Blood type O resists severe malaria

Who knew? Blood type O protects people from falciparum malaria. That's a study by Alexandra Rowe and colleagues, studying a case-control sample from Mali.

And it's not just some little piddling effect. Check out the chart:

Proportion of blood types affected by malaria

Figure 1, A and B, from Rowe et al. 2007.

Type O seems to have a large preventative effect in the severe malaria cases. It doesn't protect people from initial infection, according to these comparisons, but it seems to reduce the disease severity by a lot. The paper attributes that to a reduction in "rosetting" -- that is, the parasites make blood cells tend to clump together, allowing the parasites to spread more quickly through the blood. The mechanism for that clumping makes use of the ABO antigen. Type O people lack the functional trisaccharide antigen, and so they have less rosetting when infected by P. falciparum.

Here's a mystery: if O has such a large effect on malaria severity, then why isn't it fixed? Certainly it is at a higher frequency in subsaharan Africa than in many other parts of the world, but from an initially substantial frequency and no apparent disadvantages it should have become rapidly fixed anywhere P. falciparum infects a substantial proportion of people.

Now, you might point out that O is recessive, and so selection would not be as effective. But this is mostly true for the initial, very low-frequency stages of selection on an allele. Type O blood exists at a substantial frequency already in most human populations. It's not a very young mutation. So selection should have been very effective right away, despite it being recessive.

Clearly, one of two things must be true: either "severe" malaria as documented in this study haven't long been a strong selective factor, or type A and B have counterbalancing advantages.

I could imagine either scenario -- for example, maybe in the past the selective impact of "severe" and non-severe malaria was about the same, and the two only become relevantly different given a mimimal degree of medical care. Or maybe a new P. falciparum strain causing more "severe" malaria hasn't existed very long, but is resisted by type O.

Or, maybe A and B respond effectively to later stages of infection (there's some precedent, with a CD28 allele showing resistance to cerebral malaria, for example). It seems like if there were another important pathogen selecting strongly for A and B, we'd have noticed -- but then, I would have thought that an ABO-malaria association this strong would have been noticed earlier!

Here's the review section:

Earlier studies have found no consistent effect of the ABO blood group on the incidence of uncomplicated malaria, parasite density, or levels of anti-malarial antibody (for review, see ref. 16). The effect of the ABO blood group on severe falciparum malaria has received little attention, although previous studies have suggested that in African children, blood group A may predispose to severe malaria (17, 18), and in Southeast Asian adults, blood group O may confer resistance to the multiorgan failure form of severe disease (19). A rigorous study of the effect of ABO blood group on susceptibility to severe malaria using a matched case-control design with adjustment for known host protective factors such as hemoglobin variants has not been per formed (20). The possibility of a rosette-mediated protective effect of blood group O has been raised previously (1721); however, the effects of ABO blood group on rosetting and susceptibility to severe malaria have not yet been examined in a single study (Rowe et al. 2007:17471).

There you have it: it takes some doing to tease out these associations of alleles with disease stage and severity. And yet, these are precisely the associations that might be important to selection on an evolutionary timescale.

(via Gene Expression)

Rowe JA, Handel IG, Thera MA, Deans A-M, Lyke KE, Koné A, Diallo DA, Raza A, Kai O, Marsh K, Plowe CV, Doumbo OK, Moulds JM. 2007. Blood group O protects against severe Plasmodium falciparum malaria through the mechanism of reduced rosetting. Proc Nat Acad Sci 104:17471-17476. doi:10.1073/pnas.0705390104