Individuals Of African Origin Research Articles

Technical note: investigating activity-induced 3d hand entheseal variation in a documented South African sample

For reconstructing physical activity in the past, the surfaces of bones where muscles and ligaments attach, “entheses,” are routinely studied. Previous research has introduced an experimentally validated virtual approach for reconstructing habitual activity based on entheses. The present study relies on this virtual method to further investigate the effects of various biological factors on entheses, including variation by ancestry. Our skeletal sample includes 39 individuals from the well-preserved Pretoria Bone Collection in South Africa. Although the size of the sample is limited, all selected individuals present excellently preserved left- and right-hand bones. Moreover, all individuals are reliably documented for sex, biological age, and ancestry (i.e., African or European origin). Multivariate analyses were run on both raw and size-adjusted hand entheseal three-dimensional measurements. Our findings showed that, after size adjustment, entheseal multivariate patterns did not significantly vary by sex, biological age, or estimated body mass. However, a significant (p-value = 0.01) variation was found between individuals of different ancestries in only the right-hand side of our South African skeletal sample. The observed entheseal patterns were consistent with the habitual performance of power grasping in individuals of African origin, while our small sample’s European individuals showed distinctive indications of precision grasping behaviors. This pilot research provided important new insights into potentially activity-induced differences between population samples from South Africa, supporting the value of the applied protocol in reconstructing aspects of past human lifestyles. In the future, the functional interpretations of this study on interpopulation variation may be validated using increased sample sizes and individuals with long-term occupational documentation.

Blood donation among individuals of African origin in the Netherlands: how are barriers and motivators associated with intention?

Blood donors of African origin are under-represented in high-income Western countries, while their extended blood types closely match chronic transfusion patients with similar ancestral backgrounds. To prevent alloimunisation, it is important to recruit and retain more African blood donors. The aim of this study was to gain insight into blood donation barriers and motivators of individuals of African origin, and to assess how these are associated with the intention to donate blood. An online survey sample included 300 participants of sub-Saharan African, Afro-Surinamese and Afro-Caribbean origin living in the Netherlands. They ranked 25 barriers and 19 motivators on the level of impediment and facilitation in blood donation. We compared differences in barriers and motivators between ever- and never-donors and tested associations with the intention to donate blood using univariate and multivariate linear regression analyses, adjusted for gender, age, ethnicity, immigrant generation, educational level, and blood donation history. Receiving information about the donation procedure was a highly ranked motivator especially among never-donors (50%) and was positively associated with the intention to donate (p<0.05). Non-monetary incentives, convenience factors and awareness were other important motivators. Highly ranked barriers related to fears and not feeling healthy enough to donate, although only "believing donation is scary or stressful" (reported by 8% of the ever-donors and 25% of the never-donors) remained significantly associated with intention to donate in the multivariate model (p<0.05). Recipient preferences, religion and distrust were less often reported and were not associated with donation intention. The highest ranked barriers and motivators were not necessarily the best predictors of donation intention. These findings have valuable implications for future interventions focussing on individuals of African origin.

A focus on the association of Apol1 with kidney disease in children.

Individuals of African origin have an increased risk of developing various progressive chronic kidney diseases (CKD). This risk has been attributed to genetic variants (G1, G2) in apolipoprotein-L1 (APOL1) gene. In the pediatric population, especially in children affected by sickle cell disease (SCD), by human immunodeficiency virus (HIV), or with various glomerular diseases, APOL1 risk variants have been associated with the development of hypertension, albuminuria, and more rapid decline of kidney function. The present review focuses on existing APOL1-related epidemiological data in children with CKD. It also includes data from studies addressing racial disparities in CKD, the APOL1-related innate immunity, and the relationship between APOL1 and CKD and pathogenic pathways mediating APOL1-related kidney injury.

Strategies for screening cord blood for a public cord blood bank in high HIV prevalence regions

The probability of a Black African finding a matched unrelated donor for a hematopoietic stem cell transplant is minimal due to the high degree of genetic diversity amongst individuals of African origin. This problem could be resolved in part by the establishment of a public cord blood (CB) stem cell bank. The high prevalence of human immunodeficiency virus (HIV) amongst women attending antenatal clinics in sub-Saharan Africa together with the risk of mother-to-child transmission increases the risk of transplant transmissible infection. In addition to screening the mother in a period inclusive of 7 days prior to the following delivery, we propose that all CB units considered for storage undergo rigorous and reliable screening for HIV. The Ultrio-plus® assay is a highly specific and sensitive test for detecting HIV, hepatitis-B and hepatitis-C viruses in peripheral blood. We validated the Ultrio-plus® assay for analytical sensitivity in detecting HIV in CB at the level of detection of the assay. Until more comprehensive and sensitive methods are developed, the sensitivity and reliability of the Ultrio-plus® assay suggest that it could be used for the routine screening of CB units in conjunction with currently recommended maternal screening to reduce the risk of transplant transmissible infection.

An Anatolian-Persian tomb relief from Gökçeler in Lydia

AbstractThe relief block at the centre of this study was found in 2004 in a ploughed field in the northern region of Lydia near the village of Gökçeler in the district of Akhisar, in what is today the Manisa province. A standing male figure is depicted on the block, which probably belonged to a chamber tomb. Holding a cock and a bud in his hands, stylistically the figure points to a date between the late sixth century BC and the early fifth century BC. He has short, spiral curls and wears a long-sleeved, tight-fitting garment that appears to be influenced by the Persian style. Within the scope of Anatolian-Persian funerary reliefs, this example is particularly significant due to its typological and iconographical elements. Specifically, following comparisons with other works of the Persian period, it is possible to suggest that the figure on the Gökçeler relief is an African who is offering a gift to the tomb owner; the latter may have been Persian or have served a Persian. Thus, this relief has particular significance since it is the only known work of Anatolian-Persian sculpture which indicates that individuals of African origin lived in the Anatolian region under Persian rule.

Multilocus sequence typing (MLST) of JP2 genotype isolates of Aggregatibacter actinomycetemcomitans collected from carriers of African and non-African origin

ABSTRACTThe bacterium Aggregatibacter actinomycetemcomitans is associated with aggressive periodontitis. Individuals colonised with the highly leukotoxic JP2 genotype of the bacterium, are at increased risk for developing periodontitis. The JP2 genotype is considered to emerge from North Africa and subsequently spread to individuals of African origin, living geographically widespread including in other parts of Africa and outside Africa. Reports of non-African carriers of the JP2 genotype are scares. However, in this study we characterize by multilocus sequence analysis JP2 genotype isolates collected from individuals of both African and non- African origin.Materials and Methods: The study collection comprised 43 JP2 genotype strains. Among those 23 were isolated at the Clinical laboratory of Dental School, Umeå, Sweden, from samples collected from patients living in Sweden, but of both non-Africa and African origin. Seven housekeeping genes were sequenced and the strains were distributed according to different sequence types (ST).Results: In total, 8 ST were identified. The 11 isolates collected from patients of non-African origin were distributed in two ST groups, while the 12 isolates from patients of African origin were distributed in eight ST groups.Conclusions: The JP2 genotype colonizing individuals of African origin may be more susceptible to mutations than those colonizing non- African individuals.

Inflammation and Healthy Lifestyle Choices Influence Cardiometabolic Risks in African American Women.

Individuals of African origin in Europe and the Caribbean have a lower prevalence of coronary heart disease (CHD) than do Europeans and European Americans; however, African Americans, especially women, do not possess the same low CHD prevalence as Africans. As such, this study was designed to determine whether highly sensitive C-reactive protein (hsCRP) and fitness (V˙O2max) cluster with other cardiometabolic risks (CMRs) or whether their influence is independent of other CMRs in African American women. Fifty African American women were compared on fasting glucose, triglyceride, high-density lipoprotein cholesterol, blood pressure, and adiposity-based hsCRP classifications (low <1, group 1; moderate >1, group 2). Participants were obese but metabolically healthy. Oxygen uptake (V˙O2max) was correlated with systolic blood pressure, and percentage of fat in group 1. V˙O2max was related to systolic blood pressure, diastolic blood pressure, low-density lipoprotein-cholesterol, and percentage of fat, and hsCRP was related to triglycerides, and percentage of fat was related to diastolic blood pressure in group 2. These data indicate that CMRs are inversely related to V˙O2max at moderate hsCRP values in African American women. Inflammation and obesity are relatively independent of other CMRs. Inflammation along with sedentary lifestyles may contribute to the disparity observed for CHD morbidity and mortality in African American women. Adding the CMR profile may improve the prediction of CHD in African American women.

Five-year risk of HIV diagnosis subsequent to 147 hospital-based indicator diseases: a Danish nationwide population-based cohort study.

BackgroundIt has been suggested that targeted human immunodeficiency virus (HIV) testing programs are cost-effective in populations with an HIV prevalence >0.1%. Several indicator diseases are known to be associated with increased risk of HIV infection, but estimates of HIV frequency in persons with relevant indicator diseases are nonexistent.MethodsIn a nationwide population-based cohort study encompassing all Danish residents aged 20–60 years during 1994–2013, we estimated the 5-year risk of an HIV diagnosis (FYRHD) after a first-time diagnosis of 147 prespecified potential indicator diseases. To estimate the risk of HIV diagnosis in the general population without any indicator diseases, we calculated the FYRHD starting at age 25, 35, 45, and 55 years.ResultsThe risk in the male general population was substantially higher than the female general population, and the risk was lower in the older age categories. Individuals of African origin had a higher FYRHD than individuals of Danish origin. A number of diseases were identified with a FYRHD >0.1%, with infectious diseases, such as syphilis, hepatitis, and endocarditis, associated with a particularly high FYRHD. Other potential indicator diseases, such as most urologic, nephrologic, rheumatologic, and endocrine disorders were generally associated with a low FYRHD.ConclusionOur study identified a large number of indicator diseases associated with a FYRHD >0.1%. These data can be used as a tool for planning targeted HIV screening programs.

The Augustine blood group system, 48 years in the making

The high-prevalence antigen, Ata, was first identified in 1967, but it was not until 2015 that Ata became AUG1 of a new blood group system, Augustine (AUG). The new system was established after the identification of the gene encoding Ata and the recognition of a null phenotype (AUG:–1,–2) in an At(a–) patient with an antibody (anti-AUG2) reactive with At(a–) red blood cells. The At(a–) phenotype is very rare and, with the exception of the one family with the null phenotype, has only been found in individuals of African origin. Anti-Ata has been implicated in immediate and delayed hemolytic transfusion reactions, but not in severe hemolytic disease of the fetus and newborn. The Augustine gene is SLC29A1, which encodes the equilibrative nucleoside transporter ENT1. At(a–) (AUG:–1,2) results from homozygosity for c.1171G>A, encoding Glu391Lys, whereas the AUGnull (AUG:–1,–2) phenotype results from homozygosity for a splice site mutation, c.589+1G>C, in the only family where it has been found. Absence of ENT1 in that family may be associated with pseudogout and abnormal bone calcification.

A UGT2B10 splicing polymorphism common in african populations may greatly increase drug exposure.

RO5263397 [(S)-4-(3-fluoro-2-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine], a new compound that showed promising results in animal models of schizophrenia, is mainly metabolized in humans by N-glucuronidation. Enzyme studies, using the (then) available commercial uridine 5'-diphosphate-glucuronosyltransferases (UGTs), suggested that UGT1A4 is responsible for its conjugation. In the first clinical trial, in which RO5263397 was administered orally to healthy human volunteers, a 136-fold above-average systemic exposure to the parent compound was found in one of the participants. Further administration in this trial identified two more such poor metabolizers, all three of African origin. Additional in vitro studies with recombinant UGTs showed that the contribution of UGT2B10 to RO5263397 glucuronidation is much higher than UGT1A4 at clinically relevant concentrations. DNA sequencing in all of these poor metabolizers identified a previously uncharacterized splice site mutation that prevents assembly of full-length UGT2B10 mRNA and thus functional UGT2B10 protein expression. Further DNA database analyses revealed the UGT2B10 splice site mutation to be highly frequent in individuals of African origin (45%), moderately frequent in Asians (8%) and almost unrepresented in Caucasians (<1%). A prospective study using hepatocytes from 20 individual African donors demonstrated a >100-fold lower intrinsic clearance of RO5263397 in cells homozygous for the splice site variant allele. Our results highlight the need to include UGT2B10 when screening the human UGTs for the enzymes involved in the glucuronidation of a new compound, particularly when there is a possibility of N-glucuronidation. Moreover, this study demonstrates the importance of considering different ethnicities during drug development.

A Novel RHCE*ce Variant Allele Is Highly Frequent in Chinese D-Negative Individuals and Results in C-Expression

Background: The RHCE allele is highly polymorphic and many variants have been described, especially in individuals of African origin. Donors carrying these variants can be falsely typed and elicit transfusion reactions, and patients carrying such a variant may be at risk to develop allo-antibodies in response to mismatched transfusions. Not much is known about the frequency of RHCE variants in Chinese populations, whereas in China genotyping assays are increasingly applied for typing of blood donors and patients.Methods: Standard column agglutination was used to serologically type for C/c and E/e expression in 200 serologically D-negative and 200 serologically D-positive Chinese donors. The RH Multiplex Ligation-dependent Probe Amplification (MLPA) genotyping assay was used for genotyping the RHCE status (Transfusion 2013;53:1559). In donors with discrepant results of genotyping and phenotyping all 10 exons of RHCE were amplified and directly sequenced. A lentivirus containing the novel RHce variant was created to transduce human erythroblasts cultured from peripheral blood from 3 ccDee and 3 CCDee donors as previously described (Haematologica 2010;95:1594). FACS analysis was used to assess the c- and C-expression caused by the variant.Results: In 6 out of 200 Chinese D-negative donors the results of the RH-MLPA indicated the presence of only one copy of exon 2 of the CE*c-allele, and no copy of exon 2 of the CE*C-allele, whereas these donors were serologically typed as Cc. Sequencing of all 10 RHCE exons revealed a novel RHCE*ce allele defined by 308C>T (p.103Pro>Leu) mutation next to a normal RHCE*ce allele. The variant allele was not found in the 200 Chinese D-positive donors, indicating the linkage of this new variant RHCE*ce allele with the D-negative haplotype. Wild type Rhce cDNA was mutated to create the RHce*308C>T mutation and subsequently cloned into a lentiviral vector. Transduction of human ccDee erythroblasts with this vector resulted in C expression, whereas virtually no c-expression was induced by transduction of human CCDee erythroblasts as assessed by FACS analysis with the monoclonals MS33, MS35 and MS42 to detect c expression and monoclonals MS24 and MS273 to detect C.Discussion: A new RHCE variant (RHCE*ce308T) is identified, which is present in 3% of D-negative Chinese individuals. The 308C>T mutation in the triplet encoding the 103Pro results in the expression of 103Leu. Position 103 is one of the 4 aminoacid differences between the c- and C-carrying polypeptides (Pro and Ser, respectively). The Pro>Leu mutation in the novel variant leads to C-expression and loss or strongly diminished c-expression. Most Rhc-genotyping assays target the c-specific-307C nucleotide and most RhC-genotyping assays target the C-specific-intron 2, which are respectively present and absent in this variant allele. Therefore, when individuals carrying this allele are genotyped, the predictive phenotype will be falsely C-negative.Conclusion:RHC-genotyping assays applied in Chinese populations, should be adapted to recognize the presence of this new RHCE*ce308T allele to prevent C-mismatched transfusions. DisclosuresNo relevant conflicts of interest to declare.

Characterization of the HLA-C∗07:01:01G allele group in European and African-American cohorts

The HLA-C*07:01:01G allele group consists of three nonsynonymous alleles, C*07:01:01, C*07:06 and C*07:18, plus C*07:01:02, which is synonymous to C*07:01:01. All of these alleles have identical exons 2, 3 and 4, but differ in exons 5 or 6. Therefore routine sequence-based typing (SBT) of exons 2 and 3 is unable to resolve these subtypes, resulting in ambiguous typing results in population and disease cohort studies. In the present study, we fully characterized C*07:01:01G subtypes in European and African Americans and examined their relative frequency distributions. In European Americans C*07:01:01G is predominantly represented by C*07:01:01 (94.4%), whereas C*07:01:02 (1.1%) and C*07:18 (4.5%) were detected relatively infrequently. In African Americans C*07:18 (42.4%) showed a high frequency similar to that of C*07:01:01 (44.7%) whereas C*07:06 was detected at a low frequency (4.7%). C*07:06 was found exclusively on B*44:03 carrying haplotypes in both ethnic groups, but C*07:18 showed multiple linkage relationships with HLA-B. These results demonstrate that C*07:01:01G as defined by routine SBT is a heterogeneous group of alleles, especially among individuals of African origin. If C*07:01:01G subtypes prove to bear divergent functional significance, it would be necessary to include these subtypes in routine HLA-C typing for clinical transplantation and disease association studies.

Prenatal programming—effects on blood pressure and renal function

Impaired intrauterine nephrogenesis-most clearly illustrated by low nephron number-is frequently associated with low birthweight and has been recognized as a powerful risk factor for renal disease; it increases the risks of low glomerular filtration rate, of more rapid progression of primary kidney disease, and of increased incidence of chronic kidney disease or end-stage renal disease. Another important consequence of impaired nephrogenesis is hypertension, which further amplifies the risk of onset and progression of kidney disease. Hypertension is associated with low nephron numbers in white individuals, but the association is not universal and is not seen in individuals of African origin. The derangement of intrauterine kidney development is an example of a more general principle that illustrates the paradigm of plasticity during development-that is, that transcription of the genetic code is modified by epigenetic factors (as has increasingly been documented). This Review outlines the concept of prenatal programming and, in particular, describes its role in kidney disease and hypertension.

Analysis of RhCE variants among 806 individuals in France: considerations for transfusion safety, with emphasis on patients with sickle cell disease

DNA testing has enabled the documenting of numerous variants of RHCE alleles, especially in individuals of African origin. The risk for production of clinically significant alloantibodies to Rh antigens of patients carrying variant RHCE alleles has led us to analyze the different RhCE variants investigated by molecular biology. Alloimmunization was analyzed regarding the RHCE genetic profile. Samples from 806 individuals with altered expression of RhCE antigens and/or producing anti-RhCE in the presence of the corresponding antigen were analyzed. A total of 572 individuals were shown to express RhCE variants. Variant RHCE*ce alleles and RH haplotypes were identified in 83% of cases, the most frequent ones being the R(N) haplotype, the ceMO allele, the (C)ce(s) haplotype/ce(s) 1006 allele, and the ceAR allele identified in 36, 23, 20, and 17% of the tested samples, respectively. The absence of a high-prevalence Rh antigen was documented in 93 individuals. Partial C and partial e were expressed by 53% of individuals with RhCE variants. Rh antibodies were identified in 127 (20%) of 623 patients. They were found to be alloantibodies in 48 (38%) of these 127 patients. Alloimmunization against a high-prevalence Rh antigen was detected in 25% of cases. The challenge in clinical red blood cell (RBC) transfusion of patients with sickle cell disease, notably, would be to provide not only phenotypically matched, but also genetically matched, RBC units regarding RhCE variants.

Further Evidence Supporting a Role for Gs Signal Transduction in Severe Malaria Pathogenesis

With the functional demonstration of a role in erythrocyte invasion by Plasmodium falciparum parasites, implications in the aetiology of common conditions that prevail in individuals of African origin, and a wealth of pharmacological knowledge, the stimulatory G protein (Gs) signal transduction pathway presents an exciting target for anti-malarial drug intervention. Having previously demonstrated a role for the G-alpha-s gene, GNAS, in severe malaria disease, we sought to identify other important components of the Gs pathway. Using meta-analysis across case-control and family trio (affected child and parental controls) studies of severe malaria from The Gambia and Malawi, we sought evidence of association in six Gs pathway candidate genes: adenosine receptor 2A (ADORA2A) and 2B (ADORA2B), beta-adrenergic receptor kinase 1 (ADRBK1), adenylyl cyclase 9 (ADCY9), G protein beta subunit 3 (GNB3), and regulator of G protein signalling 2 (RGS2). Our study amassed a total of 2278 cases and 2364 controls. Allele-based models of association were investigated in all genes, and genotype and haplotype-based models were investigated where significant allelic associations were identified. Although no significant associations were observed in the other genes, several were identified in ADORA2A. The most significant association was observed at the rs9624472 locus, where the G allele (∼20% frequency) appeared to confer enhanced risk to severe malaria [OR = 1.22 (1.09–1.37); P = 0.001]. Further investigation of the ADORA2A gene region is required to validate the associations identified here, and to identify and functionally characterize the responsible causal variant(s). Our results provide further evidence supporting a role of the Gs signal transduction pathway in the regulation of severe malaria, and request further exploration of this pathway in future studies.

Ethnic and sex differences in circulating endotoxin levels: A novel marker of atherosclerotic and cardiovascular risk in a British multi-ethnic population

Background Circulating endotoxin levels are associated with atherosclerosis. Moreover, ethnic differences in pro-inflammatory markers may be associated with ethnic differences in atherosclerotic and cardiovascular (CVD) and coronary heart disease (CHD) risk. Objective and methods To investigate ethnic differences in circulating plasma endotoxin levels, its soluble receptor (sCD14), and high-sensitivity CRP (hs-CRP). 192 individuals, aged 40–59 years (61 white (30 women), 68 of African origin (33 women) and 63 South Asians (33 women)), free from coronary heart disease (CHD), stroke, CVD and diabetes were randomly selected from the UK ‘Wandsworth Heart and Stroke Study’. Results Age-adjusted endotoxin levels were lower in women than in men ( p = 0.002) and were highest in South Asians (13.3 EU/mL [95% CI 12.0–14.7]) and lowest in individuals of African origin (10.1 EU/mL [9.1–11.1]) than in whites ( p for linear trend <0.001). Endotoxin levels were positively associated with waist, waist–hip ratio, total cholesterol, serum triglycerides and serum insulin levels and negatively associated with serum HDL-cholesterol. Serum hs-CRP and plasma sCD14 varied by ethnic group ( p < 0.001) but was not associated with endotoxin. Conclusions This study is the first to indicate a graded increase in endotoxin levels from black Africans to whites to South Asians, which is consistent with the ethnic difference in CHD risk. Whilst these findings support the concept that the innate immune system (IIS) may contribute significantly to the metabolic component underlying the development of CVD and CHD risk, further studies are required to see whether endotoxin levels are causally related to the development of CHD.

Genetic variation in the epithelial sodium channel: a risk factor for hypertension in people of african origin

High blood pressure occurs commonly in individuals of African origin, leading to an increased risk of cardiovascular and end-stage renal disease (ESRD). Black individuals frequently have low plasma renin activity, and their blood pressure responds well to salt reduction, suggesting that abnormalities in renal sodium handling may be important in the etiology of hypertension in this population. The epithelial sodium channel (ENaC) has a central role in sodium transport across membranes, and in the kidney it contributes to the regulation of blood pressure via changes in sodium balance and blood volume. Rare monogenetic disorders have been described in association with hypertension, such as Liddle’s syndrome. In addition, other ENaC polymorphisms have also been described, some of which are more common in black individuals. The T594M polymorphism of ENaC occurs exclusively in black individuals and is associated with hypertension in a black South London population. There is preliminary evidence that amiloride is effective as monotherapy in hypertensives with the T594M polymorphism, and a further study is underway to determine whether this is indeed a safe and specific treatment. If so, then amiloride may provide an important new strategy for blood pressure control in affected black hypertensives.

T594M variant of the epithelial sodium channel β-subunit gene and hypertension in individuals of African ancestry in South Africa

BackgroundThe T594M variant of the β-subunit of the sodium epithelial channel (ENaC) gene may contribute to hypertension in individuals of African origin. MethodsA case-control study was performed to assess the role of the ENaC gene variant as an independent risk factor for hypertension in subjects of African ancestry. The effects of the ENaC gene variant on ambulatory blood pressure (BP) in hypertensive individuals and on office BP in hypertensive individuals and control subjects were also assessed. A total of 519 hypertensive patients with 24-h ambulatory BP (ABP) values determined while off medication, and 514 normotensive South African individuals of African ancestry were genotyped for the T594M polymorphism of the ENaC gene. ResultsA total of 22 (4.2%) hypertensive participants compared with 23 (4.5%) normotensive participants possessed the T594M variant (odds ratio = 1.06, confidence interval = 0.58 to 1.92, not significant). A similar genotype frequency distribution was noted in subjects representing the two predominant chiefdoms (Nguni and Sotho) in both case and control groups. No differences in frequency distribution of the T594M variant were noted with respect to either body mass index or gender. There were no differences in clinic or ambulatory mean, day, or night BP between hypertensive patients with or without the variant. Similarly, no differences were noted in clinic BP between control subjects with or without the variant. Other phenotypic parameters (including age and hypertension duration and severity) were also similar among hypertensive patients with or without the variant. ConclusionThese results do not support an important role for the T594M variant of the ENaC gene contributing to either the development or severity of hypertension in subjects of African ancestry.

Sequence and phylogenetic analysis of human T cell lymphotropic virus type 1 from Tumaco, Colombia.

Human T cell lymphotropic virus type 1 (HTLV-1) is a retrovirus that causes leukemia and the neurological disorder HTLV-1 associated myelopathy or tropical spastic paraparesis (HAM/TSP). Infection with this virus - although it is distributed worldwide - is limited to certain endemic areas of the world. Despite its specific distribution and slow mutation rate, molecular epidemiology on this virus has been useful to follow the movements of human populations and routes of virus spread to different continents. In the present study, we analyzed the genetic variability of a region of the env gene of isolates obtained from individuals of African origin that live on the Pacific coast of Colombia. Sequencing and comparison of the fragment with the same fragment from different HTLV-1 isolates showed a variability ranging from 0.8% to 1.2%. Phylogenetic studies permit us to include these isolates in the transcontinental subgroup A in which samples isolated from Brazil and Chile are also found. Further analyses will be necessary to determine if these isolates were recently introduced into the American continent or if they rather correspond to isolates introduced during the Paleolithic period.

Global survey of genetic variation in CCR5, RANTES, and MIP-1alpha: impact on the epidemiology of the HIV-1 pandemic.

Expression of CC chemokine receptor 5 (CCR5), the major coreceptor for HIV-1 cell entry, and its ligands (e.g., RANTES and MIP-1alpha) is widely regarded as central to the pathogenesis of HIV-1 infection. By surveying nearly 3,000 HIV+ and HIV- individuals from worldwide populations for polymorphisms in the genes encoding RANTES, MIP-1alpha, and CCR5, we show that the evolutionary histories of human populations have had a significant impact on the distribution of variation in these genes, and that this may be responsible, in part, for the heterogeneous nature of the epidemiology of the HIV-1 pandemic. The varied distribution of RANTES haplotypes (AC, GC, and AG) associated with population-specific HIV-1 transmission- and disease-modifying effects is a striking example. Homozygosity for the AC haplotype was associated with an increased risk of acquiring HIV-1 as well as accelerated disease progression in European Americans, but not in African Americans. Yet, the prevalence of the ancestral AC haplotype is high in individuals of African origin, but substantially lower in non-Africans. In a Japanese cohort, AG-containing RANTES haplotype pairs were associated with a delay in disease progression; however, we now show that their contribution to HIV-1 pathogenesis and epidemiology in other parts of the world is negligible because the AG haplotype is infrequent in non-Far East Asians. Thus, the varied distribution of RANTES, MIP-1alpha, and CCR5 haplotype pairs and their population-specific phenotypic effects on HIV-1 susceptibility and disease progression results in a complex pattern of biological determinants of HIV-1 epidemiology. These findings have important implications for the design, assessment, and implementation of effective HIV-1 intervention and prevention strategies.