Received: 1 June 2016 | Accepted: 12 June 2016 DOI 10.1002/ajpa.23045 LETTER TO THE EDITOR The evolutionary adaptation of hemochromatosis associated mutations during the neolithic Correspondence Joris Delanghe, Department of Clinical chemistry, Ghent University, Ghent, Belgium. Email: joris.delanghe@ugent.be In a recent paper (Heath, Axton, McCullough, & Harris, 2016), the In case of hemochromatosis, iron overload does not spread uni- spread of the C282Y allele in Europe was considered as a genetic adap- formly over the human body. It is remarkably that HFE-linked hemo- tation to the chilly and damp environments of Neolithic Europe, where chromatosis patients display a widespread tissue iron overload, but adequate iron was required for thermoregulation. The C282Y allele fre- rather limited iron storage in macrophages and enterocytes until later quency has an inverse linear relationship with mean daily temperatures, stages of the disease (Valberg, Simon, Manley, Corbett, & Ludwig, an inverse linear relationship with the mean maximum temperatures, 1975). In this respect, the HFE mutation could be regarded as a and a linear relationship with mean wet days per year. protection mechanism against siderophilic infections (Lettinga et al., Many genetic polymorphisms in Europe are characterized by a 2002). North–South gradient, such as pigmentation of hair and eyes (Cavalli- The role of iron conservation as a driver in human evolution is fur- Sforza, Menozzi, & Piazza, 1994). Correlations do not always offer an ther highlighted by the transient gene equilibrium of other iron con- explanation for the observed findings. There are some facts which serving mutations like the haptoglobin-2 allele (Langlois & Delanghe, plead against the C282Y climate hypothesis. 1996). A similar mutation occurred in Sub-Saharan Africa, where a ferro- Apart from providing iron storages (which may help to recover portin Q248H mutation, which has a strikingly similar biological effect, from blood loss and anemia), HFE may play an important role in causes hemochromatosis type IV, which was spread all over Western, immune defence. Next to climatological explanations, biological factors Central, and Southern Africa during the Bantu Trek (2000 BC–AD may play a causative role in the spread of C282Y in Northwestern 1000) (Gordeuk et al., 2003). Here, the average temperature is much Europe. higher; a lowering environmental temperature cannot have been a driver since the Q248H mutation initially moved toward the equator. In the cold climates of Central Asia, hemochromatosis-like conditions causing iron overload are very rare (Lok et al., 2009). Heath et al. use rather artificial national averages based on present-day European states. In this way, contributions of Celtic minor- ACKNOWLEDGMENT The authors have no conflict of interest. Joris R. Delanghe, MD, PhD1, Marijn M. Speeckaert, MD, PhD2, ities are diluted into pooled national data and are underrepresented in Marc L. De Buyzere, MSc2 the final statistics. The sunny North Portugal, with a C282Y allele fre- 1 quency of 5.8% (Cardoso et al., 2001), which has a mild Mediterranean 2 Department of Clinical chemistry, Ghent University, Ghent, Belgium Department of Internal Medicine, Ghent University, Ghent, Belgium climate, has a higher allele frequency than many North European countries like Denmark or the Orkney Islands. Similarly, the sunny Jersey Island has the double C282Y allele frequency than the cold and rainy Orkneys (Heath et al., 2016). These findings plead against a climate driven spread of C282Y in Europe. In HFE hemochromatosis, the clinical penetrance of symptoms of iron-loading disease is relatively low and highly variable. Large studies of newly diagnosed C282Y homozygotes have obtained data showing that penetrance occurs in 24–43% of males and 1–14% of females (Rossi, Olynyk, & Jeffrey, 2008). Current evidence suggests a limited role for digenic inheritance of mutations in iron homeostasis genes in modifying the penetrance of HFE hemochromatosis. American Journal of Physical Anthropology 2016; 00: 00-00 R EF RE N CE S Cardoso, C. S., Oliveira, P., Porto, G., Oberkanins, C., Mascarenhas, M., Rodrigues, P., . . . de Sousa, M. (2001). Comparative study of the two more frequent HFE mutations (C282Y and H63D): Significant different allelic frequencies between the North and South of Portugal. European Journal of Human Genetics, 9, 843–848. Cavalli-Sforza, L., Menozzi, P., & Piazza, A. (1994). The history and geography of human genes (pp. 255–301). New Jersey: Princeton University Press. Gordeuk, V. R., Caleffi, A., Corradini, E., Ferrara, F., Jones, R. A., Castro, O., . . . Pietrangelo, A. (2003). Iron overload in Africans and African- wileyonlinelibrary.com/journal/ajpa C 2016 Wiley Periodicals, Inc. V | 1 2 | LETTER TO THE EDITOR Americans and a common mutation in the SCL40A1 (ferroportin 1) gene. Blood Cells, Molecules and Diseases, 31, 299–304. Interscience Conference On Antimicrobial Agents & Chemotherapy, 42, 40. Heath, K. M., Axton, J. H., McCullough, J. M., & Harris, N. (2016). The evolutionary adaptation of the C282Y mutation to culture and climate during the European neolithic. American Journal of Physical Anthropology, 160, 86–101. Lok, C. Y., Merryweather-Clarke, A. T., Viprakasit, V., Chinthammitr, Y., Srichairatanakool, S., Limwongse, C., . . . Robson, K. J. H. (2009). Iron overload in the Asian community. Blood, 114, 20–25. Langlois, M. R., & Delanghe, J. R. (1996). Biological and clinical significance of haptoglobin polymorphism in humans. Clinical Chemistry, 42, 1589–1600. Lettinga, K. D., Delanghe, J. R., Prins, J., Langlois, M. R., Speelman, P., Reitsma, P., & Verbon, A. (2002). Iron status does not influence susceptibility and outcome in patients with Legionnaires’ disease (LD). Abstracts Of The Rossi, E., Olynyk, J. K., & Jeffrey, G. P. (2008). Clinical penetrance of C282Y homozygous HFE hemochromatosis. Expert Review of Hematology, 1, 205–216. Valberg, L. S., Simon, J. B., Manley, P. N., Corbett, W. E., & Ludwig, J. (1975). Distribution of storage iron as body stores expand in patients with hemochromatosis. Journal of Laboratory and Clinical Medicine, 86, 479–489.