other Associationsmentioning

confidence: 99%

Genetic aspects of anti-neutrophil cytoplasmic antibody-associated vasculitis

Alberici

Martorana

Vaglio

2014

Nephrology Dialysis Transplantation

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The genetics of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a complex area of investigation because of the low frequency of AAVs, the rarity of familial cases and the complexity of disease phenotypes. However, recent studies have been able to gather significant numbers of patients, and multicentre collaborative efforts have allowed the performance of two genome-wide association studies (GWASs). Genetic association studies based on candidate gene approaches and the two GWASs have greatly contributed to our current understanding of the genetic basis of AAV. The central role of autoimmunity has been confirmed by the significant association with HLA polymorphisms; interestingly, the three main AAV subtypes are associated with distinct HLA variants, i.e. granulomatosis with polyangiitis (Wegener's GPA) with HLA-DP1, microscopic polyangiitis with HLA-DQ and eosinophilic GPA (Churg-Strauss) with HLA-DRB4. GWASs also revealed that polymorphic variants of genes encoding proteinase 3 (PR3), the predominant antigenic target of ANCA in GPA, and its main inhibitor, alpha-1 antitrypsin, are highly associated with GPA and, even more significantly, with PR3-ANCA positivity (regardless of the clinical diagnosis); this emphasizes the central pathogenic role of PR3 and humoral autoimmunity in PR3-ANCA positive vasculitis. Finally, candidate gene approach studies have shown associations with other variants involved in autoimmunity, such as those belonging to the CTLA-4 and PTPN22 genes, although these findings warrant replication in larger studies. Additional studies are underway to better characterize disease associations within the AAV spectrum, which could provide new pathogenetic clues and possibly new treatment targets.

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“…The role of SEMA6A in GPA is still unclear; a possible theory explains that semaphorins have an important role in the immune response in autoimmune and allergic disorders ( 62 ). The association between the rs26595 SNP of the SEM6A6 gene and GPA was recently investigated in 879 GPA patients, 150 MPA patients and 191 EGPA patients, compared with 1,376 healthy control subjects ( 63 ). All of the subjects were white Europeans.…”

Section: Gwas Aav Geneticsmentioning

confidence: 99%

Genetic Susceptibility to ANCA-Associated Vasculitis: State of the Art

et al. 2014

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ANCA-associated vasculitis (AAV) is a group of disorders that is caused by inflammation affecting small blood vessels. Both arteries and veins are affected. AAV includes microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA) renamed from Wegener’s granulomatosis, and eosinophilic granulomatosis with polyangiitis (EGPA), renamed from Churg–Strauss syndrome. AAV is primarily due to leukocyte migration and resultant damage. Despite decades of research, the mechanisms behind AAV disease etiology are still not fully understood, although it is clear that genetic and environmental factors are involved. To improve the understanding of the disease, the genetic component has been extensively studied by candidate association studies and two genome-wide association studies. The majority of the identified genetic AAV risk factors are common variants. These have uncovered information that still needs further investigation to clarify its importance. In this review, we summarize and discuss the results of the genetic studies in AAV. We also present the novel approaches to identifying the causal variants in complex susceptibility loci and disease mechanisms. Finally, we discuss the limitations of current methods and the challenges that we still have to face in order to incorporate genomic and epigenomic data into clinical practice.

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The SEM6A6 Locus Is Not Associated With Granulomatosis With Polyangiitis or Other Forms of Antineutrophil Cytoplasmic Antibody–Associated Vasculitides in Europeans: Comment on the Article by Xie et al

Cited by 12 publications

References 5 publications

Leveraging Genetic Findings for Precision Medicine in Vasculitis

Leveraging Genetic Findings for Precision Medicine in Vasculitis

Genetic aspects of anti-neutrophil cytoplasmic antibody-associated vasculitis

Genetic Susceptibility to ANCA-Associated Vasculitis: State of the Art

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