Abstract
Background: Eczema herpeticum (EH) is a rare complication of atopic dermatitis (AD) caused by disseminated herpes simplex virus (HSV) infection. The role of rare and/or deleterious genetic variants in disease etiology is largely unknown. This study aimed to identify genes that harbor damaging genetic variants associated with HSV infection in AD with a history of recurrent eczema herpeticum (ADEH+). Methods: Whole genome sequencing (WGS) was performed on 49 recurrent ADEH+ (≥3 EH episodes), 491 AD without a history of eczema herpeticum (ADEH−) and 237 non-atopic control (NA) subjects. Variants were annotated, and a gene-based approach (SKAT-O) was used to identify genes harboring damaging genetic variants associated with ADEH+. Genes identified through WGS were studied for effects on HSV responses and keratinocyte differentiation. Results: Eight genes were identified in the comparison of recurrent ADEH+to ADEH−and NA subjects: SIDT2, CLEC7A, GSTZ1, TPSG1, SP110, RBBP8NL, TRIM15, and FRMD3. Silencing SIDT2 and RBBP8NL in normal human primary keratinocytes (NHPKs) led to significantly increased HSV-1 replication. SIDT2-silenced NHPKs had decreased gene expression of IFNk and IL1b in response to HSV-1 infection. RBBP8NL-silenced NHPKs had decreased gene expression of IFNk, but increased IL1b. Additionally, silencing SIDT2 and RBBP8NL also inhibited gene expression of keratinocyte differentiation markers keratin 10 (KRT10) and loricrin (LOR). Conclusion: SIDT2 and RBBP8NL participate in keratinocyte's response to HSV-1 infection. SIDT2 and RBBP8NL also regulate expression of keratinocyte differentiation genes of KRT10 and LOR.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 2510-2523 |
| Number of pages | 14 |
| Journal | Allergy: European Journal of Allergy and Clinical Immunology |
| Volume | 76 |
| Issue number | 8 |
| DOIs | |
| State | Published - Aug 2021 |
| Externally published | Yes |
Keywords
- SIDT2
- atopic dermatitis
- eczema herpeticum
- genetics
- herpes simplex virus
- whole genome sequencing
ASJC Scopus subject areas
- Immunology and Allergy
- Immunology
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In: Allergy: European Journal of Allergy and Clinical Immunology, Vol. 76, No. 8, 08.2021, p. 2510-2523.
Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Whole genome sequencing identifies novel genetic mutations in patients with eczema herpeticum
AU - Bin, Lianghua
AU - Malley, Claire
AU - Taylor, Patricia
AU - Preethi Boorgula, Meher
AU - Chavan, Sameer
AU - Daya, Michelle
AU - Mathias, Malaika
AU - Shankar, Gautam
AU - Rafaels, Nicholas
AU - Vergara, Candelaria
AU - Potee, Joseph
AU - Campbell, Monica
AU - Hanifin, Jon M.
AU - Simpson, Eric
AU - Schneider, Lynda C.
AU - Gallo, Richard L.
AU - Hata, Tissa
AU - Paller, Amy S.
AU - De Benedetto, Anna
AU - Beck, Lisa A.
AU - Ong, Peck Y.
AU - Guttman-Yassky, Emma
AU - Richers, Brittany
AU - Baraghoshi, David
AU - Ruczinski, Ingo
AU - Barnes, Kathleen C.
AU - Leung, Donald Y.M.
AU - Mathias, Rasika A.
N1 - Funding Information: This work was funded by NIH/NIAID Atopic Dermatitis Research Network grants 1U19AI117673-01 and 1UM1AI151958. The authors acknowledge the nurses of Clinical Translational Research Center at National Jewish Health for their hard work in recruiting human subjects for this study. Clinical Translational Research Center at National Jewish Health is supported in part by the Colorado Clinical and Translational Science Award/Colorado Clinical & Translational Sciences Institute grant UL1 RR025780 from National Center for Research Resources/NIH and UL1 TR000154 from NIH/National Center for Advancing Translational Sciences. The authors also thank Dr. Matthew Strand for his help on statistical analyses of the data. The authors have no financial conflict of interest related to this manuscript. Dr. Bin has nothing to disclose. Dr. Malley has nothing to disclose. Patricia Taylor, NP-C, has nothing to disclose. Ms. Boorgula, Mr. Chavan, Dr. Daya, Ms. Mathias, Mr. Shankar, Mr. Rafaels, Dr. Vergara, Mr. Potee, Ms Campbell, Dr. Hanifin, Dr. Simpson, Dr. Gallo, Dr. Hatta, Dr. Ong, Dr. Richers, Dr. Baraghoshi, Dr. Ruczinski, Dr. Barnes, Dr. Leung, and Dr. Mathias have nothing to disclose. Dr. Schneider reports other from Regeneron, personal fees from AbbVie, grants from Pfizer, outside the submitted work. Dr. Paller has been an investigator (without personal compensation) for AbbVie, AnaptysBio, Eli Lilly, Incyte, Leo, Janssen, Novartis, and Regeneron, and a consultant with honorarium for AbbVie, Asana, Boehringer Ingelheim, Dermavant, Dermira, Eli Lilly, Forte, Galderma, Incyte, Inmed, Leo, Lifemax, Novartis, Pfizer, RAPT, Regeneron, and Sanofi Genzyme, outside the submitted work. Dr. De Benedetto reports other from Kiniksa, grants from Pfizer, personal fees from Regeneron Sanofi, outside the submitted work. Dr. Beck reports grants and personal fees from AbbVie, personal fees from Allakos, personal fees from AstraZeneca, personal fees from Benevolent AIBio, personal fees from Incyte, personal fees from LEO Pharma, grants and personal fees from Lilly, personal fees from NAOS Bioderma, personal fees from Novartis, grants and personal fees from Pfizer, personal fees from Principia Biopharma, personal fees from Rapt Therapeutics, grants and personal fees from Regeneron, grants and personal fees from Sanofi/Genzyme, personal fees from UCB, personal fees from Vimalan, personal fees from Sanofi-Aventis, stock in Medtronics, other from 3M, other from Moderna, and other from Gilead, outside the submitted work. Dr. Guttman-Yassky is an employee of Mount Sinai and has received research funds (grants paid to the institution) from AbbVie, Almirall, Amgen, AnaptysBio, Asana Biosciences, Boehringer Ingelheim, Celgene, Dermavant, DS Biopharma, Eli Lilly, Galderma, Ichnos Sciences, Innovaderm, Janssen, Kiniska, Kyowa Kirin, Leo Pharma, Novan, Pfizer, Ralexar, Regeneron Pharmaceuticals, Inc., Sienna Biopharma, UCB and Union Therapeutics, and is a consultant for AbbVie, Aditum Bio, Almirall, Amgen, Asana Biosciences, AstraZeneca, Boehringer Ingelheim, Cara Therapeutics, Celgene, Concert, DBV, Dermira, DS Biopharma, Eli Lilly, EMD Serono, Escalier, Galderma, Ichnos Sciences, Incyte Kyowa Kirin, Leo Pharma, Mitsubishi Tanabe, Pandion Therapeutics, Pfizer, RAPT Therapeutics, Regeneron Pharmaceuticals, Inc., Sanofi, Sienna Biopharma, Target PharmaSolutions, and Union Therapeutics, outside of this work. Funding Information: This work was funded by NIH/NIAID Atopic Dermatitis Research Network grants 1U19AI117673‐01 and 1UM1AI151958. The authors acknowledge the nurses of Clinical Translational Research Center at National Jewish Health for their hard work in recruiting human subjects for this study. Clinical Translational Research Center at National Jewish Health is supported in part by the Colorado Clinical and Translational Science Award/Colorado Clinical & Translational Sciences Institute grant UL1 RR025780 from National Center for Research Resources/NIH and UL1 TR000154 from NIH/National Center for Advancing Translational Sciences. The authors also thank Dr. Matthew Strand for his help on statistical analyses of the data. The authors have no financial conflict of interest related to this manuscript. Dr. Bin has nothing to disclose. Dr. Malley has nothing to disclose. Patricia Taylor, NP‐C, has nothing to disclose. Ms. Boorgula, Mr. Chavan, Dr. Daya, Ms. Mathias, Mr. Shankar, Mr. Rafaels, Dr. Vergara, Mr. Potee, Ms Campbell, Dr. Hanifin, Dr. Simpson, Dr. Gallo, Dr. Hatta, Dr. Ong, Dr. Richers, Dr. Baraghoshi, Dr. Ruczinski, Dr. Barnes, Dr. Leung, and Dr. Mathias have nothing to disclose. Dr. Schneider reports other from Regeneron, personal fees from AbbVie, grants from Pfizer, outside the submitted work. Dr. Paller has been an investigator (without personal compensation) for AbbVie, AnaptysBio, Eli Lilly, Incyte, Leo, Janssen, Novartis, and Regeneron, and a consultant with honorarium for AbbVie, Asana, Boehringer Ingelheim, Dermavant, Dermira, Eli Lilly, Forte, Galderma, Incyte, Inmed, Leo, Lifemax, Novartis, Pfizer, RAPT, Regeneron, and Sanofi Genzyme, outside the submitted work. Dr. De Benedetto reports other from Kiniksa, grants from Pfizer, personal fees from Regeneron Sanofi, outside the submitted work. Dr. Beck reports grants and personal fees from AbbVie, personal fees from Allakos, personal fees from AstraZeneca, personal fees from Benevolent AIBio, personal fees from Incyte, personal fees from LEO Pharma, grants and personal fees from Lilly, personal fees from NAOS Bioderma, personal fees from Novartis, grants and personal fees from Pfizer, personal fees from Principia Biopharma, personal fees from Rapt Therapeutics, grants and personal fees from Regeneron, grants and personal fees from Sanofi/Genzyme, personal fees from UCB, personal fees from Vimalan, personal fees from Sanofi‐Aventis, stock in Medtronics, other from 3M, other from Moderna, and other from Gilead, outside the submitted work. Dr. Guttman‐Yassky is an employee of Mount Sinai and has received research funds (grants paid to the institution) from AbbVie, Almirall, Amgen, AnaptysBio, Asana Biosciences, Boehringer Ingelheim, Celgene, Dermavant, DS Biopharma, Eli Lilly, Galderma, Ichnos Sciences, Innovaderm, Janssen, Kiniska, Kyowa Kirin, Leo Pharma, Novan, Pfizer, Ralexar, Regeneron Pharmaceuticals, Inc., Sienna Biopharma, UCB and Union Therapeutics, and is a consultant for AbbVie, Aditum Bio, Almirall, Amgen, Asana Biosciences, AstraZeneca, Boehringer Ingelheim, Cara Therapeutics, Celgene, Concert, DBV, Dermira, DS Biopharma, Eli Lilly, EMD Serono, Escalier, Galderma, Ichnos Sciences, Incyte Kyowa Kirin, Leo Pharma, Mitsubishi Tanabe, Pandion Therapeutics, Pfizer, RAPT Therapeutics, Regeneron Pharmaceuticals, Inc., Sanofi, Sienna Biopharma, Target PharmaSolutions, and Union Therapeutics, outside of this work. Publisher Copyright: © 2021 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.
PY - 2021/8
Y1 - 2021/8
N2 - Background: Eczema herpeticum (EH) is a rare complication of atopic dermatitis (AD) caused by disseminated herpes simplex virus (HSV) infection. The role of rare and/or deleterious genetic variants in disease etiology is largely unknown. This study aimed to identify genes that harbor damaging genetic variants associated with HSV infection in AD with a history of recurrent eczema herpeticum (ADEH+). Methods: Whole genome sequencing (WGS) was performed on 49 recurrent ADEH+ (≥3 EH episodes), 491 AD without a history of eczema herpeticum (ADEH−) and 237 non-atopic control (NA) subjects. Variants were annotated, and a gene-based approach (SKAT-O) was used to identify genes harboring damaging genetic variants associated with ADEH+. Genes identified through WGS were studied for effects on HSV responses and keratinocyte differentiation. Results: Eight genes were identified in the comparison of recurrent ADEH+to ADEH−and NA subjects: SIDT2, CLEC7A, GSTZ1, TPSG1, SP110, RBBP8NL, TRIM15, and FRMD3. Silencing SIDT2 and RBBP8NL in normal human primary keratinocytes (NHPKs) led to significantly increased HSV-1 replication. SIDT2-silenced NHPKs had decreased gene expression of IFNk and IL1b in response to HSV-1 infection. RBBP8NL-silenced NHPKs had decreased gene expression of IFNk, but increased IL1b. Additionally, silencing SIDT2 and RBBP8NL also inhibited gene expression of keratinocyte differentiation markers keratin 10 (KRT10) and loricrin (LOR). Conclusion: SIDT2 and RBBP8NL participate in keratinocyte's response to HSV-1 infection. SIDT2 and RBBP8NL also regulate expression of keratinocyte differentiation genes of KRT10 and LOR.
AB - Background: Eczema herpeticum (EH) is a rare complication of atopic dermatitis (AD) caused by disseminated herpes simplex virus (HSV) infection. The role of rare and/or deleterious genetic variants in disease etiology is largely unknown. This study aimed to identify genes that harbor damaging genetic variants associated with HSV infection in AD with a history of recurrent eczema herpeticum (ADEH+). Methods: Whole genome sequencing (WGS) was performed on 49 recurrent ADEH+ (≥3 EH episodes), 491 AD without a history of eczema herpeticum (ADEH−) and 237 non-atopic control (NA) subjects. Variants were annotated, and a gene-based approach (SKAT-O) was used to identify genes harboring damaging genetic variants associated with ADEH+. Genes identified through WGS were studied for effects on HSV responses and keratinocyte differentiation. Results: Eight genes were identified in the comparison of recurrent ADEH+to ADEH−and NA subjects: SIDT2, CLEC7A, GSTZ1, TPSG1, SP110, RBBP8NL, TRIM15, and FRMD3. Silencing SIDT2 and RBBP8NL in normal human primary keratinocytes (NHPKs) led to significantly increased HSV-1 replication. SIDT2-silenced NHPKs had decreased gene expression of IFNk and IL1b in response to HSV-1 infection. RBBP8NL-silenced NHPKs had decreased gene expression of IFNk, but increased IL1b. Additionally, silencing SIDT2 and RBBP8NL also inhibited gene expression of keratinocyte differentiation markers keratin 10 (KRT10) and loricrin (LOR). Conclusion: SIDT2 and RBBP8NL participate in keratinocyte's response to HSV-1 infection. SIDT2 and RBBP8NL also regulate expression of keratinocyte differentiation genes of KRT10 and LOR.
KW - SIDT2
KW - atopic dermatitis
KW - eczema herpeticum
KW - genetics
KW - herpes simplex virus
KW - whole genome sequencing
UR - http://www.scopus.com/inward/record.url?scp=85102472754&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85102472754&partnerID=8YFLogxK
U2 - 10.1111/all.14762
DO - 10.1111/all.14762
M3 - Article
C2 - 33548076
AN - SCOPUS:85102472754
SN - 0105-4538
VL - 76
SP - 2510
EP - 2523
JO - Allergy: European Journal of Allergy and Clinical Immunology
JF - Allergy: European Journal of Allergy and Clinical Immunology
IS - 8
ER -