Reduced Neutrophil Count in People of African Descent Is Due To a Regulatory Variant in the Duffy Antigen Receptor for Chemokines Gene

Persistently low white blood cell count (WBC) and neutrophil count is a well-described phenomenon in persons of African ancestry, whose etiology remains unknown. We recently used admixture mapping to identify an approximately 1-megabase region on chromosome 1, where ancestry status (African or European) almost entirely accounted for the difference in WBC between African Americans and European Americans. To identify the specific genetic change responsible for this association, we analyzed genotype and phenotype data from 6,005 African Americans from the Jackson Heart Study (JHS), the Health, Aging and Body Composition (Health ABC) Study, and the Atherosclerosis Risk in Communities (ARIC) Study. We demonstrate that the causal variant must be at least 91% different in frequency between West Africans and European Americans. An excellent candidate is the Duffy Null polymorphism (SNP rs2814778 at chromosome 1q23.2), which is the only polymorphism in the region known to be so differentiated in frequency and is already known to protect against Plasmodium vivax malaria. We confirm that rs2814778 is predictive of WBC and neutrophil count in African Americans above beyond the previously described admixture association (P = 3.8×10^−5), establishing a novel phenotype for this genetic variant

Too little but not too late: Results of a literature review to improve routine immunization programs in developing countries

<p>Abstract</p> <p>Background</p> <p>Globally, immunization services have been the center of renewed interest with increased funding to improve services, acceleration of the introduction of new vaccines, and the development of a health systems approach to improve vaccine delivery. Much of the credit for the increased attention is due to the work of the GAVI Alliance and to new funding streams. If routine immunization programs are to take full advantage of the newly available resources, managers need to understand the range of proven strategies and approaches to deliver vaccines to reduce the incidence of diseases. In this paper, we present strategies that may be used at the sub-national level to improve routine immunization programs.</p> <p>Methods</p> <p>We conducted a systematic review of studies and projects reported in the published and gray literature. Each paper that met our inclusion criteria was rated based on methodological rigor and data were systematically abstracted. Routine-immunization – specific papers with a methodological rigor rating of greater than 60% and with conclusive results were reported.</p> <p>Results</p> <p>Greater than 11,000 papers were identified, of which 60 met our inclusion criteria and 25 papers were reported. Papers were grouped into four strategy approaches: bringing immunizations closer to communities (n = 11), using information dissemination to increase demand for vaccination (n = 3), changing practices in fixed sites (n = 4), and using innovative management practices (n = 7).</p> <p>Conclusion</p> <p>Immunization programs are at a historical crossroads in terms of developing new funding streams, introducing new vaccines, and responding to the global interest in the health systems approach to improving immunization delivery. However, to complement this, actual service delivery needs to be strengthened and program managers must be aware of proven strategies. Much was learned from the 25 papers, such as the use of non-health workers to provide numerous services at the community level. However it was startling to see how few papers were identified and in particular how few were of strong scientific quality. Further well-designed and well-conducted scientific research is warranted. Proposed areas of additional research include integration of additional services with immunization delivery, collaboration of immunization programs with new partners, best approaches to new vaccine introduction, and how to improve service delivery.</p

Accuracy of clinical pallor in the diagnosis of anaemia in children: a meta-analysis

BACKGROUND: Anaemia is highly prevalent in children of developing countries. It is associated with impaired physical growth and mental development. Palmar pallor is recommended at primary level for diagnosing it, on the basis of few studies. The objective of the study was to systematically assess the accuracy of clinical signs in the diagnosis of anaemia in children. METHODS: A systematic review on the accuracy of clinical signs of anaemia in children. We performed an Internet search in various databases and an additional reference tracking. Studies had to be on performance of clinical signs in the diagnosis of anaemia, using haemoglobin as the gold standard. We calculated pooled diagnostic likelihood ratios (LR's) and odds ratios (DOR's) for each clinical sign at different haemoglobin thresholds. RESULTS: Eleven articles met the inclusion criteria. Most studies were performed in Africa, in children underfive. Chi-square test for proportions and Cochran Q for DOR's and for LR's showed heterogeneity. Type of observer and haemoglobin technique influenced the results. Pooling was done using the random effects model. Pooled DOR at haemoglobin <11 g/dL was 4.3 (95% CI 2.6–7.2) for palmar pallor, 3.7 (2.3–5.9) for conjunctival pallor, and 3.4 (1.8–6.3) for nailbed pallor. DOR's and LR's were slightly better for nailbed pallor at all other haemoglobin thresholds. The accuracy did not vary substantially after excluding outliers. CONCLUSION: This meta-analysis did not document a highly accurate clinical sign of anaemia. In view of poor performance of clinical signs, universal iron supplementation may be an adequate control strategy in high prevalence areas. Further well-designed studies are needed in settings other than Africa. They should assess inter-observer variation, performance of combined clinical signs, phenotypic differences, and different degrees of anaemia

Reduced Neutrophil Count in People of African Descent Is Due To a Regulatory Variant in the Duffy Antigen Receptor for Chemokines Gene

Persistently low white blood cell count (WBC) and neutrophil count is a well-described phenomenon in persons of African ancestry, whose etiology remains unknown. We recently used admixture mapping to identify an approximately 1-megabase region on chromosome 1, where ancestry status (African or European) almost entirely accounted for the difference in WBC between African Americans and European Americans. To identify the specific genetic change responsible for this association, we analyzed genotype and phenotype data from 6,005 African Americans from the Jackson Heart Study (JHS), the Health, Aging and Body Composition (Health ABC) Study, and the Atherosclerosis Risk in Communities (ARIC) Study. We demonstrate that the causal variant must be at least 91% different in frequency between West Africans and European Americans. An excellent candidate is the Duffy Null polymorphism (SNP rs2814778 at chromosome 1q23.2), which is the only polymorphism in the region known to be so differentiated in frequency and is already known to protect against Plasmodium vivax malaria. We confirm that rs2814778 is predictive of WBC and neutrophil count in African Americans above beyond the previously described admixture association (P = 3.8×10−5), establishing a novel phenotype for this genetic variant

Enhanced Statistical Tests for GWAS in Admixed Populations: Assessment using African Americans from CARe and a Breast Cancer Consortium

While genome-wide association studies (GWAS) have primarily examined populations of European ancestry, more recent studies often involve additional populations, including admixed populations such as African Americans and Latinos. In admixed populations, linkage disequilibrium (LD) exists both at a fine scale in ancestral populations and at a coarse scale (admixture-LD) due to chromosomal segments of distinct ancestry. Disease association statistics in admixed populations have previously considered SNP association (LD mapping) or admixture association (mapping by admixture-LD), but not both. Here, we introduce a new statistical framework for combining SNP and admixture association in case-control studies, as well as methods for local ancestry-aware imputation. We illustrate the gain in statistical power achieved by these methods by analyzing data of 6,209 unrelated African Americans from the CARe project genotyped on the Affymetrix 6.0 chip, in conjunction with both simulated and real phenotypes, as well as by analyzing the FGFR2 locus using breast cancer GWAS data from 5,761 African-American women. We show that, at typed SNPs, our method yields an 8% increase in statistical power for finding disease risk loci compared to the power achieved by standard methods in case-control studies. At imputed SNPs, we observe an 11% increase in statistical power for mapping disease loci when our local ancestry-aware imputation framework and the new scoring statistic are jointly employed. Finally, we show that our method increases statistical power in regions harboring the causal SNP in the case when the causal SNP is untyped and cannot be imputed. Our methods and our publicly available software are broadly applicable to GWAS in admixed populations

Planning for precarity? Experiencing the carceral continuum of imprisonment and reentry

Drawing on qualitative interviews with formerly imprisoned people in Canada, we show that most prisoners experience reentry into communities with little to no pre-release planning, and must rely upon their own resourcefulness to navigate fragmented social services and often informal supports. In this respect, our research findings contrast with U.S. punishment and society scholarship that highlights a complex shadow carceral state that extends the reach of incarceration into communities. Our participants expressed a critical analysis of the failure of the prison to address the needs of prisoners for release planning and supports in the community. Our findings concur with other empirical studies that demonstrate the enduring effects of the continuum of carceral violence witnessed and experienced by prisoners after release. Thus, reentry must be understood in relation to the conditions of confinement and the experience of incarceration itself. We conclude that punishment and society scholarship needs to attend to a nuanced understanding of prisoner reentry and connect reentry studies to a wider critique of the prison industrial complex, offering more empirical evidence of the failure of prisons

Whole genome sequence analysis of platelet traits in the NHLBI Trans-Omics for Precision Medicine (TOPMed) initiative

Platelets play a key role in thrombosis and hemostasis. Platelet count (PLT) and mean platelet volume (MPV) are highly heritable quantitative traits, with hundreds of genetic signals previously identified, mostly in European ancestry populations. We here utilize whole genome sequencing (WGS) from NHLBI's Trans-Omics for Precision Medicine initiative (TOPMed) in a large multi-ethnic sample to further explore common and rare variation contributing to PLT (n = 61 200) and MPV (n = 23 485). We identified and replicated secondary signals at MPL (rs532784633) and PECAM1 (rs73345162), both more common in African ancestry populations. We also observed rare variation in Mendelian platelet-related disorder genes influencing variation in platelet traits in TOPMed cohorts (not enriched for blood disorders). For example, association of GP9 with lower PLT and higher MPV was partly driven by a pathogenic Bernard-Soulier syndrome variant (rs5030764, p.Asn61Ser), and the signals at TUBB1 and CD36 were partly driven by loss of function variants not annotated as pathogenic in ClinVar (rs199948010 and rs571975065). However, residual signal remained for these gene-based signals after adjusting for lead variants, suggesting that additional variants in Mendelian genes with impacts in general population cohorts remain to be identified. Gene-based signals were also identified at several genome-wide association study identified loci for genes not annotated for Mendelian platelet disorders (PTPRH, TET2, CHEK2), with somatic variation driving the result at TET2. These results highlight the value of WGS in populations of diverse genetic ancestry to identify novel regulatory and coding signals, even for well-studied traits like platelet traits

Whole-genome sequencing association analysis of quantitative red blood cell phenotypes: The NHLBI TOPMed program

Whole-genome sequencing (WGS), a powerful tool for detecting novel coding and non-coding disease-causing variants, has largely been applied to clinical diagnosis of inherited disorders. Here we leveraged WGS data in up to 62,653 ethnically diverse participants from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program and assessed statistical association of variants with seven red blood cell (RBC) quantitative traits. We discovered 14 single variant-RBC trait associations at 12 genomic loci, which have not been reported previously. Several of the RBC trait-variant associations (RPN1, ELL2, MIDN, HBB, HBA1, PIEZO1, and G6PD) were replicated in independent GWAS datasets imputed to the TOPMed reference panel. Most of these discovered variants are rare/low frequency, and several are observed disproportionately among non-European Ancestry (African, Hispanic/Latino, or East Asian) populations. We identified a 3 bp indel p.Lys2169del (g.88717175_88717177TCT[4]) (common only in the Ashkenazi Jewish population) of PIEZO1, a gene responsible for the Mendelian red cell disorder hereditary xerocytosis (MIM: 194380), associated with higher mean corpuscular hemoglobin concentration (MCHC). In stepwise conditional analysis and in gene-based rare variant aggregated association analysis, we identified several of the variants in HBB, HBA1, TMPRSS6, and G6PD that represent the carrier state for known coding, promoter, or splice site loss-of-function variants that cause inherited RBC disorders. Finally, we applied base and nuclease editing to demonstrate that the sentinel variant rs112097551 (nearest gene RPN1) acts through a cis-regulatory element that exerts long-range control of the gene RUVBL1 which is essential for hematopoiesis. Together, these results demonstrate the utility of WGS in ethnically diverse population-based samples and gene editing for expanding knowledge of the genetic architecture of quantitative hematologic traits and suggest a continuum between complex trait and Mendelian red cell disorders