Page 126 - The Vasculitides, Volume 1: General Considerations and Systemic Vasculitis

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

Subsequent studies reported a clear familial aggregation of GPA, with a relative risk of
1.56 for first-degree relatives, which indicated the importance of the genetic component for
this disease [116]. In 2012, the first GWAS in AAV [117] (including a large cohort of GPA
and MPA patients was published, reporting more consistent associations with the disease, and
suggesting genetic distinctions between the clinical entities of AAV that may be associated
with ANCA specificity.

HLA Association

Several early low-power studies [118-120] suggested that different HLA class I and class
II loci might be involved in the predisposition to GPA including HLA-DQw7, HLA-DR3,
HLA-DR1, HLA-DR9 and HLA-B50. However, only the HLA DPB1*0401 allele was firmly
associated with GPA, although other neighboring loci such as ring finger protein 1 (RING1), a
transcriptional repressor, and retinoid X receptor beta (RXRB), involved in mediating the
effects of retinoic acid may have independent effects [121, 122].

HLA-DP also showed the highest association signals in the AAV GWAS. Interestingly,
the main associations in the HLA region were observed in the subgroup of patients with
presence of anti-PR3 antibodies, although there were also associations in the cohort of AAV
patients positive for anti-MPO [117]. Hence, it is likely that HLA-DP alleles are a key factor
for autoantibody production in AAV, particularly for anti-PR3.

An increased prevalence of HLA-DR4 was also associated with AAV in general, and
more specifically with GPA. One study [123] performed in a Dutch population showed that
the three subtypes of AAV had a similar HLA antigen distribution, except for HLA-DR1,
which was more prevalent in GPA patients, and HLA-DR8, which showed a decreased
frequency in EGPA patients in comparison with the other two subtypes. Other evidences
suggested that HLA-DRB4 could represent a risk factor specific for EGPA [124].

Non-HLA Association

PRTN3 and MPO encode the two major ANCA autoantigens PR3 and MPO respectively.
PR3 is a neutrophil intracellular protease that can be also located on the plasma membrane.

It has been proposed that elevated membrane expression of PR3 is involved in
progression of chronic inflammatory diseases, including AAV, and that this fact is likely to be
genetically determined.

More than one decade ago, the entire coding and promoter sequences of PRTN3 were
analyzed to identify polymorphisms that could influence the pathophysiology of GPA. The
genetic variations described in that study [125] included seven SNP, one amino acid change
(Val119Ile), one 84 base pair insertion/deletion (INDEL), and a microsatellite.

Among them, only one SNP affecting a putative transcription factor-binding site
(rs62132295, A-564G) was associated with GPA. In the AAV GWAS [117], this PRTN3
variant was not associated at GWAS level, although a suggestive P-value with GPA but not
with MPA was yielded. However, a stronger size effect was observed when the GPA patients
were stratified accordingly with the type of autoantibody production instead of the clinically
defined syndromes.

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