A genome-wide survey of CD4+ lymphocyte regulatory genetic variants identifies novel asthma genes

Sunita Sharma, Xiaobo Zhou, Derek M. Thibault, Blanca E. Himes, Andy Liu, Stanley J. Szefler, Robert Strunk, Mario Castro, Nadia N. Hansel, Gregory B. Diette, Becky M. Vonakis, N. Franklin Adkinson, Lydiana Avila, Manuel Soto-Quiros, Albino Barraza-Villareal, Robert F. Lemanske, Julian Solway, Jerry Krishnan, Steven R. White, Chris CheadleAlan E. Berger, Jinshui Fan, Meher Preethi Boorgula, Dan Nicolae, Frank Gilliland, Kathleen Barnes, Stephanie J. London, Fernando Martinez, Carole Ober, Juan C. Celedón, Vincent J. Carey, Scott T. Weiss, Benjamin A. Raby

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

Background Genome-wide association studies have yet to identify the majority of genetic variants involved in asthma. We hypothesized that expression quantitative trait locus (eQTL) mapping can identify novel asthma genes by enabling prioritization of putative functional variants for association testing. Objective We evaluated 6706 cis-acting expression-associated variants (eSNPs) identified through a genome-wide eQTL survey of CD4+ lymphocytes for association with asthma. Methods eSNPs were tested for association with asthma in 359 asthmatic patients and 846 control subjects from the Childhood Asthma Management Program, with verification by using family-based testing. Significant associations were tested for replication in 579 parent-child trios with asthma from Costa Rica. Further functional validation was performed by using formaldehyde-assisted isolation of regulatory elements (FAIRE) quantitative PCR and chromatin immunoprecipitation PCR in lung-derived epithelial cell lines (Beas-2B and A549) and Jurkat cells, a leukemia cell line derived from T lymphocytes. Results Cis-acting eSNPs demonstrated associations with asthma in both cohorts. We confirmed the previously reported association of ORMDL3/GSDMB variants with asthma (combined P = 2.9 × 10-8). Reproducible associations were also observed for eSNPs in 3 additional genes: fatty acid desaturase 2 (FADS2; P =.002), N-acetyl-α-D-galactosaminidase (NAGA; P =.0002), and Factor XIII, A1 (F13A1; P =.0001). Subsequently, we demonstrated that FADS2 mRNA is increased in CD4+ lymphocytes in asthmatic patients and that the associated eSNPs reside within DNA segments with histone modifications that denote open chromatin status and confer enhancer activity. Conclusions Our results demonstrate the utility of eQTL mapping in the identification of novel asthma genes and provide evidence for the importance of FADS2, NAGA, and F13A1 in the pathogenesis of asthma.

Original languageEnglish (US)
Pages (from-to)1153-1162
Number of pages10
JournalJournal of Allergy and Clinical Immunology
Volume134
Issue number5
DOIs
StatePublished - Nov 1 2014

Fingerprint

Asthma
Genome
Lymphocytes
Genes
Quantitative Trait Loci
Histone Code
Fatty Acid Desaturases
Surveys and Questionnaires
Factor XIII
Hexosaminidases
Costa Rica
Cell Line
Polymerase Chain Reaction
Jurkat Cells
Chromatin Immunoprecipitation
Genome-Wide Association Study
Formaldehyde
Chromatin
Leukemia
Epithelial Cells

Keywords

  • Asthma
  • CD4 lymphocytes
  • expression quantitative trait locus
  • haplotype
  • integrative genomics
  • regulatory variants

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Sharma, S., Zhou, X., Thibault, D. M., Himes, B. E., Liu, A., Szefler, S. J., ... Raby, B. A. (2014). A genome-wide survey of CD4+ lymphocyte regulatory genetic variants identifies novel asthma genes. Journal of Allergy and Clinical Immunology, 134(5), 1153-1162. https://doi.org/10.1016/j.jaci.2014.04.011

A genome-wide survey of CD4+ lymphocyte regulatory genetic variants identifies novel asthma genes. / Sharma, Sunita; Zhou, Xiaobo; Thibault, Derek M.; Himes, Blanca E.; Liu, Andy; Szefler, Stanley J.; Strunk, Robert; Castro, Mario; Hansel, Nadia N.; Diette, Gregory B.; Vonakis, Becky M.; Adkinson, N. Franklin; Avila, Lydiana; Soto-Quiros, Manuel; Barraza-Villareal, Albino; Lemanske, Robert F.; Solway, Julian; Krishnan, Jerry; White, Steven R.; Cheadle, Chris; Berger, Alan E.; Fan, Jinshui; Boorgula, Meher Preethi; Nicolae, Dan; Gilliland, Frank; Barnes, Kathleen; London, Stephanie J.; Martinez, Fernando; Ober, Carole; Celedón, Juan C.; Carey, Vincent J.; Weiss, Scott T.; Raby, Benjamin A.

In: Journal of Allergy and Clinical Immunology, Vol. 134, No. 5, 01.11.2014, p. 1153-1162.

Research output: Contribution to journalArticle

Sharma, S, Zhou, X, Thibault, DM, Himes, BE, Liu, A, Szefler, SJ, Strunk, R, Castro, M, Hansel, NN, Diette, GB, Vonakis, BM, Adkinson, NF, Avila, L, Soto-Quiros, M, Barraza-Villareal, A, Lemanske, RF, Solway, J, Krishnan, J, White, SR, Cheadle, C, Berger, AE, Fan, J, Boorgula, MP, Nicolae, D, Gilliland, F, Barnes, K, London, SJ, Martinez, F, Ober, C, Celedón, JC, Carey, VJ, Weiss, ST & Raby, BA 2014, 'A genome-wide survey of CD4+ lymphocyte regulatory genetic variants identifies novel asthma genes', Journal of Allergy and Clinical Immunology, vol. 134, no. 5, pp. 1153-1162. https://doi.org/10.1016/j.jaci.2014.04.011
Sharma, Sunita ; Zhou, Xiaobo ; Thibault, Derek M. ; Himes, Blanca E. ; Liu, Andy ; Szefler, Stanley J. ; Strunk, Robert ; Castro, Mario ; Hansel, Nadia N. ; Diette, Gregory B. ; Vonakis, Becky M. ; Adkinson, N. Franklin ; Avila, Lydiana ; Soto-Quiros, Manuel ; Barraza-Villareal, Albino ; Lemanske, Robert F. ; Solway, Julian ; Krishnan, Jerry ; White, Steven R. ; Cheadle, Chris ; Berger, Alan E. ; Fan, Jinshui ; Boorgula, Meher Preethi ; Nicolae, Dan ; Gilliland, Frank ; Barnes, Kathleen ; London, Stephanie J. ; Martinez, Fernando ; Ober, Carole ; Celedón, Juan C. ; Carey, Vincent J. ; Weiss, Scott T. ; Raby, Benjamin A. / A genome-wide survey of CD4+ lymphocyte regulatory genetic variants identifies novel asthma genes. In: Journal of Allergy and Clinical Immunology. 2014 ; Vol. 134, No. 5. pp. 1153-1162.
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abstract = "Background Genome-wide association studies have yet to identify the majority of genetic variants involved in asthma. We hypothesized that expression quantitative trait locus (eQTL) mapping can identify novel asthma genes by enabling prioritization of putative functional variants for association testing. Objective We evaluated 6706 cis-acting expression-associated variants (eSNPs) identified through a genome-wide eQTL survey of CD4+ lymphocytes for association with asthma. Methods eSNPs were tested for association with asthma in 359 asthmatic patients and 846 control subjects from the Childhood Asthma Management Program, with verification by using family-based testing. Significant associations were tested for replication in 579 parent-child trios with asthma from Costa Rica. Further functional validation was performed by using formaldehyde-assisted isolation of regulatory elements (FAIRE) quantitative PCR and chromatin immunoprecipitation PCR in lung-derived epithelial cell lines (Beas-2B and A549) and Jurkat cells, a leukemia cell line derived from T lymphocytes. Results Cis-acting eSNPs demonstrated associations with asthma in both cohorts. We confirmed the previously reported association of ORMDL3/GSDMB variants with asthma (combined P = 2.9 × 10-8). Reproducible associations were also observed for eSNPs in 3 additional genes: fatty acid desaturase 2 (FADS2; P =.002), N-acetyl-α-D-galactosaminidase (NAGA; P =.0002), and Factor XIII, A1 (F13A1; P =.0001). Subsequently, we demonstrated that FADS2 mRNA is increased in CD4+ lymphocytes in asthmatic patients and that the associated eSNPs reside within DNA segments with histone modifications that denote open chromatin status and confer enhancer activity. Conclusions Our results demonstrate the utility of eQTL mapping in the identification of novel asthma genes and provide evidence for the importance of FADS2, NAGA, and F13A1 in the pathogenesis of asthma.",
keywords = "Asthma, CD4 lymphocytes, expression quantitative trait locus, haplotype, integrative genomics, regulatory variants",
author = "Sunita Sharma and Xiaobo Zhou and Thibault, {Derek M.} and Himes, {Blanca E.} and Andy Liu and Szefler, {Stanley J.} and Robert Strunk and Mario Castro and Hansel, {Nadia N.} and Diette, {Gregory B.} and Vonakis, {Becky M.} and Adkinson, {N. Franklin} and Lydiana Avila and Manuel Soto-Quiros and Albino Barraza-Villareal and Lemanske, {Robert F.} and Julian Solway and Jerry Krishnan and White, {Steven R.} and Chris Cheadle and Berger, {Alan E.} and Jinshui Fan and Boorgula, {Meher Preethi} and Dan Nicolae and Frank Gilliland and Kathleen Barnes and London, {Stephanie J.} and Fernando Martinez and Carole Ober and Celed{\'o}n, {Juan C.} and Carey, {Vincent J.} and Weiss, {Scott T.} and Raby, {Benjamin A.}",
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T1 - A genome-wide survey of CD4+ lymphocyte regulatory genetic variants identifies novel asthma genes

AU - Sharma, Sunita

AU - Zhou, Xiaobo

AU - Thibault, Derek M.

AU - Himes, Blanca E.

AU - Liu, Andy

AU - Szefler, Stanley J.

AU - Strunk, Robert

AU - Castro, Mario

AU - Hansel, Nadia N.

AU - Diette, Gregory B.

AU - Vonakis, Becky M.

AU - Adkinson, N. Franklin

AU - Avila, Lydiana

AU - Soto-Quiros, Manuel

AU - Barraza-Villareal, Albino

AU - Lemanske, Robert F.

AU - Solway, Julian

AU - Krishnan, Jerry

AU - White, Steven R.

AU - Cheadle, Chris

AU - Berger, Alan E.

AU - Fan, Jinshui

AU - Boorgula, Meher Preethi

AU - Nicolae, Dan

AU - Gilliland, Frank

AU - Barnes, Kathleen

AU - London, Stephanie J.

AU - Martinez, Fernando

AU - Ober, Carole

AU - Celedón, Juan C.

AU - Carey, Vincent J.

AU - Weiss, Scott T.

AU - Raby, Benjamin A.

PY - 2014/11/1

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N2 - Background Genome-wide association studies have yet to identify the majority of genetic variants involved in asthma. We hypothesized that expression quantitative trait locus (eQTL) mapping can identify novel asthma genes by enabling prioritization of putative functional variants for association testing. Objective We evaluated 6706 cis-acting expression-associated variants (eSNPs) identified through a genome-wide eQTL survey of CD4+ lymphocytes for association with asthma. Methods eSNPs were tested for association with asthma in 359 asthmatic patients and 846 control subjects from the Childhood Asthma Management Program, with verification by using family-based testing. Significant associations were tested for replication in 579 parent-child trios with asthma from Costa Rica. Further functional validation was performed by using formaldehyde-assisted isolation of regulatory elements (FAIRE) quantitative PCR and chromatin immunoprecipitation PCR in lung-derived epithelial cell lines (Beas-2B and A549) and Jurkat cells, a leukemia cell line derived from T lymphocytes. Results Cis-acting eSNPs demonstrated associations with asthma in both cohorts. We confirmed the previously reported association of ORMDL3/GSDMB variants with asthma (combined P = 2.9 × 10-8). Reproducible associations were also observed for eSNPs in 3 additional genes: fatty acid desaturase 2 (FADS2; P =.002), N-acetyl-α-D-galactosaminidase (NAGA; P =.0002), and Factor XIII, A1 (F13A1; P =.0001). Subsequently, we demonstrated that FADS2 mRNA is increased in CD4+ lymphocytes in asthmatic patients and that the associated eSNPs reside within DNA segments with histone modifications that denote open chromatin status and confer enhancer activity. Conclusions Our results demonstrate the utility of eQTL mapping in the identification of novel asthma genes and provide evidence for the importance of FADS2, NAGA, and F13A1 in the pathogenesis of asthma.

AB - Background Genome-wide association studies have yet to identify the majority of genetic variants involved in asthma. We hypothesized that expression quantitative trait locus (eQTL) mapping can identify novel asthma genes by enabling prioritization of putative functional variants for association testing. Objective We evaluated 6706 cis-acting expression-associated variants (eSNPs) identified through a genome-wide eQTL survey of CD4+ lymphocytes for association with asthma. Methods eSNPs were tested for association with asthma in 359 asthmatic patients and 846 control subjects from the Childhood Asthma Management Program, with verification by using family-based testing. Significant associations were tested for replication in 579 parent-child trios with asthma from Costa Rica. Further functional validation was performed by using formaldehyde-assisted isolation of regulatory elements (FAIRE) quantitative PCR and chromatin immunoprecipitation PCR in lung-derived epithelial cell lines (Beas-2B and A549) and Jurkat cells, a leukemia cell line derived from T lymphocytes. Results Cis-acting eSNPs demonstrated associations with asthma in both cohorts. We confirmed the previously reported association of ORMDL3/GSDMB variants with asthma (combined P = 2.9 × 10-8). Reproducible associations were also observed for eSNPs in 3 additional genes: fatty acid desaturase 2 (FADS2; P =.002), N-acetyl-α-D-galactosaminidase (NAGA; P =.0002), and Factor XIII, A1 (F13A1; P =.0001). Subsequently, we demonstrated that FADS2 mRNA is increased in CD4+ lymphocytes in asthmatic patients and that the associated eSNPs reside within DNA segments with histone modifications that denote open chromatin status and confer enhancer activity. Conclusions Our results demonstrate the utility of eQTL mapping in the identification of novel asthma genes and provide evidence for the importance of FADS2, NAGA, and F13A1 in the pathogenesis of asthma.

KW - Asthma

KW - CD4 lymphocytes

KW - expression quantitative trait locus

KW - haplotype

KW - integrative genomics

KW - regulatory variants

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