In malaria hyper-endemic settings, protection from malaria mortality and morbidity is achieved with age as a consequence of immunity and this protection is augmented in subpopulations by inherent, genetically controlled host factors. The genetic factors involved in resistance to malaria are clearly numerous, the best known involving various balanced polymorphisms in haemoglobin genes. In this study, the number of malaria episodes over nine years of clinical and parasitological follow-up was recorded for a cohort of around half of the Daraweesh village inhabitants. The data showed who was most susceptible/resistant to malaria infection. Integration of this data together with genotyping of GM/KM allotypes and measurement of total IgG and IgG isotypes to four malaria antigens revealed interesting findings. The study showed that, the GM allelic combinations but not the KM allelic combinations had significant influence in uncomplicated malaria susceptibly and in the type and concentration of IgG isotype. While the implication of GM allotypes in susceptibility to bacterial infections and other diseases have been known for some time [20, 21], the role of GM/KM polymorphisms in malaria susceptibility has only recently been investigated [12, 22]. In this study, the GM 1,17 5,13,14,6 phenotype was significantly associated with increased susceptibility to malaria infections although paradoxically it was significantly associated with the highest baseline concentration of certain IgG and IgG isotypes. Both associations were age independent, and the latter one was largely dependent on the target antigen.
GM allotypes have been assessed in all villagers tested and the frequencies of each GM or KM allotype determined. Nearly all villagers have GM allotypes 5, 17, 1 and 14 in their GM phenotype. This leaves allotypes 13 and 6 as the major GM allotype differences between villagers, both of which are located within the G3 constant region. Allotypes 1 and 17 are believed to be located in the G1 constant region, and do not, therefore, differ in 215 of the 216 villagers. The fact that the GM differences in this cohort are almost entirely in the G3 constant region and the significance of the GM polymorphisms in terms of possible differences in antibody functionality between the susceptible (i.e. 13, 6 containing allotypes) and the less susceptible (i.e. phenotypes not containing 13, 6 allotypes), worth further investigation. In this study, the GM 1,17 5,14 carriers, compared with the carriers of the other phenotypes or the non-carriers of 1,17 5,14 phenotype, had experienced the least number of malaria episodes although the differences were not significant. The significantly raised antibodies in the plasma of the carriers of the GM 1,17 5,13,14,6 phenotype, were mainly the total IgG and IgG2, but not the IgG3 isotype. The levels of IgG4 isotype to all antigens were generally very low, not associated with age and apparently were not increased after acute infection (unpublished data). The allotype-specific variation in the levels of IgG subclasses was antigen-dependent. This finding is supporting and adding to a previous report suggesting inherent ability of individual malaria antigens in antibody class switching .
The GM 1,17 5,13,14,6 phenotype was the second most prevalent phenotype in the area. This same phenotype was found to be more dominant in the Massalit, a tribe presumed to be more susceptible to malaria than Fulani . The above-mentioned implication of GM 1,17 5,13,14,6 phenotype, might be due to the GM 6 allotype component. The allotype 6 was detected in half of the Daraweesh inhabitants, while at a global level the GM phenotypes containing GM 6 was recognized only in Africans, but not in other populations . Recently, it was shown that, there was an inverse relationship between carriage of GM 1,17 5,13,14,6 phenotype and occurrence of uncomplicated malaria in Benin . That observation does not contradict this study findings, as in their study all individuals involved in the study were infected with malaria and there were small in age (less than 10 years). Furthermore, in the Benin study, the clinical grouping was based on a single observation, also, the immune profile of the patients was not known. In this study, the above limitations were surmounted. In addition, the diversity that could result from the differences due to ethnicity was overcome by having a single homogenous ethnic study group. The KM allotypes were not statistically associated with malaria susceptibility.
The influence of GM/KM allotypes on antibody response is assumed to be due to alteration of antibody specificity through variable regions  or by modification of antibody constant region . The data showed limited effects for the GM/KM phenotypes on the concentration of IgG isotypes. However, there was a tendency for an antigen-dependent pattern of responses. Having examined five (IgG and subclasses) antibody titres to four antigens in the same individual, lack of consistency in levels of any subclass to all examined antigens in any of the GM/KM phenotypes carrier groups, was an evidence for lack of an innate effect for allotypes in levels of subclasses without the influence of the antigens. The antigen-dependent IgGs responses in malaria, are shown to have opposing significances i.e. exposure or protection, in a recent study from Kenya .
Recently, it has also been found that, there is a higher prevalence than previously expected, of primary partial immune deficiencies including IgG isotypes and GM allotypes, in apparently healthy individuals . Finally, the influence of GM allotypes (immunoglobulin C-region) in immunity is conventionally thought to be associated with the V-region, as a particular allotype might be in linkage disequilibrium with a particular V- region determinant . Alternatively, GM6 and GM13 allotypes, in this study, could contribute to formation of idiotypes associated with lower immunological responsiveness. On the other hand, the C-region (namely CH2 and CH3 domains) could modify the immunity through its affinity to the FcγR, and there might be certain GM allotype interaction with particular FcγR variant leading to either increased or decreased immune response . A work showing the association between GM allotypes and FcγR polymorphisms and another showing the association between the levels of total IgG and IgG subclasses to different antigens and protection from malaria in the same cohort, are in progress.