Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8644786 | Gene | 2018 | 35 Pages |
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 (â) status. Linkage analysis with 32 members using three methods and whole-exome sequencing analysis with three HLA-B27 (+) patients, one HLA-B27 (â) 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 (LODâ¯=â¯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.
Keywords
The major histocompatibility complexIL-23RBASFIASDASESRHLA-B27IBSAnkylosing spondylitislinkage analysisExome sequencingerythrocyte sedimentation rateTREMMHCGenome-wide association studiesGWASC-reactive proteinCRPSingle nucleotide polymorphismSNPtriggering receptor expressed on myeloid cellsinterleukin-23 receptor
Related Topics
Life Sciences
Biochemistry, Genetics and Molecular Biology
Genetics
Authors
Yuan Feng, Yaqiang Hong, Xin Zhang, Chunwei Cao, Xichao Yang, Shujuan Lai, Chunmei Fan, Feng Cheng, Mei Yan, Chaohua Li, Wan Huang, Wei Chen, Ping Zhu, Changqing Zeng,