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Evidence of transmission ratio distortion of DLG5 R30Q variant in general and implication of an association with Crohn disease in men

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Abstract

Recently, we described the association of genetic variation in the discs large homolog 5 (DLG5) gene with inflammatory bowel disease (IBD) in a large European study sample (Stoll et al. in Nat Genet 36:476–480, 2004). Here, we report that the R30Q variant constitutes a susceptibility factor for Crohn disease (CD) in men [odds ratio (OR)=2.49, 95% confidence interval (CI) 1.53–4.06, P<0.001] but not women (OR=1.01, 95% CI=0.70–1.45, P=0.979) using multivariate logistic regression analyses in a unified study sample from Germany, Italy and Quebec. R30Q is a significant predictor for CD in men even when accounting for CARD15 and IBD5 risk variants (adjusted OR=2.41, 95% CI=1.41–4.12, P=0.001). The observed association is driven by a gender-dependent transmission ratio distortion (TRD) among healthy controls (frequency of Q allele: men 5.2%, women 11.3%), an effect that is offset in CD patients (frequency of Q allele: men 10.1%, women 10.9%). This finding is further substantiated by two non-IBD study samples, one of which consists of a newborn screening sample (newborn males 7.1%; newborn females 11%, P=0.036). Further investigation of the observed TRD may contribute towards enlightening the role of DLG5 in physiological processes influencing transmission of chromosomes to the surviving offspring, which, in turn, may help in understanding its implication in the development of CD among men.

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Acknowledgments

The authors would like to thank all cooperating clinical centres, clinicians, families and patients with IBD. Also, special thanks to the German Crohn’s and Colitis Foundation for their invaluable participation in the patient collection as well as to gastroenterologists Alain Bitton, Albert Cohen, Gary Wild and Diane Langelier from Quebec. This study was supported by the Federal Ministry of Science and Education through the National Genome Research Network, the Competence Network “Inflammatory Bowel Disease” and the Italian Ministry of Health (RC0503GA18).

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Authors and Affiliations

  1. Leibniz-Institute for Arteriosclerosis Research, Domagkstr. 3, 48149, Muenster, Germany

    Frauke Friedrichs & Monika Stoll

  2. Istituto Superiore di Sanita’, Rome, Italy

    Sonia Brescianini

  3. Ospedale CSS-IRCCS, San Giovanni Rotondo, Italy

    Vito Annese & Anna Latiano

  4. Institute for Epidemiology and Social Medicine, University of Muenster, Muenster, Germany

    Klaus Berger

  5. Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA

    Subra Kugathasan

  6. Human Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, WI, USA

    Ulrich Broeckel

  7. Institute for Clinical Molecular Biology, Kiel, Germany

    Susanna Nikolaus, Stefan Schreiber & Monika Stoll

  8. The Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Sonia Brescianini, Mark J. Daly & John D. Rioux

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  1. Frauke Friedrichs
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  2. Sonia Brescianini
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  3. Vito Annese
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  4. Anna Latiano
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  5. Klaus Berger
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Corresponding author

Correspondence to Monika Stoll.

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Frauke Friedrichs and Sonia Brescianini equally contributed to the work.

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Friedrichs, F., Brescianini, S., Annese, V. et al. Evidence of transmission ratio distortion of DLG5 R30Q variant in general and implication of an association with Crohn disease in men. Hum Genet 119, 305–311 (2006). https://doi.org/10.1007/s00439-006-0133-1

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  • DOI: https://doi.org/10.1007/s00439-006-0133-1

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