Genetic variants of TREML2 are associated with HLA-B27-positive ankylosing spondylitis

Genetic variants of TREML2 are associated with HLA-B27-positive ankylosing spondylitis Although ankylosing spondylitis (AS) is a common, highly heritable arthropathy, the precise genetic mechanism underlying the disease remains elusive. Here, we investigate the disease-causing mutations in a large AS family with distinguished complexity, consisting of 23 patients covering four generations and exhibiting a mixed HLA-B27 (+) and (−) status. Linkage analysis with 32 members using three methods and whole-exome sequencing analysis with three HLA-B27 (+) patients, one HLA-B27 (−) patient, and one healthy individual did not identify a mutation common to all of the patients, strongly suggesting the existence of genetic heterogeneity in this large pedigree. However, if only B27-positive patients were analyzed, the linkage analysis located a 22-Mb region harboring the HLA gene cluster in chromosome 6 (LOD = 4.2), and the subsequent exome analysis identified two non-synonymous mutations in the TREML2 and IP6K3 genes. These genes were resequenced among 370 sporadic AS patients and 487 healthy individuals. A significantly higher mutation frequency of TREML2 was observed in AS patients (1.51% versus 0.21%). The results obtained for the AS pedigree and sporadic patients suggest that mutation of TREML2 is a major factor leading to AS for HLA-B27 (+) members in this large family and that TREML2 is also a susceptibility gene promoting the development of ankylosing spondylitis in HLA-B27 (+) individuals. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Gene Elsevier

Genetic variants of TREML2 are associated with HLA-B27-positive ankylosing spondylitis

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Publisher
Elsevier
Copyright
Copyright © 2018 Elsevier B.V.
ISSN
0378-1119
eISSN
1879-0038
D.O.I.
10.1016/j.gene.2018.05.057
Publisher site
See Article on Publisher Site

Abstract

Although ankylosing spondylitis (AS) is a common, highly heritable arthropathy, the precise genetic mechanism underlying the disease remains elusive. Here, we investigate the disease-causing mutations in a large AS family with distinguished complexity, consisting of 23 patients covering four generations and exhibiting a mixed HLA-B27 (+) and (−) status. Linkage analysis with 32 members using three methods and whole-exome sequencing analysis with three HLA-B27 (+) patients, one HLA-B27 (−) patient, and one healthy individual did not identify a mutation common to all of the patients, strongly suggesting the existence of genetic heterogeneity in this large pedigree. However, if only B27-positive patients were analyzed, the linkage analysis located a 22-Mb region harboring the HLA gene cluster in chromosome 6 (LOD = 4.2), and the subsequent exome analysis identified two non-synonymous mutations in the TREML2 and IP6K3 genes. These genes were resequenced among 370 sporadic AS patients and 487 healthy individuals. A significantly higher mutation frequency of TREML2 was observed in AS patients (1.51% versus 0.21%). The results obtained for the AS pedigree and sporadic patients suggest that mutation of TREML2 is a major factor leading to AS for HLA-B27 (+) members in this large family and that TREML2 is also a susceptibility gene promoting the development of ankylosing spondylitis in HLA-B27 (+) individuals.

Journal

GeneElsevier

Published: Aug 20, 2018

References

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