Factor analysis in the Genetics of Asthma International Network family study identifies five major quantitative asthma phenotypes

doi:10.1111/j.1365-2222.2007.02918.x

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Wiley InterScience

Clinical & Experimental Allergy

Volume 38 Issue 3, Pages 421 - 429

Published Online: 3 Jan 2008

The Official Journal of the British Society for Allergy & Clinical Immunology

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ORIGINAL PAPER/Asthma and Rhinitis

Factor analysis in the Genetics of Asthma International Network family study identifies five major quantitative asthma phenotypes

S. G. Pillai ^* , Y. Tang ^*,† , E. van den Oord ^‡ , M. Klotsman ^* , K. Barnes ^§ , K. Carlsen ^¶ , J. Gerritsen ^∥ , W. Lenney ^** , M. Silverman ^†† , P. Sly ^‡‡ , J. Sundy ^§§ , J. Tsanakas ^¶¶ , A. von Berg ^∥∥ , M. Whyte ^*** , H. G. Ortega ^††† , W. H. Anderson ^* and P. J. Helms ^‡‡‡

^* Medical Genetics, GlaxoSmithKline, Research Triangle Park, NC, USA, ^† Department of Psychiatry, SUNY Downstate Medical Center, Brooklyn, NY, USA, ^‡ Virginia Institute for Psychiatric and Behavioral Genetics, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA, USA, ^§ Departments of Medicine & Epidemiology, Johns Hopkins University, Baltimore, MD, USA, ^¶ Ullevaal University Hospital, Oslo, Norway, ^∥ University Medical Center Groningen, University of Groningen, Groningen, The Netherlands, ^** Academic Department of Pediatrics, North Staffordshire Hospital, Stoke on Trent, UK, ^†† Division of Child Health, University of Leicester, Leicester, UK, ^‡‡ Center for Child Health Research, University of Western Australia, Perth, Australia, ^§§ Duke University Medical Center, Durham, NC, USA, ^¶¶ Pediatric Respiratory Unit, Hippokration General Hospital, Thessaloniki, Greece, ^∥∥ Abt. Fuer Kinderheilkunde Foschungsinstitut zur Praevention von Allergien und Atemwegserkrankungen im Kindesalter, Wesel, Germany, ^*** Academic Unit of Respiratory Medicine, University of Sheffield, Sheffield, UK, ^††† Respiratory Medicine Development Center, Glaxo SmithKline, Research Triangle Park, NC, USA and ^‡‡‡ Department of Child Health, University of Aberdeen Royal Aberdeen Children's Hospital, Aberdeen, UK

Correspondence:
Sreekumar G. Pillai, Medical Genetics, 5 Moore Drive, GlaxoSmithKline, Research Triangle Park, NC 27709, USA. E-mail: Sreekumar.g.pillai@gsk.com

KEYWORDS

atopy • FEV₁ • IgE • PC₂₀ • rhinitis

ABSTRACT

Background Asthma is a clinically heterogeneous disease caused by a complex interaction between genetic susceptibility and diverse environmental factors. In common with other complex diseases the lack of a standardized scheme to evaluate the phenotypic variability poses challenges in identifying the contribution of genes and environments to disease expression.

Objective To determine the minimum number of sets of features required to characterize subjects with asthma which will be useful in identifying important genetic and environmental contributors.

Methods Probands aged 7–35 years with physician diagnosed asthma and symptomatic siblings were identified in 1022 nuclear families from 11 centres in six countries forming the Genetics of Asthma International Network. Factor analysis was used to identify distinct phenotypes from questionnaire, clinical, and laboratory data, including baseline pulmonary function, allergen skin prick test (SPT).

Results Five distinct factors were identified:(1) baseline pulmonary function measures [forced expiratory volume in 1 s (FEV₁) and forced vital capacity (FVC)], (2) specific allergen sensitization by SPT, (3) self-reported allergies, (4) symptoms characteristic of rhinitis and (5) symptoms characteristic of asthma. Replication in symptomatic siblings was consistent with shared genetic and/or environmental effects, and was robust across age groups, gender, and centres. Cronbach's α ranged from 0.719 to 0.983 suggesting acceptable internal scale consistencies. Derived scales were correlated with serum IgE, methacholine PC₂₀, age and asthma severity (interrupted sleep). IgE correlated with all three atopy-related factors, the strongest with the SPT factor whereas severity only correlated with baseline lung function, and with symptoms characteristic of rhinitis and of asthma.

Conclusion In children and adolescents with established asthma, five distinct sets of correlated patient characteristics appear to represent important aspects of the disease. Factor scores as quantitative traits may be better phenotypes in epidemiological and genetic analyses than those categories derived from the presence or absence of combinations of +ve SPTs and/or elevated IgE.

Submitted 18 June 2007; revised 2 October 2007; accepted 9 November 2007

DIGITAL OBJECT IDENTIFIER (DOI)

10.1111/j.1365-2222.2007.02918.x About DOI