Celiac Disease: The Evolutionary Paradox

Kayla Morrell¹ and Melissa K. Melby^{2, 3,}

¹Department of Biological Sciences, University of Delaware, Newark, United States

²Department of Anthropology, University of Delaware, Newark, United States

³College of Health Sciences, University of Delaware, Newark, United States

Cite this paper:
Kayla Morrell and Melissa K. Melby. Celiac Disease: The Evolutionary Paradox. International Journal of Celiac Disease. 2017; 5(3):86-94. doi: 10.12691/ijcd-5-3-3

Abstract

Celiac disease (CD), an autoimmune disorder triggered by gluten ingestion, negatively affects individuals’ health if left untreated. In individuals with the requisite genes, CD destroys the intestinal lining because specific peptide fragments of gluten (protein found in wheat and related grains) bind to the receptor proteins coded for by HLA-DQ2 and DQ8 genes, thereby causing an autoimmune response that damages intestinal cells and results in malnutrition. Because the disease has a genetic basis and can lead to impaired reproductive functioning and death, natural selection should lead to a decrease in CD prevalence over time. However, evidence suggesting CD increases in some populations contradicts this hypothesis, resulting in the ‘Celiac Disease Evolutionary Paradox.’ The worldwide average prevalence rate is around 1%, although rates of up to 5% have been observed in certain populations. Maintenance or increase in the frequency of CD-predisposing genes in certain populations suggests potential evolutionary benefits for those genes, which may exhibit antagonistic pleiotropy, such as being beneficial for infectious disease but detrimental for chronic disease such as CD. Recent dietary and environmental changes (including dietary gluten exposure, breastfeeding duration and the intestinal microbiome, and immune function) may have led to discordance with the Environment of Evolutionary Adaptedness, thus contributing to increases in CD. Consideration of potential benefits of CD-risk gene alleles, in conjunction with a deeper understanding of environmental factors exerting positive and negative selection on those alleles, may help to explain population variation in CD prevalence rates, and shed light on the complex gene-environment interactions influencing this devastating disease.

Keywords:
celiac disease evolution antagonistic pleiotropy discordance environment

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References:

[1]	Lohi S, Mustalahti K, Kaukinen K, et al. Increasing prevalence of coeliac disease over time. Aliment Pharmacol Ther. 2007; 26: 1217-25.
[2]	Lionetti E and Catassi C. Co-localization of gluten consumption and HLA-DQ2 and -DQ8 genotypes, a clue to the history of celiac disease. Digestive and Liver Disease. 2014; 46: 1057-1063.
[3]	Karell K, Louka AS, Moodie SJ, et al. Hla types in celiac disease patients not carrying the DQA1*05-DQB1*02 (DQ2) heterodimer: results from the European genetics cluster on celiac disease. Hum Immunol. 2003;64: 469-477.
[4]	Gheller-Rigoni A, Celiac Disease: celiac sprue, gluten-sensitive enteropathy. Clin Med & Res. 2004; 2: 71-72.
[5]	Basso MS, Luciano R, Ferretti F et al. Association Between Celiac Disease and Primary Lactase Deficiency. Eur J Clin Nutr. 2012; 66: 1364-1365.
[6]	Koning F. Pathophysiology of Celiac Disease. J Pediatr gastroenterl Nutr. July 2014; 59: S1-S4.
[7]	Celiac Disease: Genetics and Nutrition. http://www.nchpeg.org/nutrition/index.php?option=com_content&view=article&id=459&Itemid=56&showall=1. [Accessed 6 Oct 2016].
[8]	van den Broeck H. Presence of celiac disease epitopes in modern and old hexaploid wheat varieties: wheat breeding may have contributed to increased prevalence of celiac disease. Theor Appl Genet. 2010; 121: 1527-1539.
[9]	Copelton D. "You don't need a prescription to go gluten-free": the scientific self-diagnosis of celiac disease. Soc Sci Med. 2009; 69: 623-631.
[10]	Stevenson JC, Maki C, Bruna S, et al. Community based pilot study of diagnostic paths to the gluten free diet. Int J Celiac Disease. 2015; 3: 17-24.
[11]	Dubois PC. Translational Mini-Review Series on the Immunogenetics of Gut Disease: Immunogenetics of coeliac disease. Clin Exp Immunol. 2008; 153: 162-173.
[12]	Hoffenberg EJ, Bao F, Eisenbarth GS et al. Transglutaminase antibodies in children with a genetic risk for celiac disease. J Pediatr. 2000; 137: 356-360.
[13]	Nylund L. The microbiota as a component of the celiac disease and non-celiac gluten sensitivity. Clin Nutr Exp. 2016; 6: 17-24.
[14]	Chen J. Development of intestinal bifidobacteria and lactobacilli in breast-fed neonates. Clin Nutr (Scot) 2007; 26: 559-566.
[15]	Ivarsson A. Breast-feeding protects against celiac disease. Am J Clin Nutr. 2002; 75: 914-921.
[16]	Marasco G. Gut Microbiota and Celiac Disease. Dig Dis Sci. 2016; 61: 1461-1472.
[17]	Beres NJ and Sziksz E. Role of the Microbiome in Celiac Disease. Internat J Celiac Disease. 2014; 2: 150-3.
[18]	Dieli-Crimi R, Cénit MC, and Núñez C. The genetics of celiac disease: A comprehensive review of clinical implications. J Autoimmun. 2015; 64: 26-41.
[19]	Megiorni F PA, HLA-DQA1 and HLA-DQB1 in Celiac disease predisposition: practical implications of the HLA molecular typing. J Biomed Sci. 2012; 19: 88.
[20]	Fallang LE, Bergseng E, Hotta K, et al. Differences in the risk of celiac disease associated with HLA-DQ2.5 or HLA-DQ2.2 are related to sustained gluten antigen presentation. Nat Immunol. 2009; 10: 1096-101.
[21]	Zhernakova A, Stahl EA, Trynka G et al. Meta-Analysis of Genome-Wide Association Studies in Celiac Disease and Rheumatoid Arthritis Identifies Fourteen Non-HLA Shared Loci. PLoS Genetics. 2011; 7: e1002004.
[22]	Parkes M, Cortes A, van Heel DA,Brown MA, Genetic insights into common pathways and complex relationships among immune-mediated diseases. 2013; 14: 661-73.
[23]	Wang L, Human autoimmune diseases: a comprehensive update. J Intern Med. 2015; 278: 369-395.
[24]	Hartl DL and Jones EW. Essential genetics: a genomics perspective. Jones & Bartlett Publishers. 2006.
[25]	Popat S, Hearle N, Hogber L, et al. Variation in the CTLA4/CD28 gene region confers an increased risk of coeliac disease. Ann Hum Genet. 2002; 66: 125-137.
[26]	Mustalahti K, Catassi C, Reunanen A, et al. The prevalence of celiac disease in Europe: Results of a centralized, international mass screening project. SANN Annals of Medicine. 2010; 42: 587-595.
[27]	Lionetti E. Celiac disease from a global perspective. Bailliere's Best Practice & Research: Clinical Gastroenterology. 2015; 29: 365-379.
[28]	Malekzadeh R. Coeliac disease in developing countries: Middle East, India and North Africa. Bailliere's Best Practice & Research: Clinical Gastroenterology. 2005; 19: 351-358.
[29]	Dubé C, Rostom A, Sy R et al. The prevalence of celiac disease in average-risk and at-risk Western European populations: A systematic review. Gastroenterology. 2005; 128: S57-S67.
[30]	Cataldo F. Celiac disease in the developing countries: a new and challenging public health problem. World Journal of Gastroenterology. 2007; 13: 2153-2159.
[31]	Cohen MN and Armelagos GJ (eds). Paleopathology at the origins of agriculture. University Press of Florida. 2013.
[32]	Cordain L. Cereal Grains: Humanity's Double-Edged Sword. World Rev Nutr Diet. 1999; 19-23.
[33]	Fasano A, Catassi C, and Gatti S. The New Epidemiology of Celiac Disease, J Pediatr Gastroenterol Nutr. 2014; 59: Suppl 1:S7-9.
[34]	Visser J, Rozing J, Sapone A et al. Tight Junctions, Intestinal Permeability, and Autoimm,unity: Celiac Disease and Type 1 Diabetes Paradigms. Ann N Y Acad Sci. 2009; 1165: 195-205.
[35]	Jakaitis BM and Denning PW. Human breast milk and the gastrointestinal innate immune system. Clin Perinatol. 2014; 41: 423-35.
[36]	Eaton SB and Konner, M. Paleolithic Nutrition. A consideration of its nature and current implications. N Engl J Med. 1985; 312: 283-9.
[37]	Eaton SB, Konner M, Shostak M. Stone agers in the fast lane: chronic degenerative diseases in evolutionary perspective. Am J Med. 1988; 84: 739-49.
[38]	Kivity S. Can we explain the higher prevalence of autoimmune disease in women? Expert Rev Clin Immunol. 2010; 6: 691-694.
[39]	Sams A and Hawks J. Celiac disease as a model for the evolution of multifactorial disease in humans. Human Biology. 2014; 86: 19-36.
[40]	Myléus A, Hernell O, Gothefors L, et al. Early infections are associated with increased risk for celiac disease: an incident case-referent study. BMC Pediatrics. 2012; 12: 194.
[41]	Ivarsson A, Myleus A, Norstrom F, et al. Prevalence of childhood celiac disease and changes in infant feeding. Pediatrics. 2013; 131: e687-94.
[42]	Fasano A, Berti I, Gerarduzzi T, et al. Prevalence of celiac disease in at-risk and not-at-risk groups in the United States: a large multicenter study. Arch Intern Med. 2003; 163: 286-292.
[43]	Whittington C. The C282Y mutation may have been positively selected as it mitigates the infertility of celiac disease. Med Hypotheses. 2006; 66: 769-772.
[44]	Ercolini D. From an imbalance to a new imbalance: Italian-style gluten-free diet alters the salivary microbiota and metabolome of African celiac children. Scientific Reports. 2015; 5: 18571.
[45]	Mager J, Glaser G, Razin A et al. Metabolic effects of pyrimidines derived from fava bean glycosides on human erythrocytes deficient in glucose-6-phosphate dehydrogenase. Biochem Biophys Res Commun. 1965; 20: 235-240.
[46]	Augusto D and Petzl-Erler ML. KIR and HLA under pressure: evidences of coevolution across worldwide populations. Human Genetics. Sept 2015; 134: 929-940.
[47]	Sams A and Hawks J. Patterns of Population Differentiation and Natural Selection on the Celiac Disease Background Risk Network. PLoS ONE. 2013; 8: e70564.
[48]	Crespi BJ. The emergence of human-evolutionary medical genomics. Evolutionary Applications. 2011; 4: 292-314.
[49]	Olsson C, Stenlund H, Hörnell A, et al. Regional variation in celiac disease risk within Sweden revealed by the nationwide prospective incidence register. Acta Paediatrica. 2008; 98: 337-342.
[50]	Stuart-Macadam P and Dettwyler KA. Breastfeeding: biocultural perspectives. Routledge. 1995.
[51]	Konner M. Paleolithic nutrition: twenty-five years later. Nutr Clin Pract. 2010. 25: 594-602.
[52]	Valarini N. Association of Dental Caries with HLA Class II Allele in Brazilian Adolescents. Caries Res. 2012; 46: 530-535.
[53]	Zhernakova A, Elbers C, Ferwerda B et al. Evolutionary and Functional Analysis of Celiac Risk Loci Reveals SH2B3 as a Protective Factor against Bacterial Infection. Amer J Hum Genet. 2010; 86: 970-977.
[54]	Butterworth JR, Cooper BT, Rosenberg WMC, et al. The role of hemochromatosis susceptibility gene mutations in protecting against iron deficiency in celiac disease Gastroenterology. 2002; 123: 444-449.
[55]	Bauduer F. C282Y/H63D hemochromatosis mutations and microevolution: Speculations concerning the Basque population. HOMO - J Comp Human Biology. 2017; 68: 38-41.
[56]	Heath KM, Axton JH, McCullough JM, et al. The evolutionary adaptation of the C282Y mutation to culture and climate during the European Neolithic. Am J Phys Anthropol. 2016; 160: 86-101.
[57]	Aaron L. The last two millennias echo-catastrophes are the driving forces for the potential genetic advantage mechanisms in celiac disease. Med Hypotheses. 2011; 77: 773-776.
[58]	Kasarda D. Can an increase in celiac disease be attributed to an increase in the gluten content of wheat as a consequence of wheat breeding? J Agric Food Chem. 2013; 61: 1155-1159.
[59]	Freeman HJ The Neolithic revolution and subsequent emergence of the celiac affection. Int J Celiac Disease 2013; 1: 19-22.
[60]	Ratsch IM and Catassi C. Coeliac disease: a potentially treatable health problem of Saharawi refugee children. Bull World Health Organ. 2001; 79: 541-545.
[61]	Catassi C. The distribution of DQ genes in the Saharawi population provides only a partial explanation for the high celiac disease prevalence. Tissue Antigens. 2001; 58: 402-406.