Elsevier

Autoimmunity Reviews

Volume 7, Issue 5, May 2008, Pages 398-403
Autoimmunity Reviews

HLA-B27 and Ankylosing Spondylitis geographic distribution as the result of a genetic selection induced by malaria endemic? A review supporting the hypothesis

https://doi.org/10.1016/j.autrev.2008.03.013Get rights and content

Abstract

The geographic distribution of HLA-B27 shows a latitude-related gradient inverse to that of malaria endemic. An apparent exception occurs in New Guinea, a region where malaria is present, but where HLA-B27 frequency shows, however, an orographic gradient antithetic to that of malaria incidence. We therefore suggest that Plasmodium falciparum may have exerted a negative selection on this gene. This might be due to a higher susceptibility to severe forms of malaria, associated with HLA-B27 or other close gene(s). In addition, we suggest here that the same selective pressure that has contributed to reduce the HLA-B27 frequency in some regions has favoured the fixing of newly generated B27 subtypes included in more advantageous HLA haplotypes. In some cases, as for B2709 in Sardinia and B2706 in Southeast Asia, these haplotypes may harbour factors that protect from Ankylosing Spondylitis, an autoimmune disease strongly associated with HLA-B27, thus offering a novel, powerful tool to dissect disease pathogenesis, and to identify additional genetic factors of susceptibility.

Section snippets

Worldwide distribution of HLA-B27

The observation of a non-homogeneous geographic distribution of HLA-B27 has been reviewed by Khan [5]. In fact, there is evidence for a latitude-dependence of the HLA-B27 frequency among world populations, with the lowest value (0%) in the equatorial area and the highest (40%) in the Arctic and farthest North lands [6], [7]. Accordingly, Ankylosing Spondylitis (AS) and other HLA-B27-associated diseases, show a similar distribution. This is compatible with the hypothesis that environmental

The spreading of HLA-B27 subtypes on the light of the proposed hypothesis

Disappearance of the selective pressure exerted by malaria in some geographic areas has left behind a number of gene variants which may eventually contribute to the spreading of new infectious diseases or to susceptibility to common complex diseases [23]. An example may be the resistance to malaria conferred by HLA-B53, and the susceptibility to AIDS associated with HLA-B35. In this context, it seems particularly informative the fact that B35PY subset, which differs only at position 116 from

Other genes within the HLA region may have contributed to the fixing of HLA-B27 variants

B2709 and B2705 in Sardinia are harboured by different extended HLA haplotypes which include also cytokine genes [31]. The association between severe cerebral malaria and TNFα (-308T and -857T) promoter polymorphisms has been reported in Africa and in East Asia, respectively [32], [33], [34], [35]. Noteworthy, in Sardinia -857T is in linkage disequilibrium with HLA-B2705 whereas allele C co-occurs more frequently (95%) with the HLA-B2709 [36]. It is possible that TNFα promoter polymorphisms

Concluding remarks

Genetic studies on HLA-B27 haplotypes carrying common B27 subtypes with a special attention to the TNFα promoter should shed some light on this hypothesis. Moreover, studies have shown that some malaria vaccines on trial are partially protective [38]. HLA typing of the non-responders may reveal a significant increase in some haplotypes, disclosing a more general issue that should be considered when vaccines are designed.

In conclusion, HLA genes for their function in antigen presentation are the

Take-home messages

  • We hypothesize that the non-homogeneous distribution of HLA-B27 in the world populations, which is inverse to that of malaria endemic, is the result of a negative selective pressure exerted by P. falciparum.

  • As a consequence of this selective pressure, a number of HLA-B27 variants have been fixed in areas where malaria was endemic.

  • These HLA-B27 variants may have been selected because able to present relevant antigenic peptides from P. falciparum and/or because part of haplotypes carrying better

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