Duffy Blood System and G6PD Genetic Variants in P. Vivax Malaria Patients From Manaus, Amazonas, Brazil

Abstract Over a third of the world’s population lives at risk of potentially severe Plasmodium vivax induced malaria. Unique aspects of the parasite’s biology and interactions with the human host make it harder to control and eliminate the disease. Glucose-6-phosphate dehydrogenase (G6PD) deficiency and Duffy-negative blood groups are two red blood cell variations that confer protection against malaria. Molecular genotyping was performed in 225 patients with severe and non-severe malaria, which revealed 29 (12.94%) carriers of the G6PD 202AG/GG and 43 (19.19%) with G6PD 376GA/AA. For the Duffy genotype, 70 (31.11%) were phenotyped as Fy(a + b-), 98 (43.55%) Fy(a + b+), 56 (24.9%) Fy(a-b+) and 1 (0.44%) Fy(a-b-). The FY*01/FY*02 genotype was more frequent in both non-severe and severe malaria. However, the frequency increased when SNP c.376A > G was also present. In women, the FY*01/FY*02 allele occurred concomitantly with c.376A > G more frequently in non-severe malaria, whereas in men, this synergism was more frequent in severe malaria. In addition, G202A/A376G genotypes were more frequent in severe malaria, with c.202G > A (RR = 5.57 – p < 0.001) and c.376A > G (RR: 4.49 – p < 0.001) strongly associated with the trials malaria (p < 0.001). Parasite count and density were not observed to specifically associate with variants in G6PD or Duffy. However, Duffy phenotype Fy(a-b+) (p = 0.003) and genotype FY*02/ FY*02 (p = 0.007) presented the highest values parasitemia density of the vivax malaria. Research on G6PD and Duffy antigen deficiencies has been valuable, particularly when focused on densely populated areas. We concluded that c.202G > A and c.376A > G SNPs were risk factors for the development of severe vivax malaria and that molecular diagnosis before treatment may be necessary in the Amazonian population and uncomplicated malaria showed a greater frequency of variation for GATA and G6PD variants than severe malaria.

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Duffy Blood System and G6PD Genetic Variants In P. Vivax Malaria Patients From Manaus, Amazonas, Brazil

10.21203/rs.3.rs-41862/v3 ◽

2020 ◽

Author(s):

Natália Santos Ferreira ◽

Jéssica Lorena dos Santos Mathias ◽

Sérgio Roberto Lopes Albuquerque ◽

Anne Cristine Gomes Almeida ◽

Ana Carla Dantas ◽

...

Keyword(s):

Severe Malaria ◽

Genetic Variants ◽

Vivax Malaria ◽

Promoter Region ◽

Blood System ◽

Duffy Antigen ◽

Unique Aspect ◽

Genotype C ◽

Glucose 6 Phosphate Dehydrogenase ◽

Duffy Negative

Abstract Over a third of the world’s population lives at risk of potentially severe Plasmodium vivax induced malaria. The unique aspect of the parasite’s biology and interactions with the human host make it harder to control and eliminate the disease. Glucose-6-phosphate dehydrogenase (G6PD) deficiency and Duffy-negative blood groups are two red blood cell variations that confer protection against malaria. Molecular genotyping of G6PD and Duffy was performed in 225 patients with severe and non-severe malaria. Of the 225 patients, 29 (12.94%) and 43 (19.19%) were carriers of the G6PD c.202G>A and c.376A>G, respectively. For the Duffy genotype (c.-67T>C in the GATA promoter region), 70 (31.11%) were phenotyped as Fy(a+b-), 98 (43.55%) Fy(a+b+), 56 (24.9%) Fy(a-b+) and 1 (0.44%) Fy(a-b-). The FY*01/FY*02 genotype was prevalent in both non-severe and severe malaria. However, the frequency increased when SNP c.376A>G was also present. In women, the FY*01/FY*02 allele occurred concomitantly with c.376A>G more frequently in non-severe malaria, while in men, this combination is revealed predominantly in severe malaria. G202A and A376G G6PD variants were higher in severe malaria, with c.202G>A (RR= 4.76 – p=.009) and c.376A>G (RR: 6.47 – p<0.001) strongly associated with the trials malaria (p<0.001). Duffy phenotype Fy(a-b+) (p=0.003) and genotype FY*02/ FY*02 (p=0.007) presented the highest values parasitemia density of the vivax malaria. Research on G6PD and Duffy antigen deficiencies has been valuable, particularly when focused on densely populated areas. Altogether, c.202G>A and c.376A>G SNPs seem to be risk factors for the development of severe vivax malaria. Molecular diagnosis before treatment may be necessary in the Amazonian population and uncomplicated malaria showed a greater frequency of variation for GATA and G6PD variants than severe malaria.

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Duffy Blood System and G6PD Genetic Variants In P. Vivax Malaria Patients From Manaus, Amazonas, Brazil

10.21203/rs.3.rs-41862/v2 ◽

2020 ◽

Author(s):

Natália Santos Ferreira ◽

Jéssica Lorena dos Santos Mathias ◽

Sérgio Roberto Lopes Albuquerque ◽

Anne Cristine Gomes Almeida ◽

Ana Carla Dantas ◽

...

Keyword(s):

Severe Malaria ◽

Genetic Variants ◽

Vivax Malaria ◽

Promoter Region ◽

Blood System ◽

Duffy Antigen ◽

Unique Aspect ◽

Genotype C ◽

Glucose 6 Phosphate Dehydrogenase ◽

Duffy Negative

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Assessment of glucose-6-phosphate dehydrogenase activity using CareStart G6PD rapid diagnostic test and associated genetic variants in Plasmodium vivax malaria endemic setting in Mauritania

PLoS ONE ◽

10.1371/journal.pone.0220977 ◽

2019 ◽

Vol 14 (9) ◽

pp. e0220977 ◽

Cited By ~ 2

Author(s):

Oum kelthoum Mamadou Djigo ◽

Mohamed Abdallahi Bollahi ◽

Moina Hasni Ebou ◽

Mohamed Salem Ould Ahmedou Salem ◽

Rachida Tahar ◽

...

Keyword(s):

Plasmodium Vivax ◽

Dehydrogenase Activity ◽

Diagnostic Test ◽

Rapid Diagnostic Test ◽

Genetic Variants ◽

Vivax Malaria ◽

Endemic Setting ◽

Plasmodium Vivax Malaria ◽

Glucose 6 Phosphate Dehydrogenase

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Duffy blood system and g6pd genetic variants in p. Vivax malaria patients from manaus, amazonas, brazil

10.21203/rs.3.rs-41862/v4 ◽

2021 ◽

Author(s):

Natália Santos Ferreira ◽

Jéssica Lorena dos Santos Mathias ◽

Sérgio Roberto Lopes Albuquerque ◽

Anne Cristine Gomes Almeida ◽

Ana Carla Dantas ◽

...

Keyword(s):

Severe Malaria ◽

G6pd Deficiency ◽

Vivax Malaria ◽

Pcr Rflp ◽

Before And After ◽

Genotype C ◽

Glucose 6 Phosphate Dehydrogenase ◽

The Relationship ◽

High Parasitemia

Abstract Background Over a third of the world’s population lives at risk of potentially severe Plasmodium vivax induced malaria. The unique aspect of the parasite’s biology and interactions with the human host make it harder to control and eliminate the disease. Glucose-6-phosphate dehydrogenase (G6PD) deficiency and Duffy-negative blood groups are two red blood cell variations shown to confer protection against malaria. Methods Molecular genotyping of G6PD and Duffy was performed in 225 patients with severe and non-severe malaria randomly admitted at a reference center for infectious disease from Manaus. For G6PD variants characterization of the variants, Real Time PCR (qPCR) was performed, while Duffy genotyping by PCR-RFLP. Results Of the 225 patients, 29 (12.94%) and 43 (19.19%) were carriers of the G6PD c.202G > A and c.376A > G, respectively. For the Duffy genotype (c.-67T > C in the GATA promoter region), 70 (31.11%) were phenotyped as Fy(a + b-), 98 (43.55%) Fy(a + b+), 56 (24.9%) Fy(a-b+) and 1 (0.44%) Fy(a-b-). The FY*01/FY*02 genotype was prevalent in both non-severe and severe malaria. In women, the FY*01/FY*02 allele occurred concomitantly with c.376A > G more frequently in non-severe malaria, while in men, this combination was predominant in severe malaria. Duffy phenotype Fy(a-b+) (p = 0.022) and genotypes FY*01/FY*01 / FY*02/FY*02 (p = 0.015) correlated with high parasitemia density before and after treatment. Conclusions Our results showed only one uncomplicated vivax malaria patient with Duffy phenotype Fy(a-b-). Heterozygous GATA variants did not confer protection against malaria infection in this study. Research on G6PD and Duffy antigen deficiencies has been valuable, particularly when focused on densely populated areas. Our results confirm possible genetic molding mechanisms in vivax malaria in our Amazon region and can help to improve the understanding of the relationship between G6PD deficiency and Duffy genotypes concomitantly in the protection or susceptibility to P. vivax infection. Molecular diagnosis before treatment may be necessary in the Amazonian population, regardless of the diagnosis of uncomplicated or severe malaria.

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Putative second hit rare genetic variants in families with seemingly GBA-associated Parkinson’s disease

npj Genomic Medicine ◽

10.1038/s41525-020-00163-8 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Muhammad Aslam ◽

Nirosiya Kandasamy ◽

Anwar Ullah ◽

Nagarajan Paramasivam ◽

Mehmet Ali Öztürk ◽

...

Keyword(s):

Risk Factors ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Genetic Variants ◽

Rare Variants ◽

Alpha Synuclein ◽

Younger Age ◽

Targeted Treatments ◽

Genes Encoding ◽

Rare Genetic Variants

AbstractRare variants in the beta-glucocerebrosidase gene (GBA1) are common genetic risk factors for alpha synucleinopathy, which often manifests clinically as GBA-associated Parkinson’s disease (GBA-PD). Clinically, GBA-PD closely mimics idiopathic PD, but it may present at a younger age and often aggregates in families. Most carriers of GBA variants are, however, asymptomatic. Moreover, symptomatic PD patients without GBA variant have been reported in families with seemingly GBA-PD. These observations obscure the link between GBA variants and PD pathogenesis and point towards a role for unidentified additional genetic and/or environmental risk factors or second hits in GBA-PD. In this study, we explored whether rare genetic variants may be additional risk factors for PD in two families segregating the PD-associated GBA1 variants c.115+1G>A (ClinVar ID: 93445) and p.L444P (ClinVar ID: 4288). Our analysis identified rare genetic variants of the HSP70 co-chaperone DnaJ homolog subfamily B member 6 (DNAJB6) and lysosomal protein prosaposin (PSAP) as additional factors possibly influencing PD risk in the two families. In comparison to the wild-type proteins, variant DNAJB6 and PSAP proteins show altered functions in the context of cellular alpha-synuclein homeostasis when expressed in reporter cells. Furthermore, the segregation pattern of the rare variants in the genes encoding DNAJB6 and PSAP indicated a possible association with PD in the respective families. The occurrence of second hits or additional PD cosegregating rare variants has important implications for genetic counseling in PD families with GBA1 variant carriers and for the selection of PD patients for GBA targeted treatments.

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Association between Genetic Variants in NOS2 and TNF Genes with Congenital Zika Syndrome and Severe Microcephaly

Viruses ◽

10.3390/v13020325 ◽

2021 ◽

Vol 13 (2) ◽

pp. 325

Author(s):

Julia A. Gomes ◽

Eduarda Sgarioni ◽

Juliano A. Boquett ◽

Ana Cláudia P. Terças-Trettel ◽

Juliana H. da Silva ◽

...

Keyword(s):

Risk Factors ◽

Zika Virus ◽

Genetic Variants ◽

Educational Level ◽

Congenital Anomalies ◽

Family Income ◽

First Trimester ◽

In Utero ◽

Zikv Infection ◽

Congenital Zika Syndrome

Zika virus (ZIKV) causes Congenital Zika Syndrome (CZS) in individuals exposed prenatally. Here, we investigated polymorphisms in VEGFA, PTGS2, NOS3, TNF, and NOS2 genes as risk factors to CZS. Forty children with CZS and forty-eight children who were in utero exposed to ZIKV infection, but born without congenital anomalies, were evaluated. Children with CZS were predominantly infected by ZIKV in the first trimester (p < 0.001) and had mothers with lower educational level (p < 0.001) and family income (p < 0.001). We found higher risk of CZS due the allele rs2297518[A] of NOS2 (OR = 2.28, CI 95% 1.17–4.50, p = 0.015). T allele and TT/CT genotypes of the TNF rs1799724 and haplotypes associated with higher expression of TNF were more prevalent in children with CZS and severe microcephaly (p = 0.029, p = 0.041 and p = 0.030, respectively). Our findings showed higher risk of CZS due ZIKV infection in the first trimester and suggested that polymorphisms in NOS2 and TNF genes affect the risk of CZS and severe microcephaly.

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Has the time come to integrate genetic risk scores into clinical practice?

European Heart Journal ◽

10.1093/ehjci/ehaa946.3761 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

F.V Moniz Mendonca ◽

M.I Mendonca ◽

A Pereira ◽

J Monteiro ◽

J Sousa ◽

...

Keyword(s):

Risk Factors ◽

Clinical Practice ◽

Genetic Variants ◽

Genetic Risk ◽

Odds Ratio ◽

Risk Scores ◽

Cumulative Number ◽

Genetic Risk Scores ◽

Risk Alleles ◽

Cad Risk

Abstract Background The risk for Coronary Artery Disease (CAD) is determined by both genetic and environmental factors, as well as by the interaction between them. It is estimated that genetic factors could account for 40% to 55% of the existing variability among the population (inheritability). Therefore, some authors have advised that it is time we integrated genetic risk scores into clinical practice. Aim The aim of this study was to evaluate the magnitude of the association between an additive genetic risk score (aGRS) and CAD based on the cumulative number of risk alleles in these variants, and to estimate whether their use is valuable in clinical practice. Methods A case-control study was performed in a Portuguese population. We enrolled 3120 participants, of whom 1687 were CAD patients and 1433 were normal controls. Controls were paired to cases with respect to gender and age. 33 genetic variants known to be associated with CAD were selected, and an aGRS was calculated for each individual. The aGRS was further subdivided into deciles groups, in order to estimate the CAD risk in each decile, defined by the number of risk alleles. The magnitude of the risk (odds ratio) was calculated for each group by multiple logistic regression using the 5th decile as the reference group (median). In order to evaluate the ability of the aGRS to discriminate susceptibility to CAD, two genetic models were performed, the first with traditional risk factors (TRF) and second with TRF plus aGRS. The AUC of the two ROC curves was calculated. Results A higher prevalence of cases over controls became apparent from the 6th decile of the aGRS, reflecting the higher number of risk alleles present (see figure). The difference in CAD risk was only significant from the 6th decile, increasing gradually until the 10th decile. The odds ratio (OR) for the last decile related to 5th decile (median) was 1.87 (95% CI:1.36–2.56; p<0.0001). The first model yielded an AUC=0.738 (95% CI:0.720–0.755) and the second model was slightly more discriminative for CAD risk (AUC=0.748; 95% CI:0.730–0.765). The DeLong test was significant (p=0.0002). Conclusion Adding an aGRS to the non-genetic risk factors resulted in a modest improvement in the ability to discriminate the risk of CAD. Such improvement, even if statistically significant, does not appear to be of real value in clinical practice yet. We anticipate that with the development of further knowledge about different SNPs and their complex interactions, and with the inclusion of rare genetic variants, genetic risk scores will be better suited for use in a clinical setting. Funding Acknowledgement Type of funding source: None

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