Page 120 - The Vasculitides, Volume 1: General Considerations and Systemic Vasculitis

96 F. David Carmona, Ana Márquez, Javier Martín et al.

relatives of affected patients and monozygotic twins. For most vasculitides familial
aggregation has been described in case reports or small series without quantification. In the
absence of family studies, different prevalences of these diseases in different ethnic groups
support the existence of important genetic components.

Two main approaches, candidate gene studies and genome-wide association studies
(GWAS), have been used to identify disease-associated genes in complex diseases both of
which involve genotyping of genetic variations, mainly the single-nucleotide polymorphisms
(SNP) in cases and controls. Until recently, all genetic studies in vasculitides were designed
as candidate gene studies, examining a SNP or a set of polymorphisms within certain loci
with a potential role in a particular phenotype or disease. In these studies, the selection of a
candidate gene or genomic region was based on its biological function or its location in a
region implicated by previous associations or linkage studies. In contrast to candidate gene
studies, the GWAS approach, in which hundreds of thousands of polymorphisms are analyzed
across the whole genome, is unbiased and it does not require prior hypotheses about the type
of genes or polymorphisms most likely to be associated with the phenotypes of interest.
The recent publication of GWAS in some vasculitides has increased the understanding of
potential underlying genetic mechanisms. Moreover, the two methodologies have shown that
the human leukocyte antigen (HLA) region harbors the strongest genetic contribution to the
pathophysiology of vasculitides. This genomic region occupies a large segment of DNA
extending about 3.6 megabases on the short arm of chromosome 6, and containing hundreds
of genes involved in immune function.

This chapter summarizes the genetic aspects of vasculitides especially an overview of the
recent progress in the elucidation of their genetic component. Two Chapel Hill Consensus
Conference (CHCC) nomenclatures, one in 1994 and a Revised version in 2012 [1, 2],
provided consensus on nosology and definitions for the commonest forms of vasculitis in
adults based upon the caliber of vessels involved. The Pediatric Rheumatology European
Society (PRES), European League against Rheumatism (EULAR), and the Pediatric
Rheumatology International Trials Organization (PRINTO) proposed specific classification
criteria, as well as, clinical, laboratory and radiographic characteristics for the commonest
childhood vasculitis syndromes, based upon vessel size [3, 4], similar to the 2012 Revised
CHCC nomenclature [2]. These overlapping nomenclatures form the basis for the definition
of most recent cohorts of vasculitides to which reference is made in this chapter.

Large Vessel Vasculitis

Giant Cell Arteritis

Increasing knowledge suggests that giant cell arteritis (GCA) has an important genetic
basis. Familial aggregation with sharing of HLA alleles has been reported for GCA for
several decades ago [5-12].

However, most studies have been performed in unreplicated Spanish and Italian
population studies [13] usually with small sample sizes. Despite these limitations, GCA can
be considered as one of the best examples of vasculitis in which a genetic influence has been
implicated in both disease susceptibility and severity.

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