- •
Vasculitides comprise a heterogeneous group of rare diseases with a complex etiology characterized by inflammatory lesions of blood vessels.
- •
Some forms of vasculitis are associated with severe neurologic complications that have an impact on the prognosis of the disease.
- •
An important progress in the elucidation of the genetic component of vasculitides has occurred during the last decade.
- •
Few genetic studies on specific clinical phenotypes of vasculitides have been published due to the difficulty in
Genetic Basis of Vasculitides with Neurologic Involvement
Section snippets
Key points
Behçet disease
Behçet disease (BD) is a multisystem syndrome with a male preponderance characterized by inflammatory lesions of blood vessels of variable size throughout the body, leading to heterogeneous clinical manifestations. Oral and genital ulceration as well as ocular involvement (mainly uveitis) are the most frequent phenotypes.6 Neurologic complications occur in around 10% to 30% of patients with BD, constituting the so-called neuro-Behçet syndrome (NB), which presents with fever, headache, aseptic
Large vessel vasculitis
Large vessel vasculitides (LVV) are characterized by inflammatory lesions in large-sized vessels such as the aorta, the carotid, and their major branches. This group of vasculitides comprises giant cell arteritis (GCA) and Takayasu arteritis (TAK). Both conditions present a female preponderance, being GCA more frequent in people of European origin over the fifth decade of life and TAK in younger patients with a higher incidence in Asia and Latin America.40, 41
Antineutrophil cytoplasmic antibody-associated vasculitis
Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are primary systemic diseases of which major hallmark is a necrotizing inflammation of small blood vessels (arterioles, small arteries, capillaries and, venules) and presence of ANCAs against proteinase 3 (PR3) or myeloperoxidase (MPO). They include granulomatosis with polyangiitis (GPA, formerly Wegener granulomatosis), microscopic polyangiitis (MPA), and eosinophilic GPA (EGPA, formerly Churg–Strauss syndrome).68
Polyarteritis nodosa
Polyarteritis nodosa (PAN) is a systemic vasculitis affecting mostly medium-sized arteries (generally related to the lungs' circulation but also to other internal organs such as the kidneys). Similar to AAVs, PAN involves necrotizing inflammation of blood vessels, although it is not associated with ANCA production.77 Neurologic manifestations due to ischemia (which leads to thrombosis or bleeding) are relatively common in patients with PAN with an advance disease course. They include headache,
Primary angiitis of the central nervous system
Primary angiitis of the CNS (PACNS), also known as primary CNS vasculitis, is a very rare vasculitis that involves low to medium caliber vessels of the brain, spinal cord, and the meninges, such as leptomeningeal, cortical, and subcortical arteries. The clinical manifestations range from headache to a variety of severe complications of CNS, such as behavioral dysfunction, transient ischemic attacks, or even coma.83
Summary
The use of novel technologies for high-throughput genotyping and, most importantly, the establishment of large collaborative groups, have allowed a substantial increase in the understanding of the genetic network underlying vasculitis predisposition (Table 1). However, because most vasculitides are rare diseases with a complex etiology (in which genetic risk is conferred by hundreds of loci with a low effect independently), only a tiny fraction of their heritability has been unmasked despite
Acknowledgments
FDC was recipient of a grant from the “Ramón y Cajal” program of the Spanish Ministry of Economy and Competitiveness (RYC-2014-16458). RL-M and AM were recipients of a Miguel Servet type I program fellowship from the ISCIII, co-funded by the European Social Fund (ESF, “Investing in your future”) (grants CP16/00033 and CP17/00008, respectively). JM and MAGG were founded by Instituto de Salud Carlos III (ISCIII), Spain, through the RETICS Programs RD16/0012/0004 and RD16/0012/0009 (RIER).
References (84)
- et al.
Epidemiology of the vasculitides
Rheum Dis Clin North Am
(2001) - et al.
Contribution of HLA-B51 in the susceptibility and specific clinical features of Behcet's disease in Tunisian patients
Eur J Intern Med
(2012) - et al.
Paraoxonase prevents accumulation of lipoperoxides in low-density lipoprotein
FEBS Lett
(1991) - et al.
PON1 gene polymorphisms and plasma PON1 activities in Takayasu's arteritis disease
Immunol Lett
(2013) - et al.
An interaction landscape of ubiquitin signaling
Mol Cell
(2017) - et al.
The genetics of Takayasu arteritis
Presse Med
(2017) - et al.
A large-scale genetic analysis reveals a strong contribution of the HLA class II region to giant cell arteritis susceptibility
Am J Hum Genet
(2015) - et al.
A genome-wide association study identifies risk alleles in plasminogen and P4HA2 associated with giant cell arteritis
Am J Hum Genet
(2017) - et al.
Two susceptibility loci to Takayasu arteritis reveal a synergistic role of the IL12B and HLA-B regions in a Japanese population
Am J Hum Genet
(2013) - et al.
Identification of multiple genetic susceptibility loci in Takayasu arteritis
Am J Hum Genet
(2013)
Formation of new vasa vasorum in vasculitis. Production of angiogenic cytokines by multinucleated giant cells
Am J Pathol
Involvement of the peripheral nervous system in polyarteritis nodosa and antineutrophil cytoplasmic antibodies-associated vasculitis
Rheum Dis Clin North Am
Central nervous system disease in antineutrophil cytoplasmic antibodies-associated vasculitis
Rheum Dis Clin North Am
Polyarteritis nodosa
Rheum Dis Clin North Am
Diagnosis and classification of central nervous system vasculitis
J Autoimmun
Association of primary central nervous system vasculitis with the presence of specific human leucocyte antigen gene variant
Clin Neurol Neurosurg
2012 revised International Chapel Hill consensus conference nomenclature of vasculitides
Arthritis Rheum
Nomenclature of cutaneous vasculitis: dermatologic addendum to the 2012 revised international Chapel Hill consensus conference nomenclature of vasculitides
Arthritis Rheumatol
Genetics of vasculitis
Curr Opin Rheumatol
Intravascular immunity as a key to systemic vasculitis: a work in progress, gaining momentum
Clin Exp Immunol
Behcet syndrome: a contemporary view
Nat Rev Rheumatol
Neurological complications of Behcet's syndrome
J Neurol
Genome-wide association study identifies GIMAP as a novel susceptibility locus for Behcet's disease
Ann Rheum Dis
Genome-wide association studies identify IL23R-IL12RB2 and IL10 as Behcet's disease susceptibility loci
Nat Genet
Genome-wide association study identifies variants in the MHC class I, IL10, and IL23R-IL12RB2 regions associated with Behcet's disease
Nat Genet
Genome-wide association analysis identifies new susceptibility loci for Behcet's disease and epistasis between HLA-B*51 and ERAP1
Nat Genet
Identification of multiple independent susceptibility loci in the HLA region in Behcet's disease
Nat Genet
Genetic analysis with the immunochip platform in Behcet Disease. Identification of residues associated in the HLA class I region and new susceptibility loci
PLoS One
Genome-wide association study in an admixed case series reveals IL12A as a new candidate in Behcet disease
PLoS One
Genetics of Behcet disease inside and outside the MHC
Ann Rheum Dis
Identification of novel genetic susceptibility loci for Behcet's disease using a genome-wide association study
Arthritis Res Ther
HLA-B*51 the primary risk in Behcet disease
Proc Natl Acad Sci U S A
Behcet disease-associated MHC class I residues implicate antigen binding and regulation of cell-mediated cytotoxicity
Proc Natl Acad Sci U S A
TNFAIP3 gene polymorphisms confer risk for Behcet's disease in a Chinese Han population
Hum Genet
Identification of possible pathogenic pathways in Behcet's disease using genome-wide association study data from two different populations
Eur J Hum Genet
Genetics and immunodysfunction underlying Behcet's disease and immunomodulant treatment approaches
J Immunotoxicol
Relationships of HLA-B51 or B5 genotype with Behcet's disease clinical characteristics: systematic review and meta-analyses of observational studies
Rheumatology (Oxford)
HLA-B51 subtypes in Turkish patients with Behcet's disease and their correlation with clinical manifestations
Genet Mol Res
Mannose-binding lectin: structure, function, genetics and disease associations
Rev Immunogenet
Mannose-binding lectin gene-2 polymorphisms and serum mannose-binding lectin levels in Behcet's disease
Clin Exp Rheumatol
Genetic polymorphisms of C-type lectin receptors in Behcet's disease in a Chinese Han population
Sci Rep
Altered flow-mediated vasodilatation, low paraoxonase-1 activity, and abnormal high-density lipoprotein subclass distribution in Takayasu's arteritis
Circ J
Cited by (3)
The impact on the scientific community of the 2018 addendum to the CHCC
2022, Frontiers in MedicineCentral and Peripheral Nervous System Complications of Vasculitis Syndromes From Pathology to Bedside: Part 1—Central Nervous System
2022, Current Neurology and Neuroscience ReportsRole of the IL33 and IL1RL1 pathway in the pathogenesis of Immunoglobulin A vasculitis
2021, Scientific Reports
Disclosure Statement: The authors declare no conflicts of interest related to the subject matter discussed in this review.