Regulatory polymorphisms modulate the expression of HLA class II molecules and promote autoimmunity
Targeted sequencing of sixteen SLE risk loci among 1349 Caucasian cases and controls produced a comprehensive dataset of the variations causing susceptibility to systemic lupus erythematosus (SLE). Two independent disease association signals in the HLA-D region identified two regulatory regions cont...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2016-02-01
|
| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/12089 |
| id |
doaj-9cb126754a5c4c41a78ee8db59f27c5a |
|---|---|
| record_format |
Article |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Prithvi Raj Ekta Rai Ran Song Shaheen Khan Benjamin E Wakeland Kasthuribai Viswanathan Carlos Arana Chaoying Liang Bo Zhang Igor Dozmorov Ferdicia Carr-Johnson Mitja Mitrovic Graham B Wiley Jennifer A Kelly Bernard R Lauwerys Nancy J Olsen Chris Cotsapas Christine K Garcia Carol A Wise John B Harley Swapan K Nath Judith A James Chaim O Jacob Betty P Tsao Chandrashekhar Pasare David R Karp Quan Zhen Li Patrick M Gaffney Edward K Wakeland |
| spellingShingle |
Prithvi Raj Ekta Rai Ran Song Shaheen Khan Benjamin E Wakeland Kasthuribai Viswanathan Carlos Arana Chaoying Liang Bo Zhang Igor Dozmorov Ferdicia Carr-Johnson Mitja Mitrovic Graham B Wiley Jennifer A Kelly Bernard R Lauwerys Nancy J Olsen Chris Cotsapas Christine K Garcia Carol A Wise John B Harley Swapan K Nath Judith A James Chaim O Jacob Betty P Tsao Chandrashekhar Pasare David R Karp Quan Zhen Li Patrick M Gaffney Edward K Wakeland Regulatory polymorphisms modulate the expression of HLA class II molecules and promote autoimmunity eLife targeted sequencing HLA SLE risk haplotype risk allele LD |
| author_facet |
Prithvi Raj Ekta Rai Ran Song Shaheen Khan Benjamin E Wakeland Kasthuribai Viswanathan Carlos Arana Chaoying Liang Bo Zhang Igor Dozmorov Ferdicia Carr-Johnson Mitja Mitrovic Graham B Wiley Jennifer A Kelly Bernard R Lauwerys Nancy J Olsen Chris Cotsapas Christine K Garcia Carol A Wise John B Harley Swapan K Nath Judith A James Chaim O Jacob Betty P Tsao Chandrashekhar Pasare David R Karp Quan Zhen Li Patrick M Gaffney Edward K Wakeland |
| author_sort |
Prithvi Raj |
| title |
Regulatory polymorphisms modulate the expression of HLA class II molecules and promote autoimmunity |
| title_short |
Regulatory polymorphisms modulate the expression of HLA class II molecules and promote autoimmunity |
| title_full |
Regulatory polymorphisms modulate the expression of HLA class II molecules and promote autoimmunity |
| title_fullStr |
Regulatory polymorphisms modulate the expression of HLA class II molecules and promote autoimmunity |
| title_full_unstemmed |
Regulatory polymorphisms modulate the expression of HLA class II molecules and promote autoimmunity |
| title_sort |
regulatory polymorphisms modulate the expression of hla class ii molecules and promote autoimmunity |
| publisher |
eLife Sciences Publications Ltd |
| series |
eLife |
| issn |
2050-084X |
| publishDate |
2016-02-01 |
| description |
Targeted sequencing of sixteen SLE risk loci among 1349 Caucasian cases and controls produced a comprehensive dataset of the variations causing susceptibility to systemic lupus erythematosus (SLE). Two independent disease association signals in the HLA-D region identified two regulatory regions containing 3562 polymorphisms that modified thirty-seven transcription factor binding sites. These extensive functional variations are a new and potent facet of HLA polymorphism. Variations modifying the consensus binding motifs of IRF4 and CTCF in the XL9 regulatory complex modified the transcription of HLA-DRB1, HLA-DQA1 and HLA-DQB1 in a chromosome-specific manner, resulting in a 2.5-fold increase in the surface expression of HLA-DR and DQ molecules on dendritic cells with SLE risk genotypes, which increases to over 4-fold after stimulation. Similar analyses of fifteen other SLE risk loci identified 1206 functional variants tightly linked with disease-associated SNPs and demonstrated that common disease alleles contain multiple causal variants modulating multiple immune system genes. |
| topic |
targeted sequencing HLA SLE risk haplotype risk allele LD |
| url |
https://elifesciences.org/articles/12089 |
| work_keys_str_mv |
AT prithviraj regulatorypolymorphismsmodulatetheexpressionofhlaclassiimoleculesandpromoteautoimmunity AT ektarai regulatorypolymorphismsmodulatetheexpressionofhlaclassiimoleculesandpromoteautoimmunity AT ransong regulatorypolymorphismsmodulatetheexpressionofhlaclassiimoleculesandpromoteautoimmunity AT shaheenkhan regulatorypolymorphismsmodulatetheexpressionofhlaclassiimoleculesandpromoteautoimmunity AT benjaminewakeland regulatorypolymorphismsmodulatetheexpressionofhlaclassiimoleculesandpromoteautoimmunity AT kasthuribaiviswanathan regulatorypolymorphismsmodulatetheexpressionofhlaclassiimoleculesandpromoteautoimmunity AT carlosarana regulatorypolymorphismsmodulatetheexpressionofhlaclassiimoleculesandpromoteautoimmunity AT chaoyingliang regulatorypolymorphismsmodulatetheexpressionofhlaclassiimoleculesandpromoteautoimmunity AT bozhang regulatorypolymorphismsmodulatetheexpressionofhlaclassiimoleculesandpromoteautoimmunity AT igordozmorov regulatorypolymorphismsmodulatetheexpressionofhlaclassiimoleculesandpromoteautoimmunity AT ferdiciacarrjohnson regulatorypolymorphismsmodulatetheexpressionofhlaclassiimoleculesandpromoteautoimmunity AT mitjamitrovic regulatorypolymorphismsmodulatetheexpressionofhlaclassiimoleculesandpromoteautoimmunity AT grahambwiley regulatorypolymorphismsmodulatetheexpressionofhlaclassiimoleculesandpromoteautoimmunity AT jenniferakelly regulatorypolymorphismsmodulatetheexpressionofhlaclassiimoleculesandpromoteautoimmunity AT bernardrlauwerys regulatorypolymorphismsmodulatetheexpressionofhlaclassiimoleculesandpromoteautoimmunity AT nancyjolsen regulatorypolymorphismsmodulatetheexpressionofhlaclassiimoleculesandpromoteautoimmunity AT chriscotsapas regulatorypolymorphismsmodulatetheexpressionofhlaclassiimoleculesandpromoteautoimmunity AT christinekgarcia regulatorypolymorphismsmodulatetheexpressionofhlaclassiimoleculesandpromoteautoimmunity AT carolawise regulatorypolymorphismsmodulatetheexpressionofhlaclassiimoleculesandpromoteautoimmunity AT johnbharley regulatorypolymorphismsmodulatetheexpressionofhlaclassiimoleculesandpromoteautoimmunity AT swapanknath regulatorypolymorphismsmodulatetheexpressionofhlaclassiimoleculesandpromoteautoimmunity AT judithajames regulatorypolymorphismsmodulatetheexpressionofhlaclassiimoleculesandpromoteautoimmunity AT chaimojacob regulatorypolymorphismsmodulatetheexpressionofhlaclassiimoleculesandpromoteautoimmunity AT bettyptsao regulatorypolymorphismsmodulatetheexpressionofhlaclassiimoleculesandpromoteautoimmunity AT chandrashekharpasare regulatorypolymorphismsmodulatetheexpressionofhlaclassiimoleculesandpromoteautoimmunity AT davidrkarp regulatorypolymorphismsmodulatetheexpressionofhlaclassiimoleculesandpromoteautoimmunity AT quanzhenli regulatorypolymorphismsmodulatetheexpressionofhlaclassiimoleculesandpromoteautoimmunity AT patrickmgaffney regulatorypolymorphismsmodulatetheexpressionofhlaclassiimoleculesandpromoteautoimmunity AT edwardkwakeland regulatorypolymorphismsmodulatetheexpressionofhlaclassiimoleculesandpromoteautoimmunity |
| _version_ |
1721476528010690560 |
| spelling |
doaj-9cb126754a5c4c41a78ee8db59f27c5a2021-05-05T00:15:56ZengeLife Sciences Publications LtdeLife2050-084X2016-02-01510.7554/eLife.12089Regulatory polymorphisms modulate the expression of HLA class II molecules and promote autoimmunityPrithvi Raj0Ekta Rai1Ran Song2Shaheen Khan3Benjamin E Wakeland4Kasthuribai Viswanathan5Carlos Arana6Chaoying Liang7Bo Zhang8Igor Dozmorov9Ferdicia Carr-Johnson10Mitja Mitrovic11Graham B Wiley12Jennifer A Kelly13Bernard R Lauwerys14Nancy J Olsen15Chris Cotsapas16Christine K Garcia17Carol A Wise18John B Harley19Swapan K Nath20Judith A James21Chaim O Jacob22Betty P Tsao23Chandrashekhar Pasare24David R Karp25Quan Zhen Li26Patrick M Gaffney27Edward K Wakeland28https://orcid.org/0000-0002-7107-0992Department of Immunology, University of Texas Southwestern Medical Center, Dallas, United StatesDepartment of Immunology, University of Texas Southwestern Medical Center, Dallas, United States; School of Biotechnology, Shri Mata Vaishno Devi University, Katra, IndiaDepartment of Immunology, University of Texas Southwestern Medical Center, Dallas, United StatesDepartment of Immunology, University of Texas Southwestern Medical Center, Dallas, United StatesDepartment of Immunology, University of Texas Southwestern Medical Center, Dallas, United StatesDepartment of Immunology, University of Texas Southwestern Medical Center, Dallas, United StatesDepartment of Immunology, University of Texas Southwestern Medical Center, Dallas, United StatesDepartment of Immunology, University of Texas Southwestern Medical Center, Dallas, United StatesDepartment of Immunology, University of Texas Southwestern Medical Center, Dallas, United StatesDepartment of Immunology, University of Texas Southwestern Medical Center, Dallas, United StatesDepartment of Immunology, University of Texas Southwestern Medical Center, Dallas, United StatesDepartment of Neurology, Yale School of Medicine, New Haven, United StatesArthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, United StatesArthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, United StatesPole de pathologies rhumatismales, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Bruxelles, BelgiumDivision of Rheumatology, Department of Medicine, Penn State Medical School, Hershey, United StatesDepartment of Neurology, Yale School of Medicine, New Haven, United StatesDepartment of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, United States; Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, United StatesEugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, United States; Department of Orthopaedic Surgery, University of Texas Southwestern Medical Center, Dallas, United States; Sarah M. and Charles E. Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children, Dallas, United States; Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, United StatesCincinnati VA Medical Center, Cincinnati, United States; Cincinnati Children's Hospital Medical Center, Cincinnati, United StatesArthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, United StatesArthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, United StatesDepartment of Medicine, University of Southern California, Los Angeles, United StatesDepartment of Medicine, University of California, Los Angeles, Los Angeles, United StatesDepartment of Immunology, University of Texas Southwestern Medical Center, Dallas, United StatesRheumatic Diseases Division, Department of Medicine, University of Texas Southwestern Medical Center, Dallas, United StatesDepartment of Immunology, University of Texas Southwestern Medical Center, Dallas, United StatesArthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, United StatesDepartment of Immunology, University of Texas Southwestern Medical Center, Dallas, United StatesTargeted sequencing of sixteen SLE risk loci among 1349 Caucasian cases and controls produced a comprehensive dataset of the variations causing susceptibility to systemic lupus erythematosus (SLE). Two independent disease association signals in the HLA-D region identified two regulatory regions containing 3562 polymorphisms that modified thirty-seven transcription factor binding sites. These extensive functional variations are a new and potent facet of HLA polymorphism. Variations modifying the consensus binding motifs of IRF4 and CTCF in the XL9 regulatory complex modified the transcription of HLA-DRB1, HLA-DQA1 and HLA-DQB1 in a chromosome-specific manner, resulting in a 2.5-fold increase in the surface expression of HLA-DR and DQ molecules on dendritic cells with SLE risk genotypes, which increases to over 4-fold after stimulation. Similar analyses of fifteen other SLE risk loci identified 1206 functional variants tightly linked with disease-associated SNPs and demonstrated that common disease alleles contain multiple causal variants modulating multiple immune system genes.https://elifesciences.org/articles/12089targeted sequencingHLASLE riskhaplotyperisk alleleLD |