ABSTRACT
Africa is the source of all modern humans, but characterization of genetic variation and of relationships among populations across the continent has been enigmatic. We studied 121 African populations, four African American populations, and 60 non-African populations for patterns of variation at 1327 nuclear microsatellite and insertion/deletion markers. We identified 14 ancestral population clusters in Africa that correlate with self-described ethnicity and shared cultural and/or linguistic properties. We observed high levels of mixed ancestry in most populations, reflecting historical migration events across the continent. Our data also provide evidence for shared ancestry among geographically diverse hunter-gatherer populations (Khoesan speakers and Pygmies). The ancestry of African Americans is predominantly from Niger-Kordofanian (approximately 71%), European (approximately 13%), and other African (approximately 8%) populations, although admixture levels varied considerably among individuals. This study helps tease apart the complex evolutionary history of Africans and African Americans, aiding both anthropological and genetic epidemiologic studies.
Subject(s)
Black People/genetics , Black or African American/genetics , Genetic Variation , Africa , Black or African American/ethnology , Bayes Theorem , Black People/ethnology , Cluster Analysis , Emigration and Immigration , Ethnicity/genetics , Gene Flow , Genotype , Geography , Humans , INDEL Mutation , Language , Microsatellite Repeats , Phylogeny , Polymorphism, Single Nucleotide , Principal Component Analysis , Racial Groups/geneticsABSTRACT
Respiratory syncytial virus (RSV) is a leading cause of infant mortality worldwide. Although anti-RSV Ab prophylaxis has greatly reduced infant mortality in the United States, there is currently no vaccine or effective antiviral therapy. RSV fusion (F) protein activates cells through TLR4. Two single nucleotide polymorphisms (SNPs) encoding Asp299Gly and Thr399Ile substitutions in the TLR4 ectodomain were previously associated with TLR4 hyporesponsiveness and increased susceptibility to bacterial infection. Prevalence of these SNPs was analyzed in a case series of 105 DNA samples extracted from archived nasal lavage samples from high-risk infants/young children with confirmed RSV disease who participated in two seminal clinical trials for anti-RSV prophylaxis. Frequencies of TLR4 SNPs in the case series were compared with those of literature controls, healthy adults, infants, and young children who presented with symptoms of respiratory infections (but not preselected for high risk for RSV). Both SNPs were highly associated with symptomatic RSV disease in this largely premature population (p < 0.0001), with 89.5% and 87.6% of cases being heterozygous for Asp299Gly and Thr399Ile polymorphisms versus published control frequencies of 10.5% and 6.5%, respectively. The other two control groups had similarly low frequencies. Our data suggest that heterozygosity of these two extracellular TLR4 polymorphisms is highly associated with symptomatic RSV disease in high-risk infants and support a dual role for TLR4 SNPs in prematurity and increased susceptibility to RSV not revealed by analysis of either alone.
Subject(s)
Genetic Predisposition to Disease , Polymorphism, Single Nucleotide , Respiratory Syncytial Virus Infections/genetics , Respiratory Syncytial Viruses , Toll-Like Receptor 4/genetics , Amino Acid Substitution , Aspartic Acid/chemistry , Aspartic Acid/genetics , Child , Child, Preschool , Female , Heterozygote , Humans , Infant , Male , Threonine/chemistry , Threonine/geneticsABSTRACT
SLC11A1 is known to link infections, autoimmunity and cancers. A review is presented of the mechanisms by which a balance is maintained between infections caused by pathogens (viral, bacterial and protozoan; intracellular and extracellular) and disorders resulting from (acute or chronic) inflammation, and of the interactions that determine how the initial innate immune system directs subsequent acquired immune responses in human populations.
Subject(s)
Autoimmunity , Cation Transport Proteins/physiology , Infections/complications , Inflammation , Neoplasms/etiology , Animals , Cation Transport Proteins/genetics , Humans , Immunity, Innate , Infections/immunologyABSTRACT
To determine whether variation in two interleukin 1 family genes (IL1B and interleukin 1 receptor antagonist, IL1RN) is associated with pulmonary tuberculosis (TB), two published polymorphisms at nucleotide positions -511 and +3953 in IL1B and one in the IL1RN 86 bp VNTR were genotyped in 335 smear positive Gambian TB patients, and 298 ethnically matched controls. All individuals were HIV negative. Decreased risk of pulmonary TB was associated with both heterozygosity and homozygosity for the IL1B-511-C allele (OR 0.66, P = 0.027, and OR 0.58, P = 0.015, respectively). Nonetheless, the C allele was present at a frequency of 0.66 in TB cases suggesting that whilst IL-1beta contributes to disease susceptibility, it is not the major factor. There was no association between the IL1B+3953-T/C polymorphism or the 86 bp IL1RN pentallelic repeat and TB in this population. Using an ex-vivo whole blood assay, healthy Gambian individuals who are homozygous for the IL1B-511-T allele failed to exhibit a significant increase in IL-1beta production in response to LPS after IFN-gamma priming.
Subject(s)
Interleukin-1/genetics , Tuberculosis, Pulmonary/genetics , Adolescent , Adult , Aged , Alleles , Case-Control Studies , Female , Gambia , Humans , Interferon-gamma/physiology , Lipopolysaccharides/pharmacology , Male , Middle Aged , Polymorphism, Genetic , Receptors, Interleukin-1/antagonists & inhibitors , Tuberculosis, Pulmonary/microbiologyABSTRACT
In this overview, we will present current information on known mutations in the TLR4 signaling pathway that have been associated with increased susceptibility to disease. To date, mutations in the extracellular domain of TLR4 itself, IRAK-4, NEMO (IKK gamma), and I kappa B alpha have been identified and profoundly affect the host response to infection.
Subject(s)
Disease Susceptibility , Infections/microbiology , Mutation , Signal Transduction , Toll-Like Receptor 4/genetics , Toll-Like Receptor 4/metabolism , Humans , Models, BiologicalABSTRACT
The nucleotide oligomerization binding domain 2 gene (NOD2) encodes an intracellular receptor for bacterial components, which is expressed in monocytes and is associated with Crohn's Disease (CD). This finding, along with epidemiological evidence, supports a role for infection in the pathogenesis of CD. Speculation that mycobacteria are involved in CD led us to investigate NOD2 in susceptibility to tuberculosis (TB), a global public health problem caused by Mycobacterium tuberculosis. CD-associated NOD2 variants were absent in a case-control study of 640 Gambians, where CD is rare. Novel NOD2 promoter polymorphisms were identified but showed no association with TB in this African population sample.
Subject(s)
Carrier Proteins/genetics , Crohn Disease/genetics , Intracellular Signaling Peptides and Proteins , Tuberculosis, Pulmonary/genetics , Adolescent , Adult , Alleles , Case-Control Studies , Crohn Disease/microbiology , Genetic Predisposition to Disease , Genotype , Humans , Male , Middle Aged , Mycobacterium tuberculosis/growth & development , Nod2 Signaling Adaptor Protein , Polymorphism, Single Nucleotide/genetics , Sequence Analysis, DNA , Tuberculosis, Pulmonary/complicationsSubject(s)
Membrane Glycoproteins/genetics , Meningococcal Infections/genetics , Neisseria meningitidis/genetics , Polymorphism, Genetic , Receptors, Cell Surface/genetics , Adolescent , Case-Control Studies , Child , Child, Preschool , Gambia/epidemiology , Gene Frequency , Genetic Predisposition to Disease , Genotype , Humans , Meningococcal Infections/epidemiology , Retrospective Studies , Toll-Like Receptor 4 , Toll-Like ReceptorsABSTRACT
Host genetic factors are major determinants of susceptibility to tuberculosis, and an understanding of the molecular basis of this observation has major implications for the development of novel therapies and vaccines. Slc11a1 (formerly Nramp1), the first murine infection susceptibility locus identified, regulates early innate responses to intracellular pathogens. Variation in the human homologue SLC11A1 is associated with and linked to tuberculosis in genetically different populations. In a case-control study of 329 tuberculosis case patients and 324 control subjects, the association between allele 2 of a functional SLC11A1 polymorphism and tuberculosis has been reproduced. This variant is associated with higher lipopolysaccharide-induced production of the macrophage-deactivating cytokine interleukin-10. Furthermore, monocytes from persons who develop tuberculosis innately produce more interleukin-10 than do monocytes from healthy control subjects. These data therefore confirm the importance of SLC11A1 in tuberculosis susceptibility in humans and suggest that SLC11A1 influences tuberculosis susceptibility by regulation of interleukin-10.
