Commentary: both multiplicative and additive components may contribute to parental transmission of type 2 diabetes – a response to K. Hemminki and X. Li and J. Sundquist and K. Sundquist

Authors

  • Ali Abbasi,

    1. From the Departments of Epidemiology
    2. Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen
    3. Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht
    Search for more papers by this author
  • Joline W.J. Beulens,

    1. Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht
    Search for more papers by this author
  • Harold Snieder,

    1. Department of Epidemiology, Unit of Genetic Epidemiology and Bioinformatics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
    Search for more papers by this author
  • Stephan J. L. Bakker

    1. Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen
    Search for more papers by this author

Ali Abbasi, MD, Department of Epidemiology, University Medical Center Groningen, Hanzeplein 1, PO Box 30.001, 9700RB Groningen, theNetherlands.
(fax: +31503614493; e-mail: a.abbasi@epi.umcg.nl).

Dear Sir,

We thank Hemminki and coworkers for their interest in our recent findings concerning parental transmission of type 2 diabetes [1]. Based on their and our data [1, 2], they concluded that paternal and maternal history of diabetes simply add rather than act multiplicatively to increase risk for diabetes in offspring. They do so because in the Swedish model, a fully multiplicative model was rejected on statistical grounds. We agree that based on these data, it is very unlikely that paternal and maternal transmission of diabetes act in an entirely multiplicative manner. However, both in their and in our study, the relative risk predicted by an additive model (3.7 for their study and 3.4 for our study) is lower than the actually observed risk (4.3 for their study and 3.9 for our study). Earlier findings were also consistent with these results, with relative risks of 3.6 in Pima Indians and 5.9 Framingham Offspring predicted by an additive model while actually observed risks were higher, with values of 3.9 and 6.1 respectively [3, 4]. Thus, data of all four studies to date are in the same direction, with a higher actually observed risk in subjects with two affected parents than predicted by an additive model. Therefore, given that a multiplicative model does not fit the data, acceptance of an additive model as sole valid alternative seems an oversimplification, with the truth lying in between both of these extremes. It is important to acknowledge the possibility of nonadditive genetic effects (epistasis or gene–gene interactions) of individual loci playing a role in transmission of risk of type 2 diabetes, because this is considered a source of missing heritability in complex diseases, including type 2 diabetes [5]. As many low-penetrance loci may contribute to genetic susceptibility for type 2 diabetes [6], such a scenario does not seem unrealistic.

Acknowledgements

This work was supported by the Netherlands Heart Foundation, the Dutch Diabetes Research Foundation and the Dutch Kidney Foundation. This research was performed within the framework of the Center for Translational Molecular Medicine (CTMM; http://www.ctmm.nl); project PREDICCt (grant 01C-104-07). The EPIC-NL study was funded by ‘Europe against Cancer’ Programme of the European Commission (SANCO), the Dutch Ministry of Health, the Dutch Cancer Society, the Netherlands Organization for Health Research and Development (ZonMW) and World Cancer Research Fund (WCRF).We thank Statistics Netherlands and the PHARMO Institute for follow-up data on cancer, cardiovascular disease and vital status. None of the study sponsors had a role in the study design, data collection, analysis or interpretation, report writing or the decision to submit the report for publication.

Conflict of interest

None declared.