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. 2017 Jan 5;100(1):64-74.
doi: 10.1016/j.ajhg.2016.11.013. Epub 2016 Dec 29.

A Genome-wide Association Study Identifies Risk Alleles in Plasminogen and P4HA2 Associated with Giant Cell Arteritis

F David Carmona  1 , Augusto Vaglio  2 , Sarah L Mackie  3 , José Hernández-Rodríguez  4 , Paul A Monach  5 , Santos Castañeda  6 , Roser Solans  7 , Inmaculada C Morado  8 , Javier Narváez  9 , Marc Ramentol-Sintas  7 , Colin T Pease  3 , Bhaskar Dasgupta  10 , Richard Watts  11 , Nader Khalidi  12 , Carol A Langford  13 , Steven Ytterberg  14 , Luigi Boiardi  15 , Lorenzo Beretta  16 , Marcello Govoni  17 , Giacomo Emmi  18 , Francesco Bonatti  19 , Marco A Cimmino  20 , Torsten Witte  21 , Thomas Neumann  22 , Julia Holle  23 , Verena Schönau  24 , Laurent Sailler  25 , Thomas Papo  26 , Julien Haroche  27 , Alfred Mahr  28 , Luc Mouthon  29 , Øyvind Molberg  30 , Andreas P Diamantopoulos  31 , Alexandre Voskuyl  32 , Elisabeth Brouwer  33 , Thomas Daikeler  34 , Christoph T Berger  35 , Eamonn S Molloy  36 , Lorraine O'Neill  36 , Daniel Blockmans  37 , Benedicte A Lie  38 , Paul Mclaren  39 , Timothy J Vyse  40 , Cisca Wijmenga  41 , Yannick Allanore  42 , Bobby P C Koeleman  43 ; Spanish CGA Group; UKGCA Consortium; Vasculitis Clinical Research Consortium; Jennifer H Barrett  3 , María C Cid  4 , Carlo Salvarani  15 , Peter A Merkel  44 , Ann W Morgan  3 , Miguel A González-Gay  45 , Javier Martín  46
Collaborators, Affiliations

A Genome-wide Association Study Identifies Risk Alleles in Plasminogen and P4HA2 Associated with Giant Cell Arteritis

F David Carmona et al. Am J Hum Genet. .

Abstract

Giant cell arteritis (GCA) is the most common form of vasculitis in individuals older than 50 years in Western countries. To shed light onto the genetic background influencing susceptibility for GCA, we performed a genome-wide association screening in a well-powered study cohort. After imputation, 1,844,133 genetic variants were analyzed in 2,134 case subjects and 9,125 unaffected individuals from ten independent populations of European ancestry. Our data confirmed HLA class II as the strongest associated region (independent signals: rs9268905, p = 1.94 × 10-54, per-allele OR = 1.79; and rs9275592, p = 1.14 × 10-40, OR = 2.08). Additionally, PLG and P4HA2 were identified as GCA risk genes at the genome-wide level of significance (rs4252134, p = 1.23 × 10-10, OR = 1.28; and rs128738, p = 4.60 × 10-9, OR = 1.32, respectively). Interestingly, we observed that the association peaks overlapped with different regulatory elements related to cell types and tissues involved in the pathophysiology of GCA. PLG and P4HA2 are involved in vascular remodelling and angiogenesis, suggesting a high relevance of these processes for the pathogenic mechanisms underlying this type of vasculitis.

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Figures

Figure 1
Figure 1
Manhattan Plot Representation of the GWAS Results The −log10 of the inverse variance-weighted meta-analysis p values are plotted against their physical chromosomal position. The red line represents the genome-wide level of significance (p < 5 × 10−8). The most relevant associations are highlighted.
Figure 2
Figure 2
Regional Plots of the Associated Loci with GCA outside the HLA Region in the Overall Meta-analysis (A) Plasminogen (PLG) region. (B) Prolyl 4-hydroxylase subunit alpha 2 (P4HA2) region. Lead variants are highlighted in violet.
Figure 3
Figure 3
Interaction Network Formed for GCA Risk Loci GWAS genes of this study and those previously identified through Immunochip and consistent candidate gene studies were included in the analysis. STRING database was used to look for both direct and indirect interactions among selected genes. The width of the blue lines indicates the reliability of each interaction.
See this image and copyright information in PMC

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