• CROHN'S DISEASE
• IBD - GENETICS

The article by Yang et al 1 contributes to the emerging evidence that genetic predisposition to Crohn's Disease (CD) has an ethnicity-specific variation.^s1–s4 The genetic architecture of autoimmune and inflammatory diseases has been subject to recent positive selection in human history, probably driven by the historical exposure to pathogens.2 ^s5–s7 Thus, the differing genetic susceptibilities in East Asians (Koreans and Japanese) vis-à-vis the Caucasoid Euro-Americans might reflect the differences in their historical exposure to predominant pathogens occurring during the historical migrations of anatomically modern humans (AMH) while they populated the globe.^s8 Gene(s) or gene pathways involved in innate immune control of intracellular bacteria (eg, NOD2, ATG16L1, IRGM) and in the IL-23/Th17 pathway are predominant susceptibility loci for Crohn's in Caucasoid, but characteristically not so in East Asians.^{s1, s4} Interestingly, these gene(s) or gene pathways play a primary role in the immune response to human mycobacterial infections, including tuberculosis (TB) caused by Mycobacterium tuberculosis (MTB).^{s9, s10}

MTB is unique; its long latent period with delayed reactivation allows it to survive in low-density population, while its airborne mode of transmission allows it to spread explosively in high-density crowded population.3 ^s10 MTB appears to have risen with the AMH in Africa, and disseminated the globe along with its human host reservoir in a very population-specific cladistic manner.3 However, the real epidemic outbreak of MTB occurred after the appearance of densely populated cities, with its urban poverty, due to the Industrial Revolution in Europe and North America, where TB was the cause of one in five deaths in the 18th and early 19th centuries.4 As industrialisation and colonialism spread to the rest of the globe, this epidemic ‘white plague’ followed. The peak epidemic TB mortality was in the late 18th century in Western Europe, early 19th century in North Americas (spread by the European settlers) and in the early 20th century in Eastern Europe, South Americas and East Asia and South-East Asia (as the Industrial Revolution reached late here).4 Interestingly, both the mortality and incidence of TB started waning in Western Europe and North Americas even before the advent of potent chemotherapy, probably secondary to both public health measures and natural resistance.4 ^s11 The epidemic of IBD, especially CD, appears to have arisen after the waning of this ‘white plague’, at least in Western Europe and North Americas (figure 1A–D).

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Figure 1

(A) Tuberculosis (TB) mortality worldwide at the beginning of 20th century (adapted from International Congress on Tuberculosis, Washington, 21 September to 12 October 1908. Harvard University—Countway Library of Medicine). (B) Crohn's disease incidence worldwide at the beginning of 21st century (adapted from Loftus5). (C) TB mortality in England and Wales and Crohn's disease incidence in Cardiff, Wales (adapted from Davies et al,6 Gunesh et al 7). (D) TB mortality in Minnesota, USA and Crohn's disease Incidence in Olmstead County, Minnesota (adapted from Wilson,8 Loftus et al 9).

MTB uses the innate immune response to ensure its foothold into the human host after aerosol acquisition of the bacteria (the granuloma facilitates, rather than limit, bacterial multiplication) and also the host adaptive immune response (probably predominantly Th17) to produce pulmonary immunopathology that is essential for its airborne dissemination.^{s9 s10 s12} This is reflected by the surprisingly evolutionary hyperconserved T cell epitopes in the MTB genome.^s13

My hypothesis is that polymorphisms in these genes (or gene pathways), which are essential for MTB persistence and dissemination in the human host, have been selectively preserved (by predominantly balancing selection) in the human genome,2 and are now acting as susceptibility factor in CD, which is regarded as a hyperactive immune response to commensal gut bacteria.^s14 Thus, the profile of susceptibility genes in a given population reflects the duration and intensity of their historical exposure to epidemic TB. The late exposure of East Asians to the ‘white plague’ might be responsible for the relative absence of polymorphisms in these genes as predominant susceptibility loci for CD in the Japanese and Koreans. Not only so, in ethnic groups of North America who had a delayed exposure to the ‘white plague’,4 the same polymorphisms are either infrequent (eg, Canadian Aborigines) or present only as a result of European admixture (eg, African-Americans).^s15–s17