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  • Response to Letter to the Editor
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Response to 'Challenge in interpretation of Mendelian randomization studies using lactase persistence as instrumental variable'

European Journal of Clinical Nutrition volume 72, pages 181–182 (2018)Cite this article

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We thank Vissers et al.1 for their positive comments on our Mendelian randomization study indicating most likely null effects of milk consumption on ischemic heart disease, type 2 diabetes and osteoporosis. We are also very grateful for the opportunity to address the methodological questions they raise concerning our application of two-sample Mendelian randomization. Specifically, Vissers et al. raise concerns about the validity of genetically determined lactase persistence as a consistent determinant of solely milk consumption, and the possibility that the association of genetically determined lactase persistence with health outcomes might be confounded by other attributes that determine both lactase persistence and health.

We used a genetic variant functionally relevant to the ability to digest milk as an adult (lactase persistence), that is, rs4988235 (MCM6) or its correlates rs182549 (MCM6) and rs6754331 (DARS), to predict milk consumption based on five studies from Denmark, Finland, Italy, Sweden, Austria and Germany1. Our meta-analysis of the relation of rs4988235 with milk in these studies was relatively homogeneous (I2=39%) suggesting a fairly consistent effect of genetic lactase persistence on milk consumption in these populations. To obtain the health effects of milk, we applied this genetic prediction of milk consumption to genetic studies with the outcomes, largely pertaining to similar populations, thus reducing the possibility that use of this genetic prediction of milk consumption is invalid. The estimated F-statistic for the association of rs4988235 with milk consumption is also very large, ranging from 1366 in Swedes to 3887 in Austrians, with the F-statistic calculated as , where R2 indicates the proportion of milk consumption variability explained by rs4988235, estimated as 2 × (effect of rs4988235 on milk consumption)2 × rs4988235 effect allele frequency (EAF) × (1−EAF).2 Given, an F-statistic >10 is usually taken as indicating low risk of weak instrument bias,3 our F-statistics suggest little risk of genetic lactase persistence being a weak instrument for milk consumption.

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Authors and Affiliations

  1. School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, HKSAR, China

    Q Yang & C M Schooling

  2. Graduate School of Public Health and Health Policy, City University of New York, New York, NY, USA

    C M Schooling

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  1. Q Yang
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Correspondence to C M Schooling.

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Yang, Q., Schooling, C. Response to 'Challenge in interpretation of Mendelian randomization studies using lactase persistence as instrumental variable'. Eur J Clin Nutr 72, 181–182 (2018). https://doi.org/10.1038/ejcn.2017.119

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