Biochemistry and Molecular Biology

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Seroprevalences of Helicobacter pylori infection and chronic atrophic gastritis in the United Republic of Tanzania and the Dominican Republic
(Environmental Health and Preventive Medicine, 2004-07) Nyambo, Thomas B.
Objective: The aim of this survey was to compare the seroprevalences of Helicobacter Pylori (H. pylori) and chronic atrophic gastritis (CAG) in Tanzania and the Dominican Republic, both of which are tropical countries, and thereafter compare the prevalences in Tanzania and the Dominican Republic with prevalences from our previous studies done in Japan (1991) and China (1996/97). Methods: Community-based study in which 573 inhabitants of Tanzania and 1,215 inhabitants of the Dominican Republic answered detailed questionnaires on upper digestive tract diseases, and then underwent screening for gastric cancer by serum pepsinogen and testing for antibody to H. pylori. Results: After adjusting to the ‘Age-Standardized Rate’ (ASR) using the world population in 1995, the seroprevalences of H. pylori infection in male and female subjects for Tanzania (m=85.3% & f=88.2%) were very high compared to those for the Dominican Republic (m=63.5% & f=62.4%) and Japan (m=62.0% & f=46.8%), and similar to those of China (m=78.0% & f=77.3%). Also, the age- standardized prevalences of CAG in males and females for Tanzania (m=0.237 & f=0.458) were higher than those of the Dominican Republic (m=0.168 & f=0.211) and China (m=0.111 & f=0.107) and compared well with those of Japan (m=0.266 & f=0.352). Conclusions: Although Tanzania and the Dominican Republic are both developing countries, Tanzania had a very high age-standardized prevalence of H. pylori and CAG compared to that of the Dominican Republic, which showed a trend similar to that of Japan. Key words: Helicobacter pylori, chronic atrophic gastritis, gastric cancer, Tanzania, Dominican Republic
Evaluation of dot-blot and phage replication techniques for detection of drug-resistant Mycobacterium tuberculosis.
(Tanzanian Medical Journal, 2005-03) Nyambo, Thomas B.
We have assessed the utility of two new methods, dot-blot and bacteriophage replication techniques, for use in a routine diagnosis laboratory in poor resource settings in the screening of drug resistant Mycobacteria tuberculosis by comparing with the conventional proportion method. A total of 145 M. tuberculosis clinical isolates were tested for resistance to rifampicin, isoniazid, streptomycin and ethambutol. The dot blot had sensitivities of 91.7%, 100%, 93.5% and 85.7 and specificities of 99.2%, 99.2%, 99.1% and 99.2 for rifampicin, streptomycin, isoniazid and ethambutol, respectively. The phage technique had sensitivities of 92% and 84.6% and specificities of 99.2% and 99.2%for rifampicin and streptomycin, respectively. Both techniques yielded results within 48 hours of receipt of the culture on solid media. The high sensitivity and specificity coupled with rapidity of results indicate that these methods are potentially useful tools for screening resistance to anti-tuberculosis drugs in our setting. However, the phage replication technique, which is simpler and technically less demanding, seems the most suitable for routine screening of drug resistant mycobacteria in resource deprived countries such as Tanzania. We are recommending further field evaluation of the phage replication method so that it can complement, and possibly replace, the conventional proportion method in drug susceptibility testing.
Comparison of prevalence of chronic atrophic gastritis in Japan, China, Tanzania, and the Dominican Republic.
(Annals of epidemiology, 2005-03-30) Nyambo, Thomas B.
Purpose: To compare the prevalence of chronic atrophic gastritis (CAG) in Japan, China, Tanzania, and the Dominican Republic and to assess the usefulness of Helicobacter pylori infection and serum gastrin level as markers of CAG. Methods: The subjects were volunteers from local communities in Japan (n = 859), China (n = 1741), Tanzania (n = 573), and the Dominican Republic (n = 1215). Each individual underwent a health checkup and blood sampling for measurement of serum pepsinogen I and II, pepsinogen I /II ratio, serum gastrin, and H. pylori antibodies, and responded to a questionnaire on upper digestive tract diseases. Results: The prevalences of H. pylori infection (23.5–96.1%), CAG (5.6–60.4%), and serum gastrin (62.0–136.5 pg/ml) varied by age, sex, and country. Serum gastrin level for men differed in each country according to age. In Tanzanian men, the median gastrin level (101.0 pg/ml) was the highest in the 40 to 49 years age group (p < 0.01) while there was no significant difference among different age groups in Tanzanian women. Serum gastrin level in subjects ≥ 70 years was higher than in other age groups in both sexes in the Dominican Republic (males, 92.5, females, 136.5 pg/ml). The prevalence of H. pylori infection increased (p < 0.01) with advancing age in Japan (only for women) and the Dominican Republic but was high in all age groups of both sexes in China and Tanzania. The prevalence of CAG increased (p < 0.01) with age in both sexes in Japan, China (women only), and the Dominican Republic, but not in Tanzania. The odds ratio of CAG in H. pylori infected subjects was 5.3 times that in H. pylori-negative subjects. The odds ratio of CAG increased by 0.6%/1 pg/ml increase in serum gastrin. Conclusions: Our results indicated that H. pylori infection, serum gastrin, and advancing age are good markers of CAG and that the prevalence of CAG is the highest in Japan.
Multiplicity of infections and level of recrudescence in Plasmodium falciparum malaria in Mlimba, Tanzania.
(African Journal of Biotechnology, 2006-09-18) Nyambo, Thomas B.
Polymorphism and antigenic variation are important biological survival strategies of malaria parasites determining the episode, outcome and implications of treatment interventions. In P. falciparum, polymorphic antigens are associated with the asexual blood-stage; merozoite surface protein 2 (MSP2). The MSP2 genes have been invaluable in post-treatment discrimination of parasite resurgence from new infection, especially in high transmission areas. We performed polymerase chain reaction (PCR) on DNA extracted from blood samples of 141 malaria-infected infants, followed by restriction fragment length polymorphism (RFLP) of PCR products. The findings showed multiplicity of infections of single to six infections with an average of 2.58 infections per patient. Single infections of either 3D7 or FC27 allelic families of the MSP2 gene occurred in 51 patients (50.5%) out of all PCR-RFLP successful samples (n = 101). Out of 15 (10.6%) follow up samples with resurgent parasitaemia, 3 (20%) samples had recrudescent infections while 12 (80%) had variable results. Our findings provide an insight on the prevalence of the genetic determinants of suphadoxine-pyrimethamine (SP) resistance in Mlimba during the study period, and in the face of rapidly spreading resistance, calls for the periodic surveillance in order to timely detect early warning signal of the deteriorating SP cure rate.
Drug resistance to sulphadoxine-pyrimethamine (SP) in Plasmodium falciparum malaria in Mlimba, Tanzania [MIM-EM-543567]
(Elsevier Science bv., 2006-10-31) Nyambo, Thomas B.;
Background Sulphadoxine-pyrimethamine (SP) has been and is currently used for treatment of uncomplicated Plasmodium falciparum malaria in many African countries. Nevertheless, the response of parasites to SP treatment has shown significant variation between individuals. Methods The genes for dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) were used as markers, to investigate parasite resistance to SP in 141 children aged less than 5 years. Parasite DNA was extracted by Chelex method from blood samples collected and preserved on filter papers. Subsequently, polymerase chain reaction (PCR) and restriction fragment length polymorphism (PCR-RFLP) were applied to detect the SP resistance-associated point mutations on dhfr and dhps. Commonly reported point mutations at codons 51, 59, 108 and 164 in the dhfr and codons 437, 540 and 581 in the dhps domains were examined. Results Children infected with parasites harbouring a range of single to quintuple dhfr/dhps mutations were erratically cured with SP. However, the quintuple dhfr/dhps mutant genotypes were mostly associated with treatment failures. High proportion of SP resistance-associated point mutations was detected in this study but the adequate clinical response (89.4%) observed clinically at day 14 of follow up reflects the role of semi-immunity protection and parasite clearance in the population. Conclusion In monitoring drug resistance to SP, concurrent studies on possible confounding factors pertaining to development of resistance in falciparum malaria should be considered. The SP resistance potential detected in this study, cautions on its useful therapeutic life as an interim first-line drug against malaria in Tanzania and other malaria-endemic countries.
History of click-speaking populations of Africa inferred from mtDNA and Y chromosome genetic variation.
(Molecular biology and evolution, 2007-07-28) Nyambo, Thomas B.
Little is known about the history of click-speaking populations in Africa. Prior genetic studies revealed that the click-speaking Hadza of eastern Africa are as distantly related to click speakers of southern Africa as are most other African populations. The Sandawe, who currently live within 150 km of the Hadza, are the only other population in eastern Africa whose language has been classified as part of the Khoisan language family. Linguists disagree on whether there is any detectable relationship between the Hadza and Sandawe click languages. We characterized both mtDNA and Y chromosome variation of the Sandawe, Hadza, and neighboring Tanzanian populations. New genetic data show that the Sandawe and southern African click speakers share rare mtDNA and Y chromosome haplogroups; however, common ancestry of the 2 populations dates back >35,000 years. These data also indicate that common ancestry of the Hadza and Sandawe populations dates back >15,000 years. These findings suggest that at the time of the spread of agriculture and pastoralism, the click-speaking populations were already isolated from one another and are consistent with relatively deep linguistic divergence among the respective click languages.
Convergent adaptation of human lactase persistence in Africa and Europe.
(Nature genetics, 2007-12-10) Nyambo, Thomas B.
A SNP in the gene encoding lactase (LCT) (C/T-13910) is associated with the ability to digest milk as adults (lactase persistence) in Europeans, but the genetic basis of lactase persistence in Africans was previously unknown. We conducted a genotype-phenotype association study in 470 Tanzanians, Kenyans and Sudanese and identified three SNPs (G/C-14010, T/G-13915 and C/G-13907) that are associated with lactase persistence and that have derived alleles that significantly enhance transcription from the LCT promoter in vitro. These SNPs originated on different haplotype backgrounds from the European C/T-13910 SNP and from each other. Genotyping across a 3-Mb region demonstrated haplotype homozygosity extending >2.0 Mb on chromosomes carrying C-14010, consistent with a selective sweep over the past ∼7,000 years. These data provide a marked example of convergent evolution due to strong selective pressure resulting from shared cultural traits—animal domestication and adult milk consumption.
AmpFlSTR® IdentifilerTM STR allele frequencies in Tanzania, Africa.
(Journal of forensic sciences, 2008-01) Nyambo, Thomas B.
Allele frequencies of the fifteen AMPLFlSTRÒ IdentifilerTM STR loci were determined for the population of Tanzania, East Africa. Two hundred and seventy-two saliva samples were gath- ered from unrelated healthy student or employee volunteers at Muhimbili University College of Health Sciences in Dar es Sal- aam, Tanzania during the summer of 2003. The tribal affiliation of each donor was recorded to ensure that representative sam- pling was achieved, and a total of 19 widely distributed adminis- trative regions of the country and 42 tribes were represented in the final genotypic data. DNA was extracted using the QIAamp spin column protocol for saliva (Qiagen, Valencia, CA) and quantitated using the QuantiblotÒ colorimetric system (Applied Biosystems, Foster City, CA). Approximately 1 ng of DNA was amplified from each sample using the IdentifilerTM system (Applied Biosystems) and subjected to capillary electrophoresis on a 310 Genetic Analyzer (Applied Biosystems). Raw data was collected, sorted, and sized using ABI Gene CollectionÒ and GenescanÒ software (Applied Biosystems), and alleles were assigned using ABI GenotyperÒ software (Applied Biosystems). Allele frequencies were calculated using GENEPOPÓ online software, v. 3.4 (1). Table 1 lists the frequencies of the alleles at each locus, indicates the total number of samples used to generate the table, and provides the database validation statistics. A Fisher Exact Test was used to test adherence to Hardy Wein- berg Equilibrium (HWE) at all loci (2,000 shufflings, GENEPOPÓ online software, v 3.4). Twelve of the 15 loci yielded p-values of >0.05, and thus failed to reject the hypothesis that the population is in HWE at these loci. The remaining three loci, D8S1178, D3S1358, and D2S1338, yielded p-values <0.05; however, a trun- cated product test for adherence of all loci yielded a p-value of 0.0654, thus validating the database for general use (2).
The genetic structure and history of Africans and African Americans. science, 324(5930), pp.1035-1044.
(Science, 2009-04-30) Nyambo, Thomas B.
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 (~71%), European (~13%), and other African (~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.
Effects of natural selection and gene conversion on the evolution of human glycophorins coding for MNS blood polymorphisms in malaria-endemic African populations.
(The American Journal of Human Genetics, 2011-06-10) Nyambo, Thomas B.
Malaria has been a very strong selection pressure in recent human evolution, particularly in Africa. Of the one million deaths per year due to malaria, more than 90% are in sub-Saharan Africa, a region with high levels of genetic variation and population substructure. However, there have been few studies of nucleotide variation at genetic loci that are relevant to malaria susceptibility across geograph- ically and genetically diverse ethnic groups in Africa. Invasion of erythrocytes by Plasmodium falciparum parasites is central to the pathology of malaria. Glycophorin A (GYPA) and B (GYPB), which determine MN and Ss blood types, are two major receptors that are expressed on erythrocyte surfaces and interact with parasite ligands. We analyzed nucleotide diversity of the glycophorin gene family in 15 African populations with different levels of malaria exposure. High levels of nucleotide diversity and gene conversion were found at these genes. We observed divergent patterns of genetic variation between these duplicated genes and between different extracellular domains of GYPA. Specifically, we identified fixed adaptive changes at exons 3–4 of GYPA. By contrast, we observed an allele frequency spectrum skewed toward a significant excess of intermediate-frequency alleles at GYPA exon 2 in many populations; the degree of spec- trum distortion is correlated with malaria exposure, possibly because of the joint effects of gene conversion and balancing selection. We also identified a haplotype causing three amino acid changes in the extracellular domain of glycophorin B. This haplotype might have evolved adaptively in five populations with high exposure to malaria.
Characterization of genetic variation and natural selection at the arylamine N-acetyltransferase genes in global human populations.
(Pharmacogenomics, 2011-11-01) Nyambo, Thomas B.
Functional variability at the arylamine N-acetyltransferase genes is associated with drug response in humans and may have been adaptive in the past owing to selection pressure from diet and exposure to toxins during human evolution. Aims: We have characterized nucleotide variation at the NAT1 and NAT2 genes, and at the NATP1 pseudogene in global human populations, including many previously under-represented African populations, in order to identify potential functional variants and to understand the role that natural selection has played in shaping variation at these loci in globally diverse populations. Materials & methods: We have resequenced approximately 2800 bp for each of the NAT1 and NAT2 gene regions, as well as the pseudogene NATP1, in 197 African and 132 nonAfrican individuals. Results & conclusion: We observe a signature of balancing selection maintaining variation in the 3’-UTR of NAT1, suggesting that these variants may play a functional role that is currently undefined. In addition, we observed high levels of nonsynonymous functional variation at the NAT2 locus that differs amongst ethnically diverse populations.
Haplotype variation and genotype imputation in African populations.
(Genetic epidemiology, 2011-11-28) Nyambo, Thomas B.
Sub-Saharan Africa has been identified as the part of the world with the greatest human genetic diversity. This high level of diversity causes difficulties for genome-wide association (GWA) studies in African populations—for example, by reducing the accuracy of genotype imputation in African populations compared to non-African populations. Here, we investigate haplotype variation and imputation in Africa, using 253 unrelated individuals from 15 Sub-Saharan African populations. We identify the populations that provide the greatest potential for serving as reference panels for imputing genotypes in the remaining groups. Considering reference panels comprising samples of recent African descent in Phase 3 of the HapMap Project, we identify mixtures of reference groups that produce the maximal imputation accuracy in each of the sampled populations. We find that optimal HapMap mixtures and maximal imputation accuracies identified in detailed tests of imputation procedures can instead be predicted by using simple summary statistics that measure relationships between the pattern of genetic variation in a target population and the patterns in potential reference panels. Our results provide an empirical basis for facilitating the selection of reference panels in GWA studies of diverse human populations, especially those of African ancestry.
Evolution of Functionally Diverse Alleles Associated with PTC Bitter Taste Sensitivity in Africa
(Molecular biology and evolution, 2011-11-29) Nyambo, Thomas B.
Although human bitter taste perception is hypothesized to be a dietary adaptation, little is known about genetic signatures of selection and patterns of bitter taste perception variability in ethnically diverse populations with different diets, particularly from Africa. To better understand the genetic basis and evolutionary history of bitter taste sensitivity, we sequenced a 2,975 bp region encompassing TAS2R38, a bitter taste receptor gene, in 611 Africans from 57 populations in West Central and East Africa with diverse subsistence patterns, as well as in a comparative sample of 132 non-Africans. We also examined the association between genetic variability at this locus and threshold levels of phenylthiocarbamide (PTC) bitterness in 463 Africans from the above populations to determine how variation influences bitter taste perception. Here, we report striking patterns of variation at TAS2R38, including a significant excess of novel rare nonsynonymous polymorphisms that recently arose only in Africa, high frequencies of haplotypes in Africa associated with intermediate bitter taste sensitivity, a remarkably similar frequency of common haplotypes across genetically and culturally distinct Africans, and an ancient coalescence time of common variation in global populations. Additionally, several of the rare nonsynonymous substitutions significantly modified levels of PTC bitter taste sensitivity in diverse Africans. While ancient balancing selection likely maintained common haplotype variation across global populations, we suggest that recent selection pressures may have also resulted in the unusually high level of rare nonsynonymous variants in Africa, implying a complex model of selection at the TAS2R38 locus in African populations. Furthermore, the distribution of common haplotypes in Africa is not correlated with diet, raising the possibility that common variation may be under selection due to their role in nondietary biological processes. In addition, our data indicate that novel rare mutations contribute to the phenotypic variance of PTC sensitivity, illustrating the influence of rare variation on a common trait, as well as the relatively recent evolution of functionally diverse alleles at this locus.
Structural diversity and African origin of the 17q21.31 inversion polymorphism
(2012) Nyambo, Thomas B.
The 17q21.31 inversion polymorphism exists either as direct (H1) or inverted (H2) haplotypes with differential predispositions to disease and selection. We investigated its genetic diversity in 2,700 individuals, with an emphasis on African populations. We characterize eight structural haplotypes due to complex rearrangements that vary in size from 1.08–1.49 Mb and provide evidence for a 30-kb H1-H2 double recombination event. We show that recurrent partial duplications of the KANSL1 gene have occurred on both the H1 and H2 haplotypes and have risen to high frequency in European populations. We identify a likely ancestral H2 haplotype (H2′) lacking these duplications that is enriched among African hunter-gatherer groups yet essentially absent from West African populations. Whereas H1 and H2 segmental duplications arose independently and before human migration out of Africa, they have reached high frequencies recently among Europeans, either because of extraordinary genetic drift or selective sweeps.
Evolutionary history and adaptation from high-coverage whole-genome sequences of diverse African hunter-gatherers.
(Cell, 2012-08-03) Nyambo, Thomas B.
To reconstruct modern human evolutionary history and identify loci that have shaped hunter-gatherer adaptation, we sequenced the whole genomes of five individuals in each of three different hunter-gatherer populations at >60× coverage: Pygmies from Cameroon and Khoesan-speaking Hadza and Sandawe from Tanzania. We identify 13.4 million variants, substantially increasing the set of known human variation. We found evidence of archaic introgression in all three populations, and the distribution of time to most recent common ancestors from these regions is similar to that observed for introgressed regions in Europeans. Additionally, we identify numerous loci that harbor signatures of local adaptation, including genes involved in immunity, metabolism, olfactory and taste perception, reproduction, and wound healing. Within the Pygmy population, we identify multiple highly differentiated loci that play a role in growth and anterior pituitary function and are associated with height.
Patterns of nucleotide and haplotype diversity at ICAM-1 across global human populations with varying levels of malaria exposure
(Human genetics, 2013-04-23) Nyambo, Thomas B.
Malaria is one of the strongest selective pressures in recent human evolution. African populations have been and continue to be at risk for malarial infections. However, few studies have re-sequenced malaria susceptibility loci across geographically and genetically diverse groups in Africa. We examined nucleotide diversity at Intercellular adhesion molecule-1 (ICAM-1), a malaria susceptibility candidate locus, in a number of human populations with a specific focus on diverse African ethnic groups. We used tests of neutrality to assess whether natural selection has impacted this locus and tested whether SNP variation at ICAM-1 is correlated with malaria endemicity. We observe differing patterns of nucleotide and haplotype variation in global populations and higher levels of diversity in Africa. Although we do not observe a deviation from neutrality based on the allele frequency distribution, we do observe several alleles at ICAM-1, including the ICAM-1 Kilifi allele, that are correlated with malaria endemicity. We show that the ICAM-1 Kilifi allele, which is common in Africa and Asia, exists on distinct haplotype backgrounds and is likely to have arisen more recently in Asia. Our results suggest that correlation analyses of allele frequencies and malaria endemicity may be useful for identifying candidate functional variants that play a role in malaria resistance and susceptibility.
Identifying Darwinian selection acting on different human APOL1 variants among diverse African populations.
(The American Journal of Human Genetics, 2013-07-11) Nyambo, Thomas B.
Disease susceptibility can arise as a consequence of adaptation to infectious disease. Recent findings have suggested that higher rates of chronic kidney disease (CKD) in individuals with recent African ancestry might be attributed to two risk alleles (G1 and G2) at the serum- resistance-associated (SRA)-interacting-domain-encoding region of APOL1. These two alleles appear to have arisen adaptively, possibly as a result of their protective effects against human African trypanosomiasis (HAT), or African sleeping sickness. In order to explore the distribution of potential functional variation at APOL1, we studied nucleotide variation in 187 individuals across ten geographically and genetically diverse African ethnic groups with exposure to two Trypanosoma brucei subspecies that cause HAT. We observed unusually high levels of nonsynonymous polymorphism in the regions encoding the functional domains that are required for lysing parasites. Whereas allele frequencies of G2 were similar across all populations (3%–8%), the G1 allele was only common in the Yoruba (39%). Addi- tionally, we identified a haplotype (termed G3) that contains a nonsynonymous change at the membrane-addressing-domain-encoding region of APOL1 and is present in all populations except for the Yoruba. Analyses of long-range patterns of linkage disequilibrium indi- cate evidence of recent selection acting on the G3 haplotype in Fulani from Cameroon. Our results indicate that the G1 and G2 variants in APOL1 are geographically restricted and that there might be other functional variants that could play a role in HAT resistance and CKD risk in African populations.
Genetic origins of lactase persistence and the spread of pastoralism in Africa.
(The American Journal of Human Genetics, 2014-04-03) Nyambo, Thomas B.
In humans, the ability to digest lactose, the sugar in milk, declines after weaning because of decreasing levels of the enzyme lactase- phlorizin hydrolase, encoded by LCT. However, some individuals maintain high enzyme amounts and are able to digest lactose into adulthood (i.e., they have the lactase-persistence [LP] trait). It is thought that selection has played a major role in maintaining this genet- ically determined phenotypic trait in different human populations that practice pastoralism. To identify variants associated with the LP trait and to study its evolutionary history in Africa, we sequenced MCM6 introns 9 and 13 and ~2 kb of the LCT promoter region in 819 individuals from 63 African populations and in 154 non-Africans from nine populations. We also genotyped four microsatellites in an ~198 kb region in a subset of 252 individuals to reconstruct the origin and spread of LP-associated variants in Africa. Additionally, we examined the association between LP and genetic variability at candidate regulatory regions in 513 individuals from eastern Africa. Our analyses confirmed the association between the LP trait and three common variants in intron 13 (C-14010, G-13907, and G-13915). Furthermore, we identified two additional LP-associated SNPs in intron 13 and the promoter region (G-12962 and T-956, respectively). Using neutrality tests based on the allele frequency spectrum and long-range linkage disequilibrium, we detected strong signatures of recent positive selection in eastern African populations and the Fulani from central Africa. In addition, haplotype analysis supported an eastern African origin of the C-14010 LP-associated mutation in southern Africa.
Higher frequency of genetic variants conferring increased risk for ADRs for commonly used drugs treating cancer, AIDS and tuberculosis in persons of African descent.
(The pharmacogenomics journal, 2014-04-16) Nyambo, Thomas B.
There is established clinical evidence for differences in drug response, cure rates and survival outcomes between different ethnic populations, but the causes are poorly understood. Differences in frequencies of functional genetic variants in key drug response and metabolism genes may significantly influence drug response differences in different populations. To assess this, we genotyped 1330 individuals of African (n=372) and European (n=958) descent for 4535 single-nucleotide polymorphisms in 350 key drug absorption, distribution, metabolism, elimination and toxicity genes. Important and remarkable differences in the distribution of genetic variants were observed between Africans and Europeans and among the African populations. These could translate into significant differences in drug efficacy and safety profiles, and also in the required dose to achieve the desired therapeutic effect in different populations. Our data points to the need for population-specific genetic variation in personalizing medicine and care.
Limited evidence for adaptive evolution and functional effect of allelic variation at rs702424 in the promoter of the TAS2R16 bitter taste receptor gene in Africa.
(Journal of human genetics, 2014-05-01) Nyambo, Thomas B.
Bitter taste perception, mediated by receptors encoded by the TAS2R loci, has important roles in human health and nutrition. Prior studies have demonstrated that nonsynonymous variation at site 516 in the coding exon of TAS2R16, a bitter taste receptor gene on chromosome 7, has been subject to positive selection and is strongly correlated with differences in sensitivity to salicin, a bitter anti-inflammatory compound, in human populations. However, a recent study suggested that the derived G-allele at rs702424 in the TAS2R16 promoter has also been the target of recent selection and may have an additional effect on the levels of salicin bitter taste perception. Here, we examined alleles at rs702424 for signatures of selection using Extended Haplotype Homozygosity (EHH) and F ST statistics in diverse populations from West Central, Central and East Africa. We also performed a genotype–phenotype analysis of salicin sensitivity in a subset of 135 individuals from East Africa. Based on our data, we did not find evidence for positive selection at rs702424 in African populations, suggesting that nucleotide position 516 is likely the site under selection at TAS2R16. Moreover, we did not detect a significant association between rs702424 alleles and salicin bitter taste recognition, implying that this site does not contribute to salicin phenotypic variance. Overall, this study of African diversity provides further information regarding the genetic architecture and evolutionary history of a biologically-relevant trait in humans.

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