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Impact of the method of G6PD deficiency assessment on genetic association studies of malaria susceptibility.

Johnson MK, Clark TD, Njama-Meya D, Rosenthal PJ, Parikh S - PLoS ONE (2009)

Bottom Line: Analyses have been complicated by varied methods used to diagnose G6PD deficiency.Notably, restricting the analysis to those females who were both genotypically and enzymatically deficient, the association of deficiency and protection from uncomplicated malaria was again demonstrated in females, but not in males (RR = 0.57, 95% CI 0.37-0.88 for females).We found that G6PD-deficient females were significantly protected against uncomplicated malaria, but this protection was only seen when G6PD deficiency is described using enzyme activity.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, San Francisco General Hospital, University of California San Francisco, San Francisco, California, United States of America.

ABSTRACT

Background: Clinical association studies have yielded varied results regarding the impact of glucose-6-phosphate dehydrogenase (G6PD) deficiency upon susceptibility to malaria. Analyses have been complicated by varied methods used to diagnose G6PD deficiency.

Methodology/principal findings: We compared the association between uncomplicated malaria incidence and G6PD deficiency in a cohort of 601 Ugandan children using two different diagnostic methods, enzyme activity and G6PD genotype (G202A, the predominant East African allele). Although roughly the same percentage of males were identified as deficient using enzyme activity (12%) and genotype (14%), nearly 30% of males who were enzymatically deficient were wild-type at G202A. The number of deficient females was three-fold higher with assessment by genotype (21%) compared to enzyme activity (7%). Heterozygous females accounted for the majority (46/54) of children with a mutant genotype but normal enzyme activity. G6PD deficiency, as determined by G6PD enzyme activity, conferred a 52% (relative risk [RR] 0.48, 95% CI 0.31-0.75) reduced risk of uncomplicated malaria in females. In contrast, when G6PD deficiency was defined based on genotype, the protective association for females was no longer seen (RR = 0.99, 95% CI 0.70-1.39). Notably, restricting the analysis to those females who were both genotypically and enzymatically deficient, the association of deficiency and protection from uncomplicated malaria was again demonstrated in females, but not in males (RR = 0.57, 95% CI 0.37-0.88 for females).

Conclusions/significance: This study underscores the impact that the method of identifying G6PD deficient individuals has upon association studies of G6PD deficiency and uncomplicated malaria. We found that G6PD-deficient females were significantly protected against uncomplicated malaria, but this protection was only seen when G6PD deficiency is described using enzyme activity. These observations may help to explain the discrepancy in some published association studies involving G6PD deficiency and uncomplicated malaria.

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Related in: MedlinePlus

Dot plot showing the distribution of G6PD enzyme activity stratified by genotype.
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pone-0007246-g002: Dot plot showing the distribution of G6PD enzyme activity stratified by genotype.

Mentions: Enzyme activity was stratified by gender and genotype (Figure 2). The median value of enzyme activity was 216 mU/109 erythrocytes (Interquartile Range (IQR) = 80) for wild-type males and 61 mU/109 erythrocytes (IQR = 38.5) for hemizygous males with the G202A allele. For females, the median value of enzyme activity was 225 mU/109 erythrocytes (IQR = 101) for wild-type females, 135 mU/109 erythrocytes (IQR = 77) for heterozygous females, and 63 mU/109erythrocytes (IQR = 148) for homozygous G6PD A- females. Figure 1 also reveals that while the majority of genotypically-deficient females fell into the first peak of the bimodal enzyme distribution, a significant proportion of genotypically-deficient individuals had higher enzyme levels.


Impact of the method of G6PD deficiency assessment on genetic association studies of malaria susceptibility.

Johnson MK, Clark TD, Njama-Meya D, Rosenthal PJ, Parikh S - PLoS ONE (2009)

Dot plot showing the distribution of G6PD enzyme activity stratified by genotype.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2748715&req=5

pone-0007246-g002: Dot plot showing the distribution of G6PD enzyme activity stratified by genotype.
Mentions: Enzyme activity was stratified by gender and genotype (Figure 2). The median value of enzyme activity was 216 mU/109 erythrocytes (Interquartile Range (IQR) = 80) for wild-type males and 61 mU/109 erythrocytes (IQR = 38.5) for hemizygous males with the G202A allele. For females, the median value of enzyme activity was 225 mU/109 erythrocytes (IQR = 101) for wild-type females, 135 mU/109 erythrocytes (IQR = 77) for heterozygous females, and 63 mU/109erythrocytes (IQR = 148) for homozygous G6PD A- females. Figure 1 also reveals that while the majority of genotypically-deficient females fell into the first peak of the bimodal enzyme distribution, a significant proportion of genotypically-deficient individuals had higher enzyme levels.

Bottom Line: Analyses have been complicated by varied methods used to diagnose G6PD deficiency.Notably, restricting the analysis to those females who were both genotypically and enzymatically deficient, the association of deficiency and protection from uncomplicated malaria was again demonstrated in females, but not in males (RR = 0.57, 95% CI 0.37-0.88 for females).We found that G6PD-deficient females were significantly protected against uncomplicated malaria, but this protection was only seen when G6PD deficiency is described using enzyme activity.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, San Francisco General Hospital, University of California San Francisco, San Francisco, California, United States of America.

ABSTRACT

Background: Clinical association studies have yielded varied results regarding the impact of glucose-6-phosphate dehydrogenase (G6PD) deficiency upon susceptibility to malaria. Analyses have been complicated by varied methods used to diagnose G6PD deficiency.

Methodology/principal findings: We compared the association between uncomplicated malaria incidence and G6PD deficiency in a cohort of 601 Ugandan children using two different diagnostic methods, enzyme activity and G6PD genotype (G202A, the predominant East African allele). Although roughly the same percentage of males were identified as deficient using enzyme activity (12%) and genotype (14%), nearly 30% of males who were enzymatically deficient were wild-type at G202A. The number of deficient females was three-fold higher with assessment by genotype (21%) compared to enzyme activity (7%). Heterozygous females accounted for the majority (46/54) of children with a mutant genotype but normal enzyme activity. G6PD deficiency, as determined by G6PD enzyme activity, conferred a 52% (relative risk [RR] 0.48, 95% CI 0.31-0.75) reduced risk of uncomplicated malaria in females. In contrast, when G6PD deficiency was defined based on genotype, the protective association for females was no longer seen (RR = 0.99, 95% CI 0.70-1.39). Notably, restricting the analysis to those females who were both genotypically and enzymatically deficient, the association of deficiency and protection from uncomplicated malaria was again demonstrated in females, but not in males (RR = 0.57, 95% CI 0.37-0.88 for females).

Conclusions/significance: This study underscores the impact that the method of identifying G6PD deficient individuals has upon association studies of G6PD deficiency and uncomplicated malaria. We found that G6PD-deficient females were significantly protected against uncomplicated malaria, but this protection was only seen when G6PD deficiency is described using enzyme activity. These observations may help to explain the discrepancy in some published association studies involving G6PD deficiency and uncomplicated malaria.

Show MeSH
Related in: MedlinePlus