Hathairad Hananantachai

Bio: Hathairad Hananantachai is an academic researcher from Mahidol University. The author has contributed to research in topics: Malaria & Cerebral Malaria. The author has an hindex of 18, co-authored 45 publications receiving 950 citations.

Extended linkage disequilibrium surrounding the hemoglobin E variant due to malarial selection.

Abstract: The hemoglobin E variant (HbE; β26Glu→Lys) is concentrated in parts of Southeast Asia where malaria is endemic, and HbE carrier status has been shown to confer some protection against Plasmodium falciparum malaria. To examine the effect of natural selection on the pattern of linkage disequilibrium (LD) and to infer the evolutionary history of the HbE variant, we analyzed biallelic markers surrounding the HbE variant in a Thai population. Pairwise LD analysis of HbE and 43 surrounding biallelic markers revealed LD of HbE extending beyond 100 kb, whereas no LD was observed between non-HbE variants and the same markers. The inferred haplotype network suggests a single origin of the HbE variant in the Thai population. Forward-in-time computer simulations under a variety of selection models indicate that the HbE variant arose 1,240–4,440 years ago. These results support the conjecture that the HbE mutation occurred recently, and the allele frequency has increased rapidly. Our study provides another clear demonstration that a high-resolution LD map across the human genome can detect recent variants that have been subjected to positive selection.

CD36 Polymorphism Is Associated with Protection from Cerebral Malaria

Abstract: The human protein CD36 is a major receptor for Plasmodium falciparum–infected erythrocytes and contributes to the pathology of P. falciparum malaria. We performed variation screening of the CD36 gene and examined the possible association between CD36 polymorphisms and the severity of malaria in 475 adult Thai patients with P. falciparum malaria. Accordingly, we identified nine CD36 polymorphisms with a high-frequency (>15%) minor allele. Of these, the frequencies of the −14T→C allele in the upstream promoter region and the −53G→T allele in the downstream promoter region were significantly decreased in patients with cerebral malaria compared to those with mild malaria (P=.016 for −14T→C and P=.050 for −53G→T). The analysis of linkage disequilibrium (LD) between the nine common polymorphisms revealed that there are two blocks with strong LD in the CD36 gene and that the −14T→C and −53G→T polymorphisms are within the upstream block of 35 kb from the upstream promoter to exon 8. Further association testing after the second variation screening in the upstream block indicated that the in3(TG)12 (i.e., 12 TG repeats in intron 3) allele is most strongly associated with the reduction in the risk of cerebral malaria (odds ratio 0.59; 95% confidence interval 0.40–0.87; P=.0069). We found, by reverse-transcriptase PCR amplification, that in3(TG)12 is involved in the nonproduction of the variant CD36 transcript that lacks exons 4 and 5. Since exon 5 of the gene is known to encode the ligand-binding domain for P. falciparum–infected erythrocytes, in3(TG)12 itself or a primary variant on the haplotype with in3(TG)12 may be responsible for protection from cerebral malaria in Thailand. Results of the present study suggest that LD mapping has potential for detecting a disease-associated variant on the basis of haplotype blocks.

Significant association of KIR2DL3-HLA-C1 combination with cerebral malaria and implications for co-evolution of KIR and HLA.

Abstract: Cerebral malaria is a major, life-threatening complication of Plasmodium falciparum malaria, and has very high mortality rate. In murine malaria models, natural killer (NK) cell responses have been shown to play a crucial role in the pathogenesis of cerebral malaria. To investigate the role of NK cells in the developmental process of human cerebral malaria, we conducted a case-control study examining genotypes for killer immunoglobulin-like receptors (KIR) and their human leukocyte antigen (HLA) class I ligands in 477 malaria patients. We found that the combination of KIR2DL3 and its cognate HLA-C1 ligand was significantly associated with the development of cerebral malaria when compared with non-cerebral malaria (odds ratio 3.14, 95% confidence interval 1.52–6.48, P = 0.00079, corrected P = 0.02). In contrast, no other KIR-HLA pairs showed a significant association with cerebral malaria, suggesting that the NK cell repertoire shaped by the KIR2DL3-HLA-C1 interaction shows certain functional responses that facilitate development of cerebral malaria. Furthermore, the frequency of the KIR2DL3-HLA-C1 combination was found to be significantly lower in malaria high-endemic populations. These results suggest that natural selection has reduced the frequency of the KIR2DL3-HLA-C1 combination in malaria high-endemic populations because of the propensity of interaction between KIR2DL3 and C1 to favor development of cerebral malaria. Our findings provide one possible explanation for KIR-HLA co-evolution driven by a microbial pathogen, and its effect on the global distribution of malaria, KIR and HLA.

Significant Association of Longer Forms of CCTTT Microsatellite Repeat in the Inducible Nitric Oxide Synthase Promoter with Severe Malaria in Thailand

Abstract: A CCTTT microsatellite repeat in the inducible nitric oxide synthase (iNOS) promoter was analyzed among 256 adult patients with severe Plasmodium falciparum malaria and 179 adult patients with mild malaria living in northwestern Thailand. Genotypes with longer forms of the CCTTT repeat (alleles of > or =15 repeats) were significantly associated with severe malaria (odds ratio [OR], 2.14; P=.0029, chi(2) test). More interestingly, the summed repeat number of both microsatellite alleles in an individual was found to be a significant risk factor for severe malaria (OR, 1.11; logistic regression analysis, P=.0041). The single nucleotide substitution, -954G-->C, in the iNOS promoter was rare in Thai patients with malaria. No variations were detected in the iNOS promoter region containing functional NF-kappaB elements at -5.2, -5.5, -5.8, and -6.1 kb upstream of the iNOS transcriptional start site. Thus, a CCTTT repeat in the iNOS promoter may play a key role in the pathogenesis of severe malaria.

Positive Natural Selection in the Human Lineage

Abstract: Positive natural selection is the force that drives the increase in prevalence of advantageous traits, and it has played a central role in our development as a species. Until recently, the study of natural selection in humans has largely been restricted to comparing individual candidate genes to theoretical expectations. The advent of genome-wide sequence and polymorphism data brings fundamental new tools to the study of natural selection. It is now possible to identify new candidates for selection and to reevaluate previous claims by comparison with empirical distributions of DNA sequence variation across the human genome and among populations. The flood of data and analytical methods, however, raises many new challenges. Here, we review approaches to detect positive natural selection, describe results from recent analyses of genome-wide data, and discuss the prospects and challenges ahead as we expand our understanding of the role of natural selection in shaping the human genome.

How malaria has affected the human genome and what human genetics can teach us about malaria.

Abstract: Malaria is a major killer of children worldwide and the strongest known force for evolutionary selection in the recent history of the human genome. The past decade has seen growing evidence of ethnic differences in susceptibility to malaria and of the diverse genetic adaptations to malaria that have arisen in different populations: epidemiological confirmation of the hypotheses that G6PD deficiency, α + thalassemia, and hemoglobin C protect against malaria mortality; the application of novel haplotype-based techniques demonstrating that malaria-protective genes have been subject to recent positive selection; the first genetic linkage maps of resistance to malaria in experimental murine models; and a growing number of reported associations with resistance and susceptibility to human malaria, particularly in genes involved in immunity, inflammation, and cell adhesion. The challenge for the next decade is to build the global epidemiological infrastructure required for statistically robust genomewide association analysis, as a way of discovering novel mechanisms of protective immunity that can be used in the development of an effective malaria vaccine.

Incorporating a Rapid-Impact Package for Neglected Tropical Diseases with Programs for HIV/AIDS, Tuberculosis, and Malaria

Abstract: Hotez et al. argue that achieving success in the global fight against HIV/AIDS, tuberculosis, and malaria may well require a concurrent attack on the neglected tropical diseases.