Shared genomic segments analysis identifies MHC class I and class III molecules as genetic risk factors for juvenile idiopathic arthritis
Summary: Juvenile idiopathic arthritis (JIA) is a complex rheumatic disease encompassing several clinically defined subtypes of varying severity. The etiology of JIA remains largely unknown, but genome-wide association studies (GWASs) have identified up to 22 genes associated with JIA susceptibility...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2024-04-01
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| Series: | HGG Advances |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2666247724000162 |
| _version_ | 1797272401929568256 |
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| author | Cecile N. Avery Nicole D. Russell Cody J. Steely Aimee O. Hersh John F. Bohnsack Sampath Prahalad Lynn B. Jorde |
| author_facet | Cecile N. Avery Nicole D. Russell Cody J. Steely Aimee O. Hersh John F. Bohnsack Sampath Prahalad Lynn B. Jorde |
| author_sort | Cecile N. Avery |
| collection | DOAJ |
| description | Summary: Juvenile idiopathic arthritis (JIA) is a complex rheumatic disease encompassing several clinically defined subtypes of varying severity. The etiology of JIA remains largely unknown, but genome-wide association studies (GWASs) have identified up to 22 genes associated with JIA susceptibility, including a well-established association with HLA-DRB1. Continued investigation of heritable risk factors has been hindered by disease heterogeneity and low disease prevalence. In this study, we utilized shared genomic segments (SGS) analysis on whole-genome sequencing of 40 cases from 12 multi-generational pedigrees significantly enriched for JIA. Subsets of cases are connected by a common ancestor in large extended pedigrees, increasing the power to identify disease-associated loci. SGS analysis identifies genomic segments shared among disease cases that are likely identical by descent and anchored by a disease locus. This approach revealed statistically significant signals for major histocompatibility complex (MHC) class I and class III alleles, particularly HLA-A∗02:01, which was observed at a high frequency among cases. Furthermore, we identified an additional risk locus at 12q23.2–23.3, containing genes primarily expressed by naive B cells, natural killer cells, and monocytes. The recognition of additional risk beyond HLA-DRB1 provides a new perspective on immune cell dynamics in JIA. These findings contribute to our understanding of JIA and may guide future research and therapeutic strategies. |
| first_indexed | 2024-03-07T14:27:49Z |
| format | Article |
| id | doaj.art-2a0eec16dbe84a5baca47afb40757e3f |
| institution | Directory Open Access Journal |
| issn | 2666-2477 |
| language | English |
| last_indexed | 2024-03-07T14:27:49Z |
| publishDate | 2024-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | HGG Advances |
| spelling | doaj.art-2a0eec16dbe84a5baca47afb40757e3f2024-03-06T05:28:45ZengElsevierHGG Advances2666-24772024-04-0152100277Shared genomic segments analysis identifies MHC class I and class III molecules as genetic risk factors for juvenile idiopathic arthritisCecile N. Avery0Nicole D. Russell1Cody J. Steely2Aimee O. Hersh3John F. Bohnsack4Sampath Prahalad5Lynn B. Jorde6Department of Human Genetics, University of Utah, Salt Lake City, UT 84112, USA; Corresponding authorDepartment of Human Genetics, University of Utah, Salt Lake City, UT 84112, USADepartment of Human Genetics, University of Utah, Salt Lake City, UT 84112, USADepartment of Pediatrics, University of Utah, Salt Lake City, UT 84112, USADepartment of Pediatrics, University of Utah, Salt Lake City, UT 84112, USADepartment of Pediatrics, Emory University School of Medicine, Atlanta, GA 30307, USADepartment of Human Genetics, University of Utah, Salt Lake City, UT 84112, USA; Corresponding authorSummary: Juvenile idiopathic arthritis (JIA) is a complex rheumatic disease encompassing several clinically defined subtypes of varying severity. The etiology of JIA remains largely unknown, but genome-wide association studies (GWASs) have identified up to 22 genes associated with JIA susceptibility, including a well-established association with HLA-DRB1. Continued investigation of heritable risk factors has been hindered by disease heterogeneity and low disease prevalence. In this study, we utilized shared genomic segments (SGS) analysis on whole-genome sequencing of 40 cases from 12 multi-generational pedigrees significantly enriched for JIA. Subsets of cases are connected by a common ancestor in large extended pedigrees, increasing the power to identify disease-associated loci. SGS analysis identifies genomic segments shared among disease cases that are likely identical by descent and anchored by a disease locus. This approach revealed statistically significant signals for major histocompatibility complex (MHC) class I and class III alleles, particularly HLA-A∗02:01, which was observed at a high frequency among cases. Furthermore, we identified an additional risk locus at 12q23.2–23.3, containing genes primarily expressed by naive B cells, natural killer cells, and monocytes. The recognition of additional risk beyond HLA-DRB1 provides a new perspective on immune cell dynamics in JIA. These findings contribute to our understanding of JIA and may guide future research and therapeutic strategies.http://www.sciencedirect.com/science/article/pii/S2666247724000162 |
| spellingShingle | Cecile N. Avery Nicole D. Russell Cody J. Steely Aimee O. Hersh John F. Bohnsack Sampath Prahalad Lynn B. Jorde Shared genomic segments analysis identifies MHC class I and class III molecules as genetic risk factors for juvenile idiopathic arthritis HGG Advances |
| title | Shared genomic segments analysis identifies MHC class I and class III molecules as genetic risk factors for juvenile idiopathic arthritis |
| title_full | Shared genomic segments analysis identifies MHC class I and class III molecules as genetic risk factors for juvenile idiopathic arthritis |
| title_fullStr | Shared genomic segments analysis identifies MHC class I and class III molecules as genetic risk factors for juvenile idiopathic arthritis |
| title_full_unstemmed | Shared genomic segments analysis identifies MHC class I and class III molecules as genetic risk factors for juvenile idiopathic arthritis |
| title_short | Shared genomic segments analysis identifies MHC class I and class III molecules as genetic risk factors for juvenile idiopathic arthritis |
| title_sort | shared genomic segments analysis identifies mhc class i and class iii molecules as genetic risk factors for juvenile idiopathic arthritis |
| url | http://www.sciencedirect.com/science/article/pii/S2666247724000162 |
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