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Linkage disequilibrium across the human genome is generally lower in West Africans than Europeans. However in the 5q31 region, which is rich in immune genes, we find significantly more examples of apparent nonrecombination between distant marker pairs in West Africans. Much of this effect is due to SNPs that are absent in Europeans, possibly reflecting recent positive selection in the West African population.

Well-controlled genetic studies are easier to conduct with mice than with humans, and it has long been known that certain strains of mice consistently show a greater degree of resistance to infection than other strains. It is clear that these differences are primarily genetic, rather than environmental or acquired. This chapter discusses specific genetic loci that have been identified as responsible for some of these differences. Genetic factors also appear to underlie some striking differences in resistance to malaria that have been observed between ethnic groups who live in the same area. The chapter deals with the growing list of genes that show some evidence of influencing resistance to malaria. Glycophorins A and B, encoded by the homologous genes GYPA and GYPB, are major sialoglycoproteins of the erythrocyte membrane, which carries the antigenic determinants for various blood groups. Hemoglobin S (HbS) homozygotes have sickle cell disease, a debilitating and often fatal disorder caused by the red blood cell deformities that result from this structural defect, particularly at low oxygen concentrations. The thalassemias are a group of genetic disorders due to defective production of α- or β- globin chains, arising from a diverse set of deletions and other disruptions of the globin gene clusters on chromosomes 11 and 16. Haptoglobin, encoded by the HP gene, is a protein found in plasma. Parasite sequestration in cerebral capillaries, a hallmark of human cerebral malaria, is notable by its absence in the Plasmodium berghei ANKA (PBA) experimental model.

Fulani of Burkina Faso (West Africa) are a particularly interesting ethnic group because of their lower susceptibility to Plasmodium falciparum malaria as compared to sympatric populations, Mossi and Rimaibe. Moreover, the occurrence of a Caucasoid component in their genetic make-up has been suggested on the basis of their physical traits and cultural traditions even though this view was not supported by genetic studies. A total of 149 unrelated subjects (53 Mossi, 47 Rimaibe and 49 Fulani) have been typed for 97 HLA class I alleles with the amplification refractory mutation system/polymerase chain reaction (ARMS/PCR) technique. Mossi and Rimaibe data were pooled since none of the 42 statistically testable alleles exhibited a significant heterogeneity. These pooled gene frequencies were found to be very different from those of Fulani: a certain (P

7 páginas, 3 figuras, 4 tablas.-- et al., The Fulani of west Africa have been shown to be less susceptible to malaria and to mount a stronger immune response to malaria than sympatric ethnic groups. The analysis of HLA diversity is useful for the assessment of the genetic distance between the Fulani and sympatric populations, which represents the necessary theoretical background for the investigation of genetic determinants of susceptibility to malaria. We assessed the polymorphism of HLA-DRB1 and -DQB1 loci and analyzed the distribution of alleles/haplotypes in Fulani, Mossi, and Rimaibé from Burkina Faso. We then investigated the genetic relationship of these three ethnic groups with other sub-Saharan African populations as well as with Europeans. We confirmed that the Fulani from Burkina Faso are genetically distinct from sympatric Mossi and Rimaibé. Furthermore the Fulani from Burkina Faso are close to those from The Gambia and, intriguingly, share the distribution of specific alleles with east African populations (Amhara and Oromo). It is noteworthy that the HLA-DRB1*04 and -DQB1*02 alleles, which are implicated in the development of several autoimmune diseases, are present at high frequency in the Fulani, suggesting their potential involvement in the enhanced immune reactivity observed in this population., This work is part of the activities of the BioMalPar European Network of Excellence supported by a European grant (LSHP-CT- 2004-503578) from the Priority 1 “Life Sciences, Genomics and Biotechnology for Health” in the 6th Framework Programme, and V.D.M. was funded by a BioMalPar PhD Fellowship. This work was further supported by grants from Italian Ministry of Education (COFIN, MIUR-PRIN 2006062857) and Istituto Pasteur–Fondazione Cenci Bolognetti, Sapienza Universitá di Roma.

Background: Trachoma, a chronic keratoconjunctivitis caused by Chlamydia trachomatis, is the world's commonest infectious cause of blindness. Blindness is due to progressive scarring of the conjunctiva (trachomatous scarring) leading to in-turning of eyelashes (trichiasis) and corneal opacification. We evaluated the contribution of genetic variation across the chemokine and cytokine clusters in chromosomes 4q and 5q31 respectively to risk of scarring trachoma and trichiasis in a large case-control association study in a Gambian population. Methods: Linkage disequilibrium (LD) mapping was used to investigate risk effects across the 4q and 5q31 cytokine clusters in relation to the risk of scarring sequelae of ocular Ct infection. Disease association and epistatic effects were assessed in a population based study of 651 case-control pairs by conditional logistic regression (CLR) analyses. Results: LD mapping suggested that genetic effects on risk within these regions mapped to the pro-inflammatory innate immune genes interleukin 8 (IL8) and granulocyte-macrophage colony stimulatory factor (CSF2) loci. The IL8-251 rare allele (IL8-251 TT) was associated with protection from scarring trachoma (OR = 0.29 p = 0.027). The intronic CSF2_27348 A allele in chromosome 5q31 was associated with dose dependent protection from trichiasis, with each copy of the allele reducing risk by 37% (p = 0.005). There was evidence of epistasis, with effects at IL8 and CSF2 loci interacting with those previously reported at the MMP9 locus, a gene acting downstream to IL8 and CSF2 in the inflammatory cascade. Conclusion: innate immune response SNP-haplotypes are linked to ocular Ct sequelae. This work illustrates the first example of epistatic effects of two genes on trachoma.

Many investigators are now using haplotype-tagging single-nucleotide polymorphism (htSNPs) as a way of screening regions of the genome for association with disease. A common approach is to genotype htSNPs in a study population and to use this information to draw inferences about each individual's haplotypic makeup, including SNPs that were not directly genotyped. To test the validity of this approach, we simulated the exercise of typing htSNPs in a large sample of individuals and compared the true and inferred haplotypes. The accuracy of haplotype inference varied, depending on the method of selecting htSNPs, the linkage-disequilibrium structure of the region, and the amount of missing data. At the stage of selection of htSNPs, haplotype-block-based methods required a larger number of htSNPs than did unstructured methods but gave lower levels of error in haplotype inference, particularly when there was a significant amount of missing data. We present a Web-based utility that allows investigators to compare the likely error rates of different sets of htSNPs and to arrive at an economical set of htSNPs that provides acceptable levels of accuracy in haplotype inference.

Previous studies identified an allelic variant of the IL4 promoter region (IL4-589T) that appears to enhance the transcriptional activity of IL4, and is associated with increased IgE levels. Total serum IgE levels are elevated in malaria endemic regions, and higher in children with severe malaria. Here, we investigated the relationship of the IL4-589C/T polymorphism with severity of the disease in a case-control study of severe malaria in Burkina Faso, West Africa. No association between the IL4-589T and severe malaria was observed. No difference in Plasmodium falciparum-specific IgE was detected between severe and uncomplicated malaria patients. Among children with severe malaria, total IgE levels were significantly elevated in those carrying the IL4-589T allele (P = 0.018). In children with uncomplicated malaria, no significant difference was found. These results raise the possibility that there is a relationship between susceptibility to severe malaria, IgE production and genetic variation in the IL4 region, which merits further investigation in other epidemiological settings.

Haemoglobin C (HbC; beta6Glu --> Lys) is common in malarious areas of West Africa, especially in Burkina Faso. Conclusive evidence exists on the protective role against severe malaria of haemoglobin S (HbS; beta6Glu --> Val) heterozygosity, whereas conflicting results for the HbC trait have been reported and no epidemiological data exist on the possible role of the HbCC genotype. In vitro studies suggested that HbCC erythrocytes fail to support the growth of P. falciparum but HbC homozygotes with high P. falciparum parasitaemias have been observed. Here we show, in a large case-control study performed in Burkina Faso on 4,348 Mossi subjects, that HbC is associated with a 29% reduction in risk of clinical malaria in HbAC heterozygotes (P = 0.0008) and of 93% in HbCC homozygotes (P = 0.0011). These findings, together with the limited pathology of HbAC and HbCC compared to the severely disadvantaged HbSS and HbSC genotypes and the low betaS gene frequency in the geographic epicentre of betaC, support the hypothesis that, in the long term and in the absence of malaria control, HbC would replace HbS in central West Africa.

The gene frequencies in 1993-94 for haemoglobin S, haemoglobin C, alpha-3.7 deletional thalassaemia, G6PDA-, HLAB*5301 were estimated in Fulani, Mossi and Rimaibé ethnic groups of Burkina Faso, West Africa. The aim of the study was to verify whether the previously reported Fulani lower susceptibility to Plasmodium falciparum malaria was associated with any of these malaria-resistance genes. Similar frequencies for haemoglobin S were recorded in the 3 ethnic groups (0.024 +/- 0.008, 0.030 +/- 0.011, 0.022 +/- 0.013; in Mossi, Rimaibé and Fulani, respectively). The Mossi and Rimaibé showed higher frequencies when compared to Fulani for haemoglobin C (0.117 +/- 0.018, 0.127 +/- 0.020, 0.059 +/- 0.020), alpha-3.7 deletional thalassaemia (0.227 +/- 0.040, 0.134 +/- 0.032, 0.103 +/- 0.028), G6PDA- (0.196 +/- 0.025, 0.187 +/- 0.044, 0.069 +/- 0.025) and HLA B*5301 (0.189 +/- 0.038, 0.202 +/- 0.041, 0.061 +/- 0.024). Among Fulani the proportion of individuals not having any of these protective alleles was more than 3-fold greater than in the Mossi-Rimaibé group (56.8% vs 16.7%; P0.001). These findings exclude the involvement of these genetic factors of resistance to P. falciparum in the lower susceptibility to malaria of Fulani. This evidence, in association with the previously reported higher immune reactivity to malaria of Fulani, further supports the existence in this ethnic group of unknown genetic factor(s) of resistance to malaria probably involved in the regulation of humoral immune responses.

The Fulani are less clinically susceptible and more immunologically responsive to malaria than neighbouring ethnic groups. Here we report that anti-malarial antibody levels show a wide distribution amongst the Fulani themselves, raising the possibility that quantitative analysis within the Fulani may be an efficient way of screening for important genetic factors. The Th2 cytokine interleukin-4 is an obvious candidate: in Fulani, the IL4-524 T allele is at high frequency and is associated with elevated antibody levels against malaria antigens. These data highlight the possibility of combining inter- and intra-ethnic comparisons to characterize critical determinants of malarial immunity in a natural setting.