FULL PAPER NRAMP1 is not associated with asthma, atopy, and serum immunoglobulin E levels in the French Canadian population AH Poon 1,2 , C Laprise 3,4 , M Lemire 5 , TJ Hudson 1,5,6 and E Schurr 1,2,6 1 McGill Centre for the Study of Host Resistance, Research Institute of the McGill University Health Centre, Montreal, QC, Canada; 2 Department of Biochemistry, McGill University, Montreal, QC, Canada; 3 Universite ´ du Que ´bec a ` Chicoutimi, 555 Boulevard Universite ´, Chicoutimi, QC, Canada; 4 Community Genomic Medicine Centre, University of Montreal, Chicoutimi Hospital, Chicoutimi, QC, Canada; 5 McGill University and Genome Que ´bec Innovation Centre, Montreal, QC, Canada; 6 Department of Medicine and Human Genetics, McGill University, Montreal, QC, Canada Reduced infection by mycobacteria, including Mycobacterium tuberculosis, may be partly responsible for increased prevalence of allergic and autoimmune diseases in developed countries. In a murine model of innate resistance to mycobacteria, the Nramp1 gene has been shown to affect asthma susceptibility. From this observation, it was proposed that human NRAMP1 may be a modulator of asthma risk in human populations. To experimentally test the candidacy of NRAMP1 in asthma susceptibility, we characterized five genetic variants of NRAMP1 (5 0 CA n , 274C4T, 469 þ 14G4C, D543N, and 1729 þ del4) in an asthma family-based cohort from northeastern Quebec. We did not observe any significant association between NRAMP1 variants (either allele or haplotype specific) with asthma, atopy, or serum immunoglobulin E levels. These results demonstrate that, in spite of direct involvement of Nramp1 in a murine asthma model, in human populations NRAMP1 is not likely to be a major contributor to the genetic etiology of asthma and asthma-related phenotypes. Genes and Immunity (2005) 6, 519–527. doi:10.1038/sj.gene.6364238; published online 30 June 2005 Keywords: genetic predisposition; polymorphism; natural resistance-associated macrophages protein 1; asthma; tuberculosis Introduction In 1989, David Strachan reported the findings of a prospective study of 17 414 British children from birth to 23 years of age. 1 The study found a significant inverse correlation between the number of older siblings in the household and the prevalence of hay fever at age 11 and 23 years. A similar correlation was also observed for eczema in the first year of life. Subsequent epidemiologic studies confirmed the inverse association between family size and atopic markers such as skin prick positivity and specific immunoglobulin (Ig) E titers. 2 To explain the inverse correlation between family size and atopy, it was suggested that declining family size, improved house- hold amenities, and higher standards of personal cleanliness, all associated with improved hygiene, had reduced the opportunities of cross-infection, and this may have increased the prevalence of atopic diseases. This explanation is now known as the hygiene hypothesis and it has been extended to include autoimmune diseases in general. One proposed mechanism underlying the hygiene hypothesis is that microbial exposures to viruses, bacteria, and parasites elicit an immune response towards the maturation of T helper type 1 cells (Th1), and the subsequent production of cytokines such as interleukin (IL)-2 and interferon-g. This predominating Th1 immune response suppresses the production of Ig E and IgG1, as well as cytokines IL4, IL5, IL9, and IL13, characteristic of type 2 (Th2) responses. The possibility of a Th1/Th2 imbalance and an association between Mycobacterium tuberculosis infection and atopy expression was first shown by a study of Japanese school children. 3 The study reported an inverse association between delayed hypersensitivity to tuberculin, a broad measure of exposure to mycobacteria (Th1 response), and serum IgE levels (Th2 response), and concluded that exposure to M. tuberculosis may inhibit the development of atopic diseases. In humans, M. tuberculosis is the cause of tuberculosis (TB). However, not all individuals exposed to M. tuberculosis will become infected, and of those infected only a small proportion will develop clinical disease. 4,5 It is now well established that both genetic and environmental factors determine the progression from exposure to infection and from infection to disease. Received 6 April 2005; revised 20 May 2005; accepted 23 May 2005; published online 30 June 2005 Correspondence: Dr E Schurr, Montreal General Hospital Research Institute, McGill Centre for the Study of Host Resistance, McGill University Health Centre, 1650 Cedar Avenue, Room L11-520, Montreal, QC, Canada H3G 1A4. E-mail: erwin@igloo.epi.mcgill.ca Genes and Immunity (2005) 6, 519–527 & 2005 Nature Publishing Group All rights reserved 1466-4879/05 $30.00 www.nature.com/gene