. 2015 Jun;135(6):1502-10.

doi: 10.1016/j.jaci.2014.10.033. Epub 2014 Dec 6.

Genome-wide association study and admixture mapping reveal new loci associated with total IgE levels in Latinos

Maria Pino-Yanes¹, Christopher R Gignoux², Joshua M Galanter³, Albert M Levin⁴, Catarina D Campbell⁵, Celeste Eng⁶, Scott Huntsman⁶, Katherine K Nishimura⁶, Pierre-Antoine Gourraud⁷, Kiana Mohajeri⁵, Brian J O'Roak⁸, Donglei Hu⁶, Rasika A Mathias⁹, Elizabeth A Nguyen⁶, Lindsey A Roth⁶, Badri Padhukasahasram¹⁰, Andres Moreno-Estrada¹¹, Karla Sandoval¹¹, Cheryl A Winkler¹², Fred Lurmann¹³, Adam Davis¹⁴, Harold J Farber¹⁵, Kelley Meade¹⁴, Pedro C Avila¹⁶, Denise Serebrisky¹⁷, Rocio Chapela¹⁸, Jean G Ford¹⁹, Michael A Lenoir²⁰, Shannon M Thyne²¹, Emerita Brigino-Buenaventura²², Luisa N Borrell²³, William Rodriguez-Cintron²⁴, Saunak Sen²⁵, Rajesh Kumar²⁶, Jose R Rodriguez-Santana²⁷, Carlos D Bustamante¹¹, Fernando D Martinez²⁸, Benjamin A Raby²⁹, Scott T Weiss²⁹, Dan L Nicolae³⁰, Carole Ober³⁰, Deborah A Meyers³¹, Eugene R Bleecker³¹, Steven J Mack³², Ryan D Hernandez³³, Evan E Eichler³⁴, Kathleen C Barnes⁹, L Keoki Williams³⁵, Dara G Torgerson⁶, Esteban G Burchard³

Affiliations

¹ Department of Medicine, University of California, San Francisco, Calif; CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain. Electronic address: mdelpino@ull.edu.es.
² Department of Medicine, University of California, San Francisco, Calif; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, Calif; Department of Genetics, Stanford University, Palo Alto, Calif.
³ Department of Medicine, University of California, San Francisco, Calif; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, Calif.
⁴ Department of Public Health Sciences, Henry Ford Health System, Detroit, Mich.
⁵ Department of Genome Sciences, University of Washington, Seattle, Wash.
⁶ Department of Medicine, University of California, San Francisco, Calif.
⁷ Department of Neurology, University of California, San Francisco, Calif.
⁸ Department of Genome Sciences, University of Washington, Seattle, Wash; Molecular & Medical Genetics Department, Oregon Health and Science University, Portland, Ore.
⁹ Division of Allergy & Clinical Immunology, Department of Medicine, Johns Hopkins University, Baltimore, Md.
¹⁰ Center for Health Policy and Health Services Research, Henry Ford Health System, Detroit, Mich.
¹¹ Department of Genetics, Stanford University, Palo Alto, Calif.
¹² Basic Research Laboratory, Center for Cancer Research, National Cancer Institute, Leidos Biomedical, Frederick National Laboratory for Cancer Research, Frederick, Md.
¹³ Sonoma Technology, Petaluma, Calif.
¹⁴ Children's Hospital and Research Center Oakland, Oakland, Calif.
¹⁵ Department of Pediatrics, Section of Pulmonology, Baylor College of Medicine and Texas Children's Hospital, Houston, Tex.
¹⁶ Department of Medicine, Northwestern University, Chicago, Ill.
¹⁷ Pediatric Pulmonary Division, Jacobi Medical Center, Bronx, NY.
¹⁸ Instituto Nacional de Enfermedades Respiratorias (INER), Mexico City, Mexico.
¹⁹ Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Md.
²⁰ Bay Area Pediatrics, Oakland, Calif.
²¹ Department of Pediatrics, University of California San Francisco, San Francisco General Hospital, San Francisco, Calif.
²² Department of Allergy and Immunology, Kaiser Permanente-Vallejo Medical Center, Vallejo, Calif.
²³ Department of Health Sciences, Graduate Program in Public Health, City University of New York, Bronx, NY.
²⁴ Veterans Caribbean Health Care System, San Juan, Puerto Rico.
²⁵ Department of Epidemiology and Biostatistics, University of California, San Francisco, Calif.
²⁶ Children's Memorial Hospital and the Feinberg School of Medicine, Northwestern University, Chicago, Ill.
²⁷ Centro de Neumología Pediátrica, San Juan, Puerto Rico.
²⁸ Arizona Respiratory Center, University of Arizona, Tucson, Ariz; BIO5 Institute, University of Arizona, Tucson, Ariz.
²⁹ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass.
³⁰ Department of Human Genetics, University of Chicago, Chicago, Ill.
³¹ Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC.
³² Children's Hospital Oakland Research Institute, Oakland, Calif.
³³ Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, Calif.
³⁴ Department of Genome Sciences, University of Washington, Seattle, Wash; Howard Hughes Medical Institute, Seattle, Wash.
³⁵ Center for Health Policy and Health Services Research, Henry Ford Health System, Detroit, Mich; Department of Internal Medicine, Henry Ford Health System, Detroit, Mich.

PMID: 25488688
PMCID: PMC4458233
DOI: 10.1016/j.jaci.2014.10.033

Genome-wide association study and admixture mapping reveal new loci associated with total IgE levels in Latinos

Maria Pino-Yanes et al. J Allergy Clin Immunol. 2015 Jun.

. 2015 Jun;135(6):1502-10.

doi: 10.1016/j.jaci.2014.10.033. Epub 2014 Dec 6.

Authors

Affiliations

¹ Department of Medicine, University of California, San Francisco, Calif; CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain. Electronic address: mdelpino@ull.edu.es.
² Department of Medicine, University of California, San Francisco, Calif; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, Calif; Department of Genetics, Stanford University, Palo Alto, Calif.
³ Department of Medicine, University of California, San Francisco, Calif; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, Calif.
⁴ Department of Public Health Sciences, Henry Ford Health System, Detroit, Mich.
⁵ Department of Genome Sciences, University of Washington, Seattle, Wash.
⁶ Department of Medicine, University of California, San Francisco, Calif.
⁷ Department of Neurology, University of California, San Francisco, Calif.
⁸ Department of Genome Sciences, University of Washington, Seattle, Wash; Molecular & Medical Genetics Department, Oregon Health and Science University, Portland, Ore.
⁹ Division of Allergy & Clinical Immunology, Department of Medicine, Johns Hopkins University, Baltimore, Md.
¹⁰ Center for Health Policy and Health Services Research, Henry Ford Health System, Detroit, Mich.
¹¹ Department of Genetics, Stanford University, Palo Alto, Calif.
¹² Basic Research Laboratory, Center for Cancer Research, National Cancer Institute, Leidos Biomedical, Frederick National Laboratory for Cancer Research, Frederick, Md.
¹³ Sonoma Technology, Petaluma, Calif.
¹⁴ Children's Hospital and Research Center Oakland, Oakland, Calif.
¹⁵ Department of Pediatrics, Section of Pulmonology, Baylor College of Medicine and Texas Children's Hospital, Houston, Tex.
¹⁶ Department of Medicine, Northwestern University, Chicago, Ill.
¹⁷ Pediatric Pulmonary Division, Jacobi Medical Center, Bronx, NY.
¹⁸ Instituto Nacional de Enfermedades Respiratorias (INER), Mexico City, Mexico.
¹⁹ Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Md.
²⁰ Bay Area Pediatrics, Oakland, Calif.
²¹ Department of Pediatrics, University of California San Francisco, San Francisco General Hospital, San Francisco, Calif.
²² Department of Allergy and Immunology, Kaiser Permanente-Vallejo Medical Center, Vallejo, Calif.
²³ Department of Health Sciences, Graduate Program in Public Health, City University of New York, Bronx, NY.
²⁴ Veterans Caribbean Health Care System, San Juan, Puerto Rico.
²⁵ Department of Epidemiology and Biostatistics, University of California, San Francisco, Calif.
²⁶ Children's Memorial Hospital and the Feinberg School of Medicine, Northwestern University, Chicago, Ill.
²⁷ Centro de Neumología Pediátrica, San Juan, Puerto Rico.
²⁸ Arizona Respiratory Center, University of Arizona, Tucson, Ariz; BIO5 Institute, University of Arizona, Tucson, Ariz.
²⁹ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass.
³⁰ Department of Human Genetics, University of Chicago, Chicago, Ill.
³¹ Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC.
³² Children's Hospital Oakland Research Institute, Oakland, Calif.
³³ Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, Calif.
³⁴ Department of Genome Sciences, University of Washington, Seattle, Wash; Howard Hughes Medical Institute, Seattle, Wash.
³⁵ Center for Health Policy and Health Services Research, Henry Ford Health System, Detroit, Mich; Department of Internal Medicine, Henry Ford Health System, Detroit, Mich.

PMID: 25488688
PMCID: PMC4458233
DOI: 10.1016/j.jaci.2014.10.033

Abstract

Background: IgE is a key mediator of allergic inflammation, and its levels are frequently increased in patients with allergic disorders.

Objective: We sought to identify genetic variants associated with IgE levels in Latinos.

Methods: We performed a genome-wide association study and admixture mapping of total IgE levels in 3334 Latinos from the Genes-environments & Admixture in Latino Americans (GALA II) study. Replication was evaluated in 454 Latinos, 1564 European Americans, and 3187 African Americans from independent studies.

Results: We confirmed associations of 6 genes identified by means of previous genome-wide association studies and identified a novel genome-wide significant association of a polymorphism in the zinc finger protein 365 gene (ZNF365) with total IgE levels (rs200076616, P = 2.3 × 10(-8)). We next identified 4 admixture mapping peaks (6p21.32-p22.1, 13p22-31, 14q23.2, and 22q13.1) at which local African, European, and/or Native American ancestry was significantly associated with IgE levels. The most significant peak was 6p21.32-p22.1, where Native American ancestry was associated with lower IgE levels (P = 4.95 × 10(-8)). All but 22q13.1 were replicated in an independent sample of Latinos, and 2 of the peaks were replicated in African Americans (6p21.32-p22.1 and 14q23.2). Fine mapping of 6p21.32-p22.1 identified 6 genome-wide significant single nucleotide polymorphisms in Latinos, 2 of which replicated in European Americans. Another single nucleotide polymorphism was peak-wide significant within 14q23.2 in African Americans (rs1741099, P = 3.7 × 10(-6)) and replicated in non-African American samples (P = .011).

Conclusion: We confirmed genetic associations at 6 genes and identified novel associations within ZNF365, HLA-DQA1, and 14q23.2. Our results highlight the importance of studying diverse multiethnic populations to uncover novel loci associated with total IgE levels.

Keywords: Hispanics; IgE; Latinos; admixture mapping; allergy; asthma; genome-wide association study; minority populations; next-generation sequencing.

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Figures

**Figure 1**
Fine mapping of *ZNF365* in GALA II. Included in the plot are -log₁₀(p-values) of association with total serum IgE by chromosome position. The most significant SNP is represented by a diamond and the results for the remaining SNPs are color coded to show their linkage disequilibrium (LD) with this SNP based on pairwise r² values from the Latino populations of the 1000 Genomes Project. SNPs above the dashed line are genome-wide significant (p≤5x10⁻⁸).

**Figure 2**
Boxplot showing the distribution of IgE levels for each copy of a chromosome of A) Native American, B) European, and C) African ancestry at 6p21.33.

**Figure 3**
Fine mapping results of 6p21.32-p22.1 in GALA II, focusing on the region showing genome-wide significant allelic associations. Included in the plot are -log₁₀(p-values) of association with total serum IgE by chromosome position. The most significant SNP is represented by a diamond and the results for the remaining SNPs are color coded to show their linkage disequilibrium (LD) with this SNP based on pairwise r² values from the Latino populations of the 1000 Genomes Project. SNPs above the dashed line are genome-wide significant (p≤5x10⁻⁸).

See this image and copyright information in PMC

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Genome-wide association study and admixture mapping reveal new loci associated with total IgE levels in Latinos

Affiliations

Genome-wide association study and admixture mapping reveal new loci associated with total IgE levels in Latinos

Authors

Affiliations

Abstract

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Molecular Biology Databases

Research Materials