Even though specific MHC haplotypes are heavily associated with infectious disease susceptibility, the figure below illustrates there is a wide gap between disease-associated and disease-causing variations (1). Susceptibility or protection endowed by specific MHC haplotypes thus remain loosely limited to nothing more definite than propensity.
Reasons for this are
- Technical limitations of approaches used to identify such variations in the first place, approaches which include SNP (Single Nucleotide Polymorphism), GWAS (Genome-wide Association Studies), Microarrays.
- The inherently mosaic structure of MHC with long stretches of conserved and non-conserved genes.
- Influence of epigenetic and environmental factors.
Targeted deep sequencing of the entire MHC region would overcome technical limitations of commonly used approaches. As for other influences, we now need to add the microbiome. Undeniably a dominant force shaping human evolution, the microbiome hasn’t traditionally been a focus of genomic disease-association and -causation studies. Historically, with respect to a particular disease susceptibility , be it infectious, metabolic or any other, association studies examined the human, i.e., eukaryotic, portion of the human-microbe ecosystem in isolation. This is akin to examining only the tip of the iceberg. Disease association studies will become more accurate and thus more relevant once they begin to examine both human and microbe portions of the human-microbe ecosystem. This would entail genes and loci in the case of the human, and species and genera in the case of the microbial. Older associations may then need to be refined, altered or discarded altogether.
As yet clear Native American (Amerindian) MHC allele associations with respect to specific infectious diseases have been hard to come by. However, such associations can be clearly inferred from the typically benign outcome of infections with particular viruses and bacteria historically associated with specific Native American populations. Thus far, studies on Hepatitis B virus (HBV) and Helicobacter pylori offer the clearest evidence for such protective associations.
Protective association between specific Native American (Amerindian) populations and HBV
HBV is classified into 8 genotypes, A through J, with two new ones, I and J, recently identified (2, 3). The most recent common ancestor of HBV is presumed to have traveled out of Africa with the great human migration. Specific strains dominate in Central and South America (see figure below from 4).
HBV genotypes A, B, C, D, E dominate in Old World populations, with B and C dominant in Asia, D in Africa, Europe, India, A in sub-Saharan Africa, North Africa, Western Europe, E in East Africa (3, 4). HBV genotypes G and H dominate in Mexico (5, 6). HBV genotype G dominates in Central and South America (7, 8).
Evolutionarily, humans have adapted to HBV with Roman et al assigning three levels of adaptations, incomplete, semi-complete and complete (4).
- As the word implies, incomplete adaptation can be of two types, one consisting of an extremely targeted anti-HBV immune response that efficiently eliminates the virus with minimal collateral damage to hepatocytes and other liver-associated cells and tissues, and the other associated with a hyperimmune anti-HBV response resulting in liver function impairment. The former would eliminate HBV from the body in short order but if all humans responded to HBV in this manner, it would have long been eradicated. However, the reality is an estimated 350 million chronic HBV carriers worldwide (9, 10).
- Semi-complete adaptation consists of inadequate, rather than hyperimmune, anti-HBV responses, coupled to HBV evasion mechanisms, leading to chronic infection (11, 12). Clinically, HBV DNA and HBsAg (HBV surface antigen) are detected in circulation for >6 months (11). HBV is able to complete its life cycle and transmit to susceptible individuals while such carriers carry lifelong risk of liver fibrosis and cirrhosis (11, 12).
- Complete adaptation, also called occult Hepatitis B (OHB), consists of low viral load (<200 IU/ml) and absence of circulating HBsAg (13, 14). Outcome of presumed balance between viral replication rate and tissue damage, it results from a particular dynamic of HBV genome integration into host cell, stability of , and dominance of predominantly non-tissue damaging immune responses that nevertheless keep HBV in control (15, 16, 17). Thus, patients may remain asymptomatic for years and only external triggers such as other viral infections (HIV/HCV), intravenous drug use, etc. break the human-HBV equilibrium.
In Central-South America HBV genotypes F and H prevail among indigenous peoples (6, 7) while genotype G is a minor strain (4, 5). H dominates in Mexico and F in Central and South America. Among indigenous populations (both native and mestizo), these HBV genotypes are associated with a benign course of disease, what Roman et al call complete adaptation with hepatocellular carcinoma being rare among Mexican HBV positive individuals (18). OTOH, HBV genotypes F, A and D are associated with acute and chronic HBV disease among mestizos with white ancestry (5).
Protective association between specific Native American (Amerindian) populations and H. pylori
A study of two Colombian populations with similar H. pylori carriage but different gastric cancer rates provides compelling evidence for possible MHC allele differences protecting specific Native American populations against H. pylori-associated gastric cancer rates. While the coastal communities are a mix of African, European and Amerindian ancestry have a low gastric cancer rate of 6 per 100, 000, the Andean mountainous mestizo communities have mainly Amerindian ancestry mixed with European and a high gastric cancer rate of 150 per 100,000. Critical difference between the two groups is prevalence of different H. pylori strains. Coastal communities with African ancestry tend to harbor ancestral African-type H. pylori strains. OTOH, the mountainous, whose ancestral Amerindian H. pylori strains had been replaced by European H. pylori strains (19, 20).
MHC Haplotype Implications of Specific HBV genotypes and H. pylori strains associated with Specific Central and South American populations
In both the HBV and H. pylori examples cited here, though MHC association is only implied, it’s not just possible but probable since it’s the necessary mediator presenting antigens derived from either organism to T and B cells to elicit specific anti-HBV or –H. pylori immune responses. In turn, the nature and strength of such immune responses would dictate whether the dynamic equilibrium between these microbes and the humans maintained a detente or set in motion an inexorable process of irreparable tissue damage, liver fibrosis and cirrhosis in the case of HBV, and gastric cancer in the case of H. pylori.
Association of specific HBV and H. pylori strains with certain Central and South American communities thus appears to bear the hallmark features of co-evolution and co-adaptation. Displacement of specific co-evolved viral or bacterial strains by newer ones derived as a result of more recent European ancestry yields greater susceptibility to disease-driven processes. Since admixture of Native Americans with Europeans would necessarily displace ancestral MHC haplotypes, it implies such haplotypes and the human-microbe (HBV or H. pylori)-associations they engendered in ancestral Native American populations were protective in nature.
1. Clark, P. M., M. Kunkel, and D. S. Monos. “The dichotomy between disease phenotype databases and the implications for understanding complex diseases involving the major histocompatibility complex.” International journal of immunogenetics 42.6 (2015): 413-422.
2. Kurbanov, Fuat, Yasuhito Tanaka, and Masashi Mizokami. “Geographical and genetic diversity of the human hepatitis B virus.” Hepatology Research 40.1 (2010): 14-30.
3. Kao, Jia-Horng. “Molecular epidemiology of hepatitis B virus.” The Korean journal of internal medicine 26.3 (2011): 255-261.
4. Roman, Sonia, et al. “Hepatitis B virus infection in Latin America: A genomic medicine approach.” World journal of gastroenterology: WJG 20.23 (2014): 7181.
5. Roman, Sonia, and Arturo Panduro. “HBV endemicity in Mexico is associated with HBV genotypes H and G.” World journal of gastroenterology: WJG 19.33 (2013): 5446.
6. Panduro, Arturo, et al. “Distribution of HBV genotypes F and H in Mexico and Central America.” Antivir Ther 18.3 Pt B (2013): 475-484.
7. Arauz-Ruiz, Patricia, et al. “Genotype H: a new Amerindian genotype of hepatitis B virus revealed in Central America.” Journal of general virology 83.8 (2002): 2059-2073.
8. Alvarado-Mora, Mónica V., and J. R. Pinho. “Distribution of HBV genotypes in Latin America.” Antivir Ther 18 (2013): 459-465.
9. Ioannou, George N. “Chronic hepatitis B infection: a global disease requiring global strategies.” Hepatology 58.3 (2013): 839-843.
10. Lavanchy, D. “Worldwide epidemiology of HBV infection, disease burden, and vaccine prevention.” Journal of clinical virology 34 (2005): S1-S3.
11. Liaw, Yun-Fan, and Chia-Ming Chu. “Hepatitis B virus infection.” The Lancet 373.9663 (2009): 582-592.
12. Dienstag, Jules L. “Hepatitis B virus infection.” New England Journal of Medicine 359.14 (2008): 1486-1500.
13. Van Hemert, Formijn J., et al. “Occult hepatitis B infection: an evolutionary scenario.” Virol J 5.12 (2008): 146-58.
14. Habibollahi, Peiman, et al. “Occult hepatitis B infection and its possible impact on chronic hepatitis C virus infection.” Saudi journal of gastroenterology: official journal of the Saudi Gastroenterology Association 15.4 (2009): 220.
15. Wong, GL‐H., et al. “Meta‐analysis: the association of hepatitis B virus genotypes and hepatocellular carcinoma.” Alimentary pharmacology & therapeutics 37.5 (2013): 517-526.
16. Bertoletti, Antonio, and Carlo Ferrari. “Innate and adaptive immune responses in chronic hepatitis B virus infections: towards restoration of immune control of viral infection.” Gut (2011): gutjnl-2011.
17. Dandri, Maura, and Stephen Locarnini. “New insight in the pathobiology of hepatitis B virus infection.” Gut 61.Suppl 1 (2012): i6-i17.
18. Roman, Sonia, et al. “A low steady HBsAg seroprevalence is associated with a low incidence of HBV-related liver cirrhosis and hepatocellular carcinoma in Mexico: a systematic review.” Hepatology international 3.2 (2009): 343-355.
19. Kodaman, Nuri, et al. “Human and Helicobacter pylori coevolution shapes the risk of gastric disease.” Proceedings of the National Academy of Sciences 111.4 (2014): 1455-1460.
20. Kodaman, Nuri, et al. “Disrupted human–pathogen co-evolution: a model for disease.” Frontiers in genetics 5 (2014).