A genome scan for Plasmodium falciparum malaria identifies quantitative trait loci on chromosomes 5q31, 6p21.3, 17p12, and 19p13

Brisebarre, Audrey; Kumulungui, Brice; Sawadogo, S.; Atkinson, Alexandre; Garnier, Séverine; Fumoux, Francis; Rihet, Pascal

doi:10.1186/1475-2875-13-198

Cited by 22 publications

(23 citation statements)

References 30 publications

(45 reference statements)

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“…Interestingly, chromosome 6p21.3 was linked to parasitaemia and mild malaria in the same population. 2,22 In other populations, ABO blood group genes located within chromosome 9q34 were associated with parasitemia and severe malaria, 23,24 whereas chromosome 12q22 was linked to mild malaria in a Senegalese population. 3 Because the antibody levels may depend on the exposure to parasite antigens, we further assessed the linkage of IgG and IgG subclass levels to the chromosomal regions of interest when taking into account parasitemia; the analyses yielded very similar results, ruling out the possibility of false linkage results due to this confounding factor.…”

Section: Discussionmentioning

confidence: 98%

“…2 In brief, a genome scan was performed by using 400 microsatellite markers (Panel MD-10, Applied Biosystems, Saint-Aubin, France), with an average distance of 10 cM. Multiplex polymerase was performed under standard conditions, and the products were analysed by using an ABI377 systems (Applied Biosystems).…”

Section: Subjects and Phenotype Determinationmentioning

confidence: 99%

“…Several candidate genes have been associated with resistance against clinical malaria or parasitaemia, 1 whereas genome-wide scans mapped several loci controlling mild malaria and/or parasitaemia. [2][3][4] Furthermore, cellular and humoral responses have been shown to be associated with enhanced resistance against malaria, 5 and to be genetically controlled. 6 Anti-P. falciparum immunoglobulin G (IgG0 antibodies) are thought to have a critical role in immune protection against asexual blood stages of the parasite.…”

Section: Introductionmentioning

confidence: 98%

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Genome-wide significant linkage to IgG subclass responses against Plasmodium falciparum antigens on chromosomes 8p22-p21, 9q34 and 20q13

et al. 2014

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A genome-wide scan was conducted for the levels of total immunoglobulin G (IgG) and IgG subclasses directed against Plasmodium falciparum antigens in an urban population living in Burkina Faso. Non-parametric multipoint linkage analysis provided three chromosomal regions with genome-wide significant evidence (logarithm of the odds (LOD) score >3.6), and five chromosomal regions with genome-wide suggestive evidence (LOD score >2.2). IgG3 levels were significantly linked to chromosomes 8p22-p21 and 20q13, whereas IgG4 levels were significantly linked to chromosome 9q34. In addition, we detected suggestive linkage of IgG1 levels to chromosomes 18p11-q12 and 18q12-q21, IgG4 levels to chromosomes 1p31 and 12q24 and IgG levels to chromosome 6p24-p21. Moreover, we genotyped genetic markers located within the regions of interest in a rural population living in Burkina Faso. We detected genome-wide significant and suggestive linkage results when combining the two study populations for chromosomes 1p31, 6p24-p21, 8p22-p21, 9q34, 12q24 and 20q13. Because high anti-parasite IgG3 and low anti-parasite IgG4 levels were associated with malaria resistance, the chromosomal regions linked to IgG3 and IgG4 levels are of special interest. Although the results should be confirmed in an independent population, they may provide new insights in understanding both the genetic control of IgG production and malaria resistance.

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Section: Discussionmentioning

confidence: 98%

Section: Subjects and Phenotype Determinationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

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Genome-wide significant linkage to IgG subclass responses against Plasmodium falciparum antigens on chromosomes 8p22-p21, 9q34 and 20q13

et al. 2014

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“…Previous family-based studies reported the association of 5q31-q33 with mild malaria susceptibility and resistance (20,21).…”

Section: Discussionmentioning

confidence: 99%

Genome-wide heritability analysis of severe malaria susceptibility and resistance reveals evidence of polygenic inheritance

Damena

Chimusa

2019

Preprint

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Objective: Estimating SNP-heritability (h 2 g) of severe malaria/resistance and its distribution across the genome might shed new light in to the underlying biology. Method:We investigated h 2 g of severe malaria susceptibility and resistance from genomewide association study (GWAS) dataset (sample size =11, 657). We partitioned the h 2 g in to chromosomes, allele frequencies and annotations. We further examined none-cell type specific and cell type specific enrichments from GWAS-summary statistics. Results:We estimated the h 2 g of severe malaria at 0.21 (se=0.05, p=2.7x10 -5 ), 0.20 (se =0.05, p=7.5x10 -5 ) and 0.17 (se =0.05, p= 7.2x10 -4 ) in Gambian, Kenyan and Malawi populations, respectively. The h 2 g attributed to the GWAS significant SNPs and the well-known sickle cell (HbS) variant was approximately 0.07 and 0.03, respectively. We prepared African population reference panel and obtained comparable h 2 g estimate (0.21 (se = 0.02, p< 1x10 -5 )) from GWAS-summary statistics meta-analysed across the three populations. Partitioning analysis from raw genotype data showed significant enrichment of h 2 g in protein coding genic SNPs while summary statistics analysis suggests pattern of enrichment in multiple categories. Conclusion:We report for the first time that the heritability of malaria susceptibility and resistance is largely ascribed by common SNPs and the causal variants are overrepresented in protein coding regions of the genome. Overall, our results suggest that malaria susceptibility and resistance is a polygenic trait. Further studies with larger sample sizes are needed to better understand the underpinning genetics of resistance and susceptibility to severe malaria.

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“…Among those, sickle cell trait (haemoglobin S, HbS), haemoglobin C (HbC) at homozygote 60 state, alpha+ thalassemia and glucose-6-phosphate dehydrogenase (G6PD) deficiency have been 61 associated with a protection against parasite invasion and clinical malaria attacks (7). 62Other association studies have focused on chromosomal regions linked with parasite infection levels 63 and mild malaria susceptibility, in particular 5q31-33 and 6p21-23 (8)(9)(10)(11)(12)(13)(14)(15). In this last region, TNF 64 has been the most studied candidate; NCR3, encoding a cell membrane receptor of natural killer, has 65 been also repeatedly associated with mild malaria (10,16).Since 2010, several genome-wide 66 association studies (GWAS) and meta-analysis have been published on severe malaria (17-21).…”

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confidence: 99%

First genome-wide association study of non-severe malaria in two birth cohorts in Benin

Milet

Boland

Luisi

et al. 2018

Preprint

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2 20 ABSTRACT 21 Recent research efforts to identify genes involved in the susceptibility to P. falciparum malaria have 22 focused on severe forms of malaria, with several genome-wide association studies (GWAS) and 23 multi-center analyses published this past decade. Here we present the first GWAS performed on 24 mild malaria susceptibility in young children, designed to identify genetic variants involved in 25 innate immunity or innate resistance mechanisms. Two cohorts of infants from southern Benin (525 26 and 250 individuals respectively), used as discovery and replication cohorts, were closely followed 27 from birth to 18-24 months of age, with an assessment of a space-and time-dependent risk of 28 exposure to vector bites. GWAS was performed on 15.5 million genotyped and imputed variants, 29 with the susceptibility of infants to mild malaria attacks and to malaria infections as a whole (both 30 symptomatic and asymptomatic). Infant susceptibility to malaria was assessed by considering all 31 malaria events occurring during the follow-up using a Cox-model for recurrent events. We found 32 strong statistical support for a role of PTPRT, a tyrosine phosphatase receptors involved in STAT3 33 pathway, with the protection against both mild malaria attacks and malaria infections (p=9.70x10 -8 34 and p=1.78x10 -7 respectively in the discovery cohort, and both p < 0.05 in the replication cohort).35 Furthermore, our study highlights several other genes, among them, UROC1, ACER3 and the 36 PLAG2 cluster, whose biological functions are relevant in malaria infection. Results show that 37 despite the difficulty of setting up such longitudinal field studies, GWAS on non-severe malaria can 38 successfully identify new candidate genes and inform physiological mechanisms underlying natural 39 protection against malaria. 40 41 AUTHOR SUMMARY 42 Malaria remains a major worldwide public health problem with circa 219 million cases and 435,000 43 deaths per year. As for many infectious diseases, the genetics of the host plays a role in the disease 44 course. So far, most studies on such genetic factors focused on severe malaria forms. Our study 45 aimed to find factors associated with simple forms (asymptomatic forms and uncomplicated clinical 3 46 forms). We used dense genome-wide data of two cohorts of infants closely followed during two 47 years in Benin, and we incorporated an environmental risk of exposure estimated at individual level 48 from entomological, climatic, and environmental data. This allowed us to unravel several genes that 49 appear to play a role in the susceptibility to malaria infection, thus demonstrating the feasibility of a 50 genome-wide approach on non-severe forms. Functional studies are needed to confirm the role of 51 the genetic factors highlighted here. Some of these genes represent interesting targets for future 52 prevention strategies and drug development. 4 53 INTRODUCTION 54 55 In spite of numerous prevention and control efforts in recent years, malaria remains a major 56 global public health ...

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A genome scan for Plasmodium falciparum malaria identifies quantitative trait loci on chromosomes 5q31, 6p21.3, 17p12, and 19p13

Cited by 22 publications

References 30 publications

Genome-wide significant linkage to IgG subclass responses against Plasmodium falciparum antigens on chromosomes 8p22-p21, 9q34 and 20q13

Genome-wide significant linkage to IgG subclass responses against Plasmodium falciparum antigens on chromosomes 8p22-p21, 9q34 and 20q13

Genome-wide heritability analysis of severe malaria susceptibility and resistance reveals evidence of polygenic inheritance

First genome-wide association study of non-severe malaria in two birth cohorts in Benin

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