Exploration of Host Genetic Factors associated with Malaria

Contents
About the Author
1: Human Genetics and Infectious Disease
	1.1	 Introduction
	1.2	 Hypothesis
	1.3	 Predisposition to Disease
		1.3.1	 Genetic Predisposition to Infections Due to Mendelian Traits
			1.3.1.1	 Mycobacterial Disease Predisposition
			1.3.1.2	 IRAK-4 Deficiency and Predisposition to Streptococcus pneumoniae Infection
			1.3.1.3	 X-Linked Lymphoproliferative (XLP) and Predisposition to Epstein-Barr Virus Infection
	1.4	 Mendelian Resistance
	1.5	 Genome Variability, Natural Selection, and Infectious Diseases
		1.5.1	 Single Nucleotide Polymorphisms (SNPs)
			1.5.1.1	 Coding Polymorphisms
			1.5.1.2	 Regulatory/Promoter Polymorphisms
		1.5.2	 Copy Number Variations (CNV)
	1.6	 Malaria, an Infectious Parasitic Disease Shapes Human Genome
	1.7	 Conclusion
	References
Part I: RBC Disorders
	2: Sickle Cell Gene
		2.1	 Introduction
		2.2	 Hypothesis
		2.3	 Balanced Polymorphisms
		2.4	 Sickle Cell Disease
		2.5	 Epidemiology of Sickle Cell Hemoglobin
		2.6	 Genetic Origin of Sickle Cell Disease
		2.7	 Malaria and Sickle Cell Hemoglobinopathy (HbS)
			2.7.1	 Hemoglobin C (HbC)
			2.7.2	 Mechanism of Protection by Sickle Cell Hemoglobin
			2.7.3	 Hemoglobin Degradation by Plasmepsins
		2.8	 Other Natural Protective Mechanisms
			2.8.1	 Knops Blood Group System
			2.8.2	 Adhesion Molecules
		2.9	 Conclusions
		References
	3: Alpha-Thalassemia
		3.1	 Introduction
		3.2	 Mechanism
		3.3	 Epidemiology
		3.4	 Types of Alpha-Thalassemia
			3.4.1	 Alpha-Thalassemia Trait
			3.4.2	 Silent Carrier State of Alpha-Thalassemia
			3.4.3	 Hemoglobin H (Hb H) Disease
			3.4.4	 Hb Bart’s Hydrops Fetalis Syndrome
		3.5	 Molecular Basis of Thalassemia
		3.6	 Inheritance Pattern
		3.7	 Diagnosis
			3.7.1	 Hematological Test
			3.7.2	 Molecular Diagnosis
		3.8	 Therapy
			3.8.1	 Blood Transfusion
			3.8.2	 Transplantation of Bone Marrow and Cord Blood
			3.8.3	 Gene Therapy
		3.9	 Alpha-Thalassemia and Malaria
			3.9.1	 Alpha-Thalassemia Trait and P. falciparum Malaria Protection
		3.10	 Conclusion
		References
	4: Beta-Thalassemia
		4.1	 Introduction
		4.2	 Molecular Biology and Epidemiology of Beta-Thalassemia
			4.2.1	 Molecular Biology of Disease
			4.2.2	 Epidemiology of Beta-Thalassemia
		4.3	 Hemoglobinopathies Selected as Balancing Trait Against Malaria
		4.4	 Current Treatment Options
			4.4.1	 Transfusion
			4.4.2	 Induction of Fetal Form of Hemoglobin (HbF)
			4.4.3	 Hematopoietic Stem Cell Transplantation
			4.4.4	 Splenectomy
			4.4.5	 Iron Chelation Therapy
		4.5	 Factors Affecting Global Distribution of Thalassemia
			4.5.1	 Consanguinity
			4.5.2	 Nutrition and Infections
			4.5.3	 Migration
			4.5.4	 Prevention
		4.6	 Molecular Diagnosis of Thalassemia
			4.6.1	 PCR and Sequencing Strategies
			4.6.2	 Single-Stranded Conformational Polymorphism (SSCP)
			4.6.3	 Allele-Specific Oligonucleotide Probes (ASOs)
			4.6.4	 Amplification Refractory Mutation System (ARMS)
			4.6.5	 GAP-PCR and MLPA
			4.6.6	 Method Using Melting Curve Analysis
			4.6.7	 Hemoglobin Electrophoresis
		4.7	 Conclusion
		References
	5: Duffy Blood Group Locus
		5.1	 Introduction
		5.2	 Polymorphisms and Epidemiology of Duffy Gene
		5.3	 Duffy Antigen and Malaria
			5.3.1	 Duffy Antigen as Balancing Selection in Malaria
			5.3.2	 Circulation of Duffy Gene Allelic Variants in Humans
		5.4	 Invasion of P. vivax in Duffy-Negative Individuals (Duffy-Independent Invasion Pathways)
		5.5	 Chemokines Act as Ligand for DARC
		5.6	 Duffy Negative Phenotype and Cancer Susceptibility
		5.7	 Discussion
		5.8	 Conclusion
		References
Part II: Metabolic Enzymes
	6: Pyruvate Kinase Deficiency
		6.1	 Introduction
		6.2	 Biochemical Function and Deficiency of Enzyme
		6.3	 Molecular Biology of Pyruvate Kinase Gene
		6.4	 Epidemiology of Pyruvate Kinase Deficiency
		6.5	 Analysis of Genetic Variants in pklr Gene
			6.5.1	 Pyruvate Kinase L272V Mutation
			6.5.2	 Pyruvate Kinase Arginine/Glutamine (R41Q) Mutation
			6.5.3	 Pyruvate Kinase Glutamate/Lysine (Glu277Lys) Mutation
		6.6	 Pyruvate Kinase Deficiency as Protective Trait Against Malaria
			6.6.1	 Copy Number Variation in pklr Gene
		6.7	 Mechanism of Protection Against P. falciparum Caused Malaria
		6.8	 Conclusion
		References
	7: Glucose 6-Phosphate Dehydrogenase Deficiency
		7.1	 Introduction
		7.2	 Biochemical Function and Deficiency of G6PD Enzyme
		7.3	 Epidemiology of G6PD Deficiency
		7.4	 Molecular Biology
		7.5	 Glucose 6-Phosphate Dehydrogenase Polymorphisms
		7.6	 G6PD Deficiency a Balancing Trait Against P. falciparum Caused Malaria
		7.7	 Detection of G6PD Deficiency
			7.7.1	 Fluorescent Spot Test
			7.7.2	 Spectrophotometric Assay
			7.7.3	 Cytochemical Assay
		7.8	 Conclusion
		References
Part III: Host Immune Response
	8: TNF Genetic Polymorphisms
		8.1	 Introduction
		8.2	 Molecular Biology
		8.3	 TNF-Alpha Mediates Action Through Binding with TNFR1 and TNFR2
		8.4	 Pathologic Changes in Cerebral Malaria (CM)
		8.5	 TNF Promoter Polymorphisms and P. falciparum Malaria
		8.6	 Conclusion
		References
	9: iNOS Genetic Polymorphisms
		9.1	 Introduction
		9.2	 Types and Physiological Functions of Nitric Oxide Synthase
			9.2.1	 Nitric Oxide Synthase 1 (Neuronal Nitric Oxide Synthase)
			9.2.2	 Nitric Oxide Synthase 2 (Inducible Nitric Oxide Synthase)
			9.2.3	 Nitric Oxide Synthase 3 (Endothelial Nitric Oxide Synthase)
		9.3	 Structure of Nitric Oxide Synthase Gene
		9.4	 Inducible Nitric Oxide Synthase and Malaria
		9.5	 Inducible Nitric Oxide Synthase (iNOS) Polymorphisms and Malaria
		9.6	 Discussion
		9.7	 Conclusion
		References
	10: Human Complement Receptor 1 Polymorphisms
		10.1	 Introduction
		10.2	 Molecular Genetics of CR1
			10.2.1	 Knops Blood Group Antigens
		10.3	 Role of CR1 in P. falciparum Malaria Pathogenesis
			10.3.1	 Rosetting
			10.3.2	 Malaria Induced Severe Anemia
		10.4	 Human Complement Receptor 1 (CR1) Gene Polymorphisms
			10.4.1	 Human Complement Receptor 1 Polymorphisms and Malaria
		10.5	 Conclusion
		References
	11: Interferon-Alpha Receptor-1 (IFNAR1) Polymorphisms
		11.1	 Introduction
		11.2	 Interaction of IFNs with IFNAR1 and Production of Effects
		11.3	 Interferon-Alpha Receptor-1 (IFNAR1) Gene and Protein
			11.3.1	 Promoter Polymorphisms
			11.3.2	 Coding Polymorphism
			11.3.3	 IFNAR1 Protein
		11.4	 Interferon-Alpha Receptor-1 (IFNAR1) Polymorphisms Impact Malaria
		11.5	 Conclusions
		References
Part IV: Cytoadherence
	12: Intercellular Adhesion Molecule-1 Polymorphisms
		12.1	 Introduction
		12.2	 Structure and Function of ICAM1 Gene
			12.2.1	 ICAM-1 Protein
		12.3	 Mechanism of Cytoadherence in P. falciparum Malaria
		12.4	 ICAM-1 Gene Polymorphisms
		12.5	 ICAM1 Gene Polymorphisms and Malaria
		12.6	 Soluble ICAM-1
		12.7	 Conclusion
		References
	13: Platelet Endothelial Cell Adhesion Molecule-1 (PECAM-1) Polymorphisms
		13.1	 Introduction
		13.2	 Structure and Function of PECAM-1
		13.3	 Mechanisms of Malaria Pathogenesis
		13.4	 Genetic Polymorphisms in PECAM-1 Gene and P. falciparum Malaria
			13.4.1	 Promoter Polymorphisms
		13.5	 Discussion
			13.5.1	 Antiadhesion Therapies
		13.6	 Conclusions
		References
	14: Vascular Cell Adhesion Molecule-1 (VCAM-1) Polymorphisms
		14.1	 Introduction
		14.2	 Structure of VCAM-1
		14.3	 Inflammatory Role Played by VCAM-1
		14.4	 Pathology in Cerebral Malaria
		14.5	 Polymorphisms in VCAM-1 Gene and P. falciparum Caused Malaria
		14.6	 Other Human Host Receptors for Infected Erythrocytes
			14.6.1	 Hemoglobin C and Hemoglobin S
		14.7	 Compounds Targeting Cytoadherence of Infected Red Blood Cells
		14.8	 Conclusion
		References