@article{4419478ee39d42f7bb1cd5ac5dffeee9,
title = "Lung function in African American Children with asthma is associated with novel regulatory variants of the KIT ligand KITLG/SCF and gene-by-air-pollution interaction",
abstract = "Baseline lung function, quantified as forced expiratory volume in the first second of exhalation (FEV1), is a standard diagnostic criterion used by clinicians to identify and classify lung diseases. Using whole-genome sequencing data from the National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine project, we identified a novel genetic association with FEV1 on chromosome 12 in 867 African American children with asthma (P = 1.26 3 1028, b = 0.302). Conditional analysis within 1 Mb of the tag signal (rs73429450) yielded one major and two other weaker independent signals within this peak. We explored statistical and functional evidence for all variants in linkage disequilibrium with the three independent signals and yielded nine variants as the most likely candidates responsible for the association with FEV1. Hi-C data and expression QTL analysis demonstrated that these variants physically interacted with KITLG (KIT ligand, also known as SCF), and their minor alleles were associated with increased expression of the KITLG gene in nasal epithelial cells. Gene-by-air-pollution interaction analysis found that the candidate variant rs58475486 interacted with past-year ambient sulfur dioxide exposure (P = 0.003, b = 0.32). This study identified a novel protective genetic association with FEV1, possibly mediated through KITLG, in African American children with asthma. This is the first study that has identified a genetic association between lung function and KITLG, which has established a role in orchestrating allergic inflammation in asthma.",
keywords = "African American, Air pollution, FEV gene-by-environment interaction, GWAS, GxE, KITLG, SCF",
author = "Mak, {Angel C.Y.} and Satria Sajuthi and Jaehyun Joo and Shujie Xiao and Sleiman, {Patrick M.} and White, {Marquitta J.} and Lee, {Eunice Y.} and Benjamin Saef and Donglei Hu and Hongsheng Gui and Keys, {Kevin L.} and Fred Lurmann and Deepti Jain and Gon{\c c}alo Abecasis and Kang, {Hyun Min} and Nickerson, {Deborah A.} and Soren Germer and Zody, {Michael C.} and Lara Winterkorn and Catherine Reeves and Scott Huntsman and Celeste Eng and Sandra Salazar and Oh, {Sam S.} and Gilliland, {Frank D.} and Zhanghua Chen and Rajesh Kumar and Mart{\'i}nez, {Fernando D.} and Wu, {Ann Chen} and Elad Ziv and Hakon Hakonarson and Himes, {Blanca E.} and {Keoki Williams}, L. and Seibold, {Max A.} and Burchard, {Esteban G.}",
note = "Funding Information: The authors thank the studies and participants who provided biological samples and data for TOPMed; the recruiters who obtained the data: Duanny Alva, Gaby Ayala-Rodr{\'i}guez, Lisa Caine, Elizabeth Castellanos, Jaime Col{\'o}n, Denise DeJesus, Blanca L{\'o}pez, Brenda L{\'o}pez, Louis Martos, Vivian Medina, Juana Olivo, Mario Peralta, Esther Pomares, Jihan Quraishi, Johanna Rodr{\'i}guez, Shahdad Saeedi, Dean Soto, and Ana Taveras; Mar{\'i}a Pino-Yanes for providing feedback on this study; Thomas W Blackwell for providing critical review on this manuscript; Biobank participants and researchers who contributed or collected data; and the Editors and Reviewers for providing valuable feedback on this manuscript. They authors also acknowledge the following GALA II and SAGE II study collaborators: Shannon Thyne, University of California, San Francisco (UCSF); Harold J. Farber, Texas Children{\textquoteright}s Hospital; Denise Serebrisky, Jacobi Medical Center; Rajesh Kumar, Lurie Children{\textquoteright}s Hospital of Chicago; Emerita Brigino-Buenaventura, Kaiser Permanente; Michael A. LeNoir, Bay Area Pediatrics; Kelley Meade, UCSF Benioff Children{\textquoteright}s Hospital, Oakland; William Rodr{\'i}guez-Cintr{\'o}n, VA Hospital, Puerto Rico; Pedro C. {\'A}vila, Northwestern University; Jose R. Rodr{\'i}guez-Santana, Centro de Neumolog{\'i}a Pedi{\'a}trica; Luisa N. Borrell, City University of New York; Adam Davis, UCSF Benioff Children{\textquoteright}s Hospital, Oakland; and Saunak Sen, University of Tennessee; the families and patients for their participation; and thank the numerous healthcare providers and community clinics for their support, and participation, in GALA II and SAGE II. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The GALA II study, the SAGE II study, and E.G.B. were supported by the Sandler Family Foundation, the American Asthma Foundation, the RWJF Amos Medical Faculty Development Program, the Harry W. and Diana V. Hind Distinguished Professorship in Pharmaceutical Sciences II, the National Heart, Lung, and Blood Institute (NHLBI) (R01 HL-117004, R01 HL-128439, R01 HL-135156, and X01 HL-134589), the National Institute of Environmental Health Sciences (R01 ES-015794), the National Institute on Minority Health and Health Disparities (P60 MD-006902 and R01 MD-010443), the National Human Genome Research Institute (NHGRI) (U01 HG-009080), and the Tobacco-Related Disease Research Program (24RT-0025). M.J.W. was supported by the NHLBI (K01 HL-140218). J.J. and B.E.H. were supported by the NHLBI (R01 HL-133433 and R01 HL-141992). K.L.K. was supported by the NHLBI (R01 HL-135156-S1), the UCSF Bakar Institute, the Gordon and Betty Moore Foundation (GBMF3834), and the Alfred P. Sloan Foundation (2013-10-27) grant to the University of California, Berkeley through the Moore-Sloan Data Science Environment Initiative. A.C.W. was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (1R01 HD-085993-01). The SAPPHIRE study was supported by the Fund for Henry Ford Hospital, the American Asthma Foundation, the NHLBI (R01 HL-118267, R01 HL-141485, and X01 HL-134589), the National Institute of Allergy and Infectious Diseases (R01 AI-079139), and the National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK-113003). The GCPD-A study was supported by an Institutional award from the Children{\textquoteright}s Hospital of Philadelphia and by the NHLBI (X01 HL-134589). Part of this research was conducted using the UK Biobank Resource under application number 40375. WGS for the TOPMed program was supported by the NHLBI. WGS for “NHLBI TOPMed: Gene-Environment, Admixture and Latino Asthmatics Study” (phs000920) and “NHLBI TOPMed: Study of African Americans, Asthma, Genes and Environments” (phs000921) was performed at the New York Genome Center (3R01 HL-117004-02S3) and the University of Washington Northwest Genomics Center (HHSN268201600032I). WGS for “NHLBI TOPMed: Study of Asthma Phenotypes & Pharmacogenomic Interactions by Race-Ethnicity” (phs001467) and “Genetics of Complex Pediatric Disorders - Asthma” (phs001661) was performed at the University of Washington Northwest Genomics Center (HHSN268201600032I). Centralized read mapping and genotype calling, along with variant quality metrics and filtering, were provided by the TOPMed Informatics Research Center (3R01 HL-117626-02S1; contract HHSN268201800002I). Phenotype harmonization, data management, sample identity quality control, and general study coordination were provided by the TOPMed Data Coordinating Center (3R01 HL-120393-02S1; contract HHSN268201800001I). WGS of part of GALA II was performed by New York Genome Center under The Centers for Common Disease Genomics (CCDG) of the Genome Sequencing Program (GSP) grant (UM1 HG-008901). The GSP Coordinating Center (U24 HG-008956) contributed to cross-program scientific initiatives, and provided logistical and general study coordination. GSP is funded by the NHGRI, the NHLBI, and the National Eye Institute. The TOPMed imputation panel was supported by the NHLBI and TOPMed study investigators who contributed data to the reference panel. The panel was constructed and implemented by the TOPMed Informatics Research Center at the University of Michigan (3R01 HL-117626-02S1; contract HHSN268201800002I). The TOPMed Data Coordinating Center (3R01 HL-120393-02S1; contract HHSN268201800001I) provided additional data management, sample identity checks, and overall program coordination and support. Funding Information: The authors thank the studies and participants who provided biological samples and data for TOPMed; the recruiters who obtained the data: Duanny Alva, Gaby Ayala-Rodr{\'i}guez, Lisa Caine, Elizabeth Castellanos, Jaime Col{\'o}n, Denise DeJesus, Blanca L{\'o}pez, Brenda L{\'o}pez, Louis Martos, Vivian Medina, Juana Olivo, Mario Peralta, Esther Pomares, Jihan Quraishi, Johanna Rodr{\'i}guez, Shahdad Saeedi, Dean Soto, and Ana Taveras; Mar{\'i}a Pino-Yanes for providing feedback on this study; Thomas W Blackwell for providing critical review on this manuscript; Biobank participants and researchers who contributed or collected data; and the Editors and Reviewers for providing valuable feedback on this manuscript. They authors also acknowledge the following GALA II and SAGE II study collaborators: Shannon Thyne, University of California, San Francisco (UCSF); Harold J. Farber, Texas Children{\textquoteright}s Hospital; Denise Serebrisky, Jacobi Medical Center; Rajesh Kumar, Lurie Children{\textquoteright}s Hospital of Chicago; Emerita Brigino-Buenaventura, Kaiser Per-manente; Michael A. LeNoir, Bay Area Pediatrics; Kelley Meade, UCSF Benioff Children{\textquoteright}s Hospital, Oakland; William Rodr{\'i}guez-Cintr{\'o}n, VA Hospital, Puerto Rico; Pedro C. {\'A}vila, Northwestern University; Jose R. Rodr{\'i}guez-Santana, Centro de Neumolog{\'i}a Pedi{\'a}trica; Luisa N. Borrell, City University of New York; Adam Davis, UCSF Benioff Children{\textquoteright}s Hospital, Oakland; and Saunak Sen, University of Tennessee; the families and patients for their participation; and thank the numerous healthcare providers and community clinics for their support, and participation, in GALA II and SAGE II. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The GALA II study, the SAGE II study, and E.G.B. were supported by the Sandler Family Foundation, the American Asthma Foundation, the RWJF Amos Medical Faculty Development Program, the Harry W. and Diana V. Hind Distinguished Professorship in Pharmaceutical Sciences II, the National Heart, Lung, and Blood Institute (NHLBI) (R01 HL-117004, R01 HL-128439, R01 HL-135156, and X01 HL-134589), the National Institute of Environmental Health Sciences (R01 ES-015794), the National Institute on Minority Health and Health Disparities (P60 MD-006902 and R01 MD-010443), the National Human Genome Research Institute (NHGRI) (U01 HG-009080), and the Tobacco-Related Disease Research Program (24RT-0025). M.J.W. was supported by the NHLBI (K01 HL-140218). J.J. and B.E.H. were supported by the NHLBI (R01 HL-133433 and R01 HL-141992). K.L.K. was supported by the NHLBI (R01 HL-135156-S1), the UCSF Bakar Institute, the Gordon and Betty Moore Foundation (GBMF3834), and the Alfred P. Sloan Foundation (2013-10-27) grant to the University of California, Berkeley through the Moore-Sloan Data Science Environment Initiative. A.C.W. was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (1R01 HD-085993-01). The SAPPHIRE study was supported by the Fund for Henry Ford Hospital, the American Asthma Foundation, the NHLBI (R01 HL-118267, R01 HL-141485, and X01 HL-134589), the National Institute of Allergy and Infectious Diseases (R01 AI-079139), and the National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK-113003). The GCPD-A study was supported by an Institutional award from the Children{\textquoteright}s Hospital of Philadelphia and by the NHLBI (X01 HL-134589). Part of this research was conducted using the UK Biobank Resource under application number 40375. WGS for the TOPMed program was supported by the NHLBI. WGS for “NHLBI TOPMed: Gene-Environment, Admixture and Latino Asthmatics Study” (phs000920) and “NHLBI TOPMed: Study of African Americans, Asthma, Genes and Environments” (phs000921) was performed at the New York Genome Center (3R01 HL-117004-02S3) and the University of Washington Northwest Genomics Center (HHSN268201600032I). WGS for “NHLBI TOPMed: Study of Asthma Phenotypes & Pharmacogenomic Interactions by Race-Ethnicity” (phs001467) and “Genetics of Complex Pediatric Disorders - Asthma” (phs001661) was performed at the University of Washington Northwest Genomics Center (HHSN268201600032I). Centralized read mapping and genotype calling, along with variant quality metrics and filtering, were provided by the TOPMed Informatics Research Center (3R01 HL-117626-02S1; contract HHSN268201800002I). Phenotype harmonization, data management, sample identity quality control, and general study coordination were provided by the TOPMed Data Coordinating Center (3R01 HL-120393-02S1; contract HHSN268201800001I). WGS of part of GALA II was performed by New York Genome Center under The Centers for Common Disease Genomics (CCDG) of the Genome Sequencing Program (GSP) grant (UM1 HG-008901). The GSP Coordinating Center (U24 HG-008956) contributed to cross-program scientific initiatives, and provided logistical and general study coordination. GSP is funded by the NHGRI, the NHLBI, and the National Eye Institute. The TOPMed imputation panel was supported by the NHLBI and TOPMed study investigators who contributed data to the reference panel. The panel was constructed and implemented by the TOPMed Informatics Research Center at the University of Michigan (3R01 HL-117626-02S1; contract HHSN268201800002I). The TOPMed Data Coordinating Center (3R01 HL-120393-02S1; contract HHSN268201800001I) provided additional data management, sample identity checks, and overall program coordination and support. Publisher Copyright: Copyright {\textcopyright} 2020 by the Genetics Society of America.",
year = "2020",
month = jul,
doi = "10.1534/genetics.120.303231",
language = "English (US)",
volume = "215",
pages = "869--886",
journal = "Genetics",
issn = "0016-6731",
publisher = "Genetics Society of America",
number = "3",
}