A genome-wide association study suggests new susceptibility loci for primary antiphospholipid syndrome
ABSTRACT <jats:sec id="s21">Objectives Primary antiphospholipid syndrome (PAPS) is a rare autoimmune disease characterized by the presence of antiphospholipid antibodies and the occurrence of thrombotic events and pregnancy complications. Our study aimed to identify novel genetic susceptibility loci associated with PAPS.<jats:sec id="s22">Methods We performed a genome-wide association study comprising 5,485 individuals (482 affected individuals) of European ancestry. Significant and suggestive independent variants from a meta-analysis of approximately 7 million variants were evaluated for functional and biological process enrichment. The genetic risk variability for PAPS in different populations was also assessed. Hierarchical clustering, Mahalanobis distance, and Dirichlet Process Mixtures with uncertainty clustering methods were used to assess genetic similarities between PAPS and other immune-mediated diseases.<jats:sec id="s23">Results We revealed genetic associations with PAPS in a regulatory locus within the HLA class II region nearHLA-DRAand inSTAT4with a genome-wide level of significance. 34 additional suggestive genetic susceptibility loci for PAPS were also identified. The disease risk allele in the HLA class II locus is associated with overexpression ofHLA-DRB6,HLA-DRB9,HLA-DPB2,HLA-DQA2andHLA-DQB2, and is independent of the association between PAPS andHLA-DRB1*1302. Functional analyses highlighted immune and nervous system related pathways in PAPS-associated loci. The comparison with other immune-mediated diseases revealed a close genetic relatedness to neuromyelitis optica, systemic sclerosis, and Sjögren’s syndrome, suggesting colocalized causal variations close toSTAT4,TNPO3, andBLK.<jats:sec id="s24">Conclusions This study represents a comprehensive large-scale genetic analysis for PAPS and provides new insights into the genetic basis and pathophysiology of this rare disease..
| Medienart: |
|
|---|
Preprint| Erscheinungsjahr: |
2023 |
|---|---|
| Erschienen: |
2023 |
| Enthalten in: |
bioRxiv.org - (2023) vom: 08. Dez. Zur Gesamtaufnahme - year:2023 |
|---|
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Casares-Marfil, Desiré [VerfasserIn] |
|---|
| Links: |
Volltext [kostenfrei] |
|---|
| Themen: |
|---|
| doi: |
10.1101/2023.12.05.23299396 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
XBI041769538 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | XBI041769538 | ||
| 003 | DE-627 | ||
| 005 | 20231209132651.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231206s2023 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1101/2023.12.05.23299396 |2 doi | |
| 035 | |a (DE-627)XBI041769538 | ||
| 035 | |a (biorXiv)10.1101/2023.12.05.23299396 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Casares-Marfil, Desiré |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a A genome-wide association study suggests new susceptibility loci for primary antiphospholipid syndrome |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a Computermedien |b c |2 rdamedia | ||
| 338 | |a Online-Ressource |b cr |2 rdacarrier | ||
| 520 | |a ABSTRACT <jats:sec id="s21">Objectives Primary antiphospholipid syndrome (PAPS) is a rare autoimmune disease characterized by the presence of antiphospholipid antibodies and the occurrence of thrombotic events and pregnancy complications. Our study aimed to identify novel genetic susceptibility loci associated with PAPS.<jats:sec id="s22">Methods We performed a genome-wide association study comprising 5,485 individuals (482 affected individuals) of European ancestry. Significant and suggestive independent variants from a meta-analysis of approximately 7 million variants were evaluated for functional and biological process enrichment. The genetic risk variability for PAPS in different populations was also assessed. Hierarchical clustering, Mahalanobis distance, and Dirichlet Process Mixtures with uncertainty clustering methods were used to assess genetic similarities between PAPS and other immune-mediated diseases.<jats:sec id="s23">Results We revealed genetic associations with PAPS in a regulatory locus within the HLA class II region nearHLA-DRAand inSTAT4with a genome-wide level of significance. 34 additional suggestive genetic susceptibility loci for PAPS were also identified. The disease risk allele in the HLA class II locus is associated with overexpression ofHLA-DRB6,HLA-DRB9,HLA-DPB2,HLA-DQA2andHLA-DQB2, and is independent of the association between PAPS andHLA-DRB1*1302. Functional analyses highlighted immune and nervous system related pathways in PAPS-associated loci. The comparison with other immune-mediated diseases revealed a close genetic relatedness to neuromyelitis optica, systemic sclerosis, and Sjögren’s syndrome, suggesting colocalized causal variations close toSTAT4,TNPO3, andBLK.<jats:sec id="s24">Conclusions This study represents a comprehensive large-scale genetic analysis for PAPS and provides new insights into the genetic basis and pathophysiology of this rare disease. | ||
| 650 | 4 | |a Biology |7 (dpeaa)DE-84 | |
| 650 | 4 | |a 570 |7 (dpeaa)DE-84 | |
| 700 | 1 | |a Martínez-Bueno, Manuel |4 aut | |
| 700 | 1 | |a Borghi, Maria Orietta |4 aut | |
| 700 | 1 | |a Pons-Estel, Guillermo |4 aut | |
| 700 | 1 | |a Reales, Guillermo |4 aut | |
| 700 | 1 | |a Zuo, Yu |4 aut | |
| 700 | 1 | |a Espinosa, Gerard |4 aut | |
| 700 | 1 | |a Radstake, Timothy |4 aut | |
| 700 | 1 | |a van den Hoogen, Lucas L. |4 aut | |
| 700 | 1 | |a Wallace, Chris |4 aut | |
| 700 | 1 | |a Guthridge, Joel |4 aut | |
| 700 | 1 | |a James, Judith A |4 aut | |
| 700 | 1 | |a Cervera, Ricard |4 aut | |
| 700 | 1 | |a Meroni, Pier Luigi |4 aut | |
| 700 | 1 | |a Martin, Javier |4 aut | |
| 700 | 1 | |a Knight, Jason S. |4 aut | |
| 700 | 1 | |a Alarcón-Riquelme, Marta E. |4 aut | |
| 700 | 1 | |a Sawalha, Amr H. |0 (orcid)0000-0002-3884-962X |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t bioRxiv.org |g (2023) vom: 08. Dez. |
| 773 | 1 | 8 | |g year:2023 |g day:08 |g month:12 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1101/2023.12.05.23299396 |z kostenfrei |3 Volltext |
| 912 | |a GBV_XBI | ||
| 951 | |a AR | ||
| 952 | |j 2023 |b 08 |c 12 | ||