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High Frequency of the Duffy-Negative Genotype and Absence Of Brown et al. Malar J (2021) 20:99 https://doi.org/10.1186/s12936-021-03618-0 Malaria Journal RESEARCH Open Access High frequency of the Dufy-negative genotype and absence of Plasmodium vivax infections in Ghana Charles A. Brown1* , Prince J. Pappoe‑Ashong1, Nancy Duah2, Anita Ghansah2, Harry Asmah1, Edwin Afari3 and Kwadwo A. Koram2 Abstract Background: Recent studies from diferent malaria‑endemic regions including western Africa have now shown that Plasmodium vivax can infect red blood cells (RBCs) and cause clinical disease in Dufy‑negative people, though the Dufy‑negative phenotype was thought to confer complete refractoriness against blood invasion with P. vivax. The actual prevalence of P. vivax in local populations in Ghana is unknown and little information is available about the distribution of Dufy genotypes. The aim of this study was to assess the prevalence of P. vivax in both asymptomatic and symptomatic outpatients and the distribution of Dufy genotypes in Ghana. Methods: DNA was extracted from dried blood spots (DBS) collected from 952 subjects (845 malaria patients and 107 asymptomatic persons) from nine locations in Ghana. Plasmodium species identifcation was carried out by nested polymerase chain reaction (PCR) amplifcation of the small‑subunit (SSU) rRNA genes. For P. vivax detection, a second PCR of the central region of the Pvcsp gene was carried out. Dufy blood group genotyping was performed by allele‑specifc PCR to detect the presence of the FYES allele. Results: No cases of P. vivax were detected in any of the samples by both PCR methods used. Majority of infections (542, 94.8%) in the malaria patient samples were due to P. falciparum with only 1 infection (0.0017%) due to Plasmo- dium malariae, and 2 infections (0.0034%) due to Plasmodium ovale. No case of mixed infection was identifed. Of the samples tested for the FYES allele from all the sites, 90.5% (862/952) had the FYES allele. All positive samples were genotyped as FY*B-33/FY*B-33 (Dufy‑negative homozygous) and therefore classifed as Fy(a b ). − − Conclusions: No cases of P. vivax were detected by both PCRs and majority of the subjects tested carried the FYES allele. The lack of P. vivax infections observed can be attributed to the high frequency of the FYES allele that silences erythroid expression of the Dufy. These results provide insights on the host susceptibility for P. vivax infections that had not been investigated in Ghana before. Keywords: Plasmodium vivax, Malaria, Dufy blood group, Dufy‑negative, Ghana Background Malaria remains the most important parasitic infection in the world, with 228 million cases in 2018 (95% conf- dence interval [CI] 206–258 million) [1], caused by infec- tion with one or more of the six species of Plasmodium *Correspondence: [email protected] 1 School of Biomedical and Allied Health Sciences, College of Health parasites. Two species, Plasmodium falciparum and Plas- Sciences, University of Ghana, Legon, Ghana modium vivax, are responsible for most of the morbid- Full list of author information is available at the end of the article ity and mortality due to malaria globally [2, 3]. However, © The Author(s) 2021. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/ zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Brown et al. Malar J (2021) 20:99 Page 2 of 7 P. vivax malaria does not attract as much attention in numbers of Dufy-positive individuals in some areas in almost every aspect as does the deadlier P. falciparum Africa to maintain P. vivax transmission in areas where malaria because, traditionally, the infection was thought the majority of the population is Dufy-negative. Te to be benign and self-limiting [4, 5]. Recent evidence is frst objective of the present study was to evaluate the P. however challenging this long-held notion of the benign vivax circulation among both symptomatic and asympto- nature of P. vivax malaria, demonstrating that infection matic outpatients seeking medical care in various parts with P. vivax can also result in severe illness and death of Ghana. Te second objective was to explore the Dufy [6]. Globally, 53% of the P. vivax burden is in the WHO antigen genotype frequency among the study population. South-East Asia Region and P. vivax is the predominant parasite (75% of malaria cases) in the WHO Region of Methods the Americas [1]. In 2018, an estimated 704,000 (95% CI Study areas 91,000–1,813,000) P. vivax malaria cases were reported Te study was conducted in nine sites across Ghana in Africa [1]. (Fig. 1): Accra, Bekwai, Cape Coast, Hohoe, Tarkwa, An important biological diference between P. vivax Sunyani, are urban sites, and Navrongo, Wa, and Yendi and P. falciparum is that only P. vivax merozoites use the are rural sites. With the exception of Accra, the other Dufy (Fy) antigen receptor for chemokines (DARC) to eight are sentinel sites used as part of a surveillance invade erythrocytes [7, 8]. Te DARC-coding gene is pol- programme for monitoring malaria drug resistance in ymorphic with multiple alleles as the codominant FY*A Ghana. Te description of the sentinel sites has already and FY*B, which encode for the two antigens—Fya and been published [26–28]. Te sites are located in three Fyb. Four genotypes are possible as a result of the combi- ecological zones of Ghana. nation of the major alleles, Fy(a+b+), Fy(a+b−), Fy(a− Te Accra metropolis is the capital of Ghana and has b+) and Fy(a−b−) [9]. Te frst three correspond to a an estimated population of 2,052,341 in 2019 [29]. Te Dufy-positive phenotype, mostly prevalent in Asian and city experiences generally low and erratic rainfall pattern. in Caucasian populations and the last one corresponds to Annual rainfall in the metropolis is currently 1190 mm the Dufy-negative phenotype, mainly prevalent in Afri- can people, who are consequently deemed to be refrac- tory to P. vivax infection. Te Fy(a−b−) genotype results from a point mutation, − 33 T → C, in the promoter region of allele FY*B, in the GATA box region [10], pre- venting transcription and resulting in the null ‘erythro- cyte silent’ (ES) phenotype. Until now, the Dufy-negative phenotype was viewed as giving almost total protection against infection with P. vivax because it prevents P. vivax from invading host erythrocytes and completing its complex life cycle [11]. Field observations indicate that the conclusion of the absolute dependence on the presence of Dufy on the red cell for P. vivax infection and development in the red cell no longer holds true because of a number of reports con- cerning fndings of P. vivax in the blood of Dufy-negative persons in Brazil [12], Ethiopia [13, 14], Madagascar [15], Kenya [16], Equatorial Guinea and Angola [2] including West African countries, such as Mauritania [17], Cam- eroon [18, 19], Mali [20], and Benin [21]. Tus, contrary to expectation, there is evidence of P. vivax transmission even in areas mapped with highest Dufy-negativity fre- quencies [20, 22, 23]. Te exact frequency of Dufy blood group is poorly documented across Africa, as indeed few populations have been surveyed and there are large gaps in the documentation on Dufy genotypes and phenotypes across Africa [24], with Ghana being no exception. Cul- Fig. 1 A map of Ghana showing the 9 collection sites. U urban, R leton et al. [25] have concluded that there are sufcient rural (Adapted from Duah et al. [28]) Brown et al. Malar J (2021) 20:99 Page 3 of 7 [30]. Most of the rainfall is recorded between March and Samples were stored in a − 18 °C freezer for 3 h. Tey July. Malaria transmission in the metropolis is perennial. were retrieved, allowed to thaw, and spun at 14,000 rpm for 30 min. Ten absolute ethanol was carefully poured Sample collection and preparation of the pellet, 500 µl 70% ethanol added and the tubes Sampling was both prospective and retrospective. Retro- spun again at 14,000 rpm for 5 min. After the spun, the spective blood samples were collected by fnger prick on supernatant was poured of and the tubes were blotted flter paper (Whatman 3 MM flter paper) from subjects on flter paper and air-dried. Te formed pellets were in the study areas. Informed consent was sought from all fnally re-suspended in 200 µl TE (10 mM Tris–HCl, pH subjects. Prospective blood samples, all from Accra, were 8.0; 1 mM EDTA, pH 8.0) and stored at − 21 °C. obtained from the blood banks at the Korle Bu Teaching Hospital and 37 Military Hospital to investigate the fre- Detection and identifcation of Plasmodium species quency of the Dufy allele.
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