The Wegener's Granulomatosis quantitative trait locus on chromosome 6p21.3 as characterized by tagSNP genotyping

Michael Heckmann ¹, Julia U Holle ², Larissa Arning ¹, Silvia Knaup ¹, Bernhard Hellmich ², Michael Nothnagel ³, Peter Jagiello ¹, Wolfgang L Gross ², Joerg T Epplen ¹ and Stefan Wieczorek ^1*

¹ Ruhr-University, Human Genetics, Germany
² University Hospitalof Schleswig-Holstein, Germany
³ Christian Albrechts University Kiel, Germany

^* To whom correspondence should be addressed. E-mail: stefan.wieczorek{at}rub.de.

Accepted 13 October 2007

Abstract

Objective: A genomic region on chromosome 6p21.3, including HLA-DPB1, has been linked to Wegener’s granulomatosis (WG). The basis of this association is difficult to be evaluated because of the complex haplotype block architecture of this region. We have designed a detailed HapMap based fine-mapping approach to identify the causative molecular genetic variation(s).

Methods: 282 WG patients and 380 healthy controls were genotyped for HLA-DPB1 as well as for 35 informative SNPs within the respective region. 25 of these SNPs have been selected as tagging SNPs for another 219 associated SNPs. Allele and genotype frequencies were analyzed separately, by means of contingency tables and logistic regression. Finally, the coding region of RING1 was directly sequenced in individuals who carried haplotypes that were correlated with contrasting WG risks.

Results: The previously reported strong association of WG with the HLA-DPB1*0401 allele was confirmed in an independent WG sample (n=108, pc=6.4E-08). Considering the complete cohort (n=282) the association remained highly significant in ANCA-positive (pc=1.26E-22), but not in ANCA-negative patients. A SNP 3’ of HLA-DPB1 yielded the smallest p value and was associated with WG partly independently from the HLA-DPB1 alleles. Another informative SNP in the vicinity of RING1 revealed significant WG association that was also partly independent of HLA-DPB1. RING1 sequencing, however, did not reveal any variation potentially predisposing to WG.

Conclusions: The HLA-DPB1/RING1 region is strongly associated with WG in ANCA-positive individuals. Further analyses of potential cis regulatory sequences of candidate genes HLA-DPB1, RING1 and RXRB appear warranted.

Keywords: Autoinflammatory Diseases, Genetics, Risk Factors, Statistical Methods, Wegener's

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