Genetic Variants of Glucose-6-Phosphate Dehydrogenase and Their Associated Enzyme Activity: A Systematic Review and Meta-Analysis

Abstract

Low glucose-6-phosphate dehydrogenase enzyme (G6PD) activity is a key determinant of drug-induced haemolysis. More than 230 clinically relevant genetic variants have been described. We investigated the variation in G6PD activity within and between different genetic variants. In this systematic review, individual patient data from studies reporting G6PD activity measured by spectrophotometry and corresponding the G6PD genotype were pooled (PROSPERO: CRD42020207448). G6PD activity was converted into percent normal activity applying study-specific definitions of 100%. In total, 4320 individuals from 17 studies across 10 countries were included, where 1738 (40.2%) had one of the 24 confirmed G6PD mutations, and 61 observations (3.5%) were identified as outliers. The median activity of the hemi-/homozygotes with A-(c.202G>A/c.376A>G) was 29.0% (range: 1.7% to 76.6%), 10.2% (range: 0.0% to 32.5%) for Mahidol, 16.9% (range 3.3% to 21.3%) for Mediterranean, 9.0% (range: 2.9% to 23.2%) for Vanua Lava, and 7.5% (range: 0.0% to 18.3%) for Viangchan. The median activity in heterozygotes was 72.1% (range: 16.4% to 127.1%) for A-(c.202G>A/c.376A>G), 54.5% (range: 0.0% to 112.8%) for Mahidol, 37.9% (range: 20.7% to 80.5%) for Mediterranean, 53.8% (range: 10.9% to 82.5%) for Vanua Lava, and 52.3% (range: 4.8% to 78.6%) for Viangchan. A total of 99.5% of hemi/homozygotes with the Mahidol mutation and 100% of those with the Mediterranean, Vanua Lava, and Viangchan mutations had <30% activity. For A-(c.202G>A/c.376A>G), 55% of hemi/homozygotes had <30% activity. The G6PD activity for each variant spanned the current classification thresholds used to define clinically relevant categories of enzymatic deficiency.

Keywords: G6PD activity; G6PD deficiency; G6PD genotype; glucose-6-phosphate dehydrogenase.

Figure 1

Flow diagram of the data collation procedure.

Figure 2

G6PD activity distributions (% Normal) for the data-rich variants—A-, Mahidol, Mediterranean, Vanua Lava, and Viangchan. Footnote: G6PD activity (% Normal) was measured by spectrophotometry for individuals with data-rich variants (n = 1296). The median and interquartile range of each variant are overlaid as black lines. Horizontal lines indicate diagnostic thresholds: 100% (black), 80%, 70%, 60%, and 30% (grey, dashed) G6PD activity. Homozygotes are indicated on the left panel using hollow points, and outliers are highlighted as grey points.

Figure 3

G6PD activity distributions for the variants investigated used the G6PD/6PGD ratio method. Footnote: G6PD activity (G6PD/6PGD) was measured by spectrophotometry (n = 242). The median and interquartile range of the variants with >3 observations are overlaid as black lines. Homozygotes are indicated on the left panel using hollow points, and outliers are highlighted as grey points.

Figure 4

G6PD activity distributions (% Normal) for the data-poor variants. Footnote: G6PD activity (% Normal) was measured by spectrophotometry for individuals with data-poor variants (n = 154). The median and interquartile range of each variant are overlaid as black lines. Horizontal lines indicate diagnostic thresholds: 100% (black), 80%, 70%, 60%, and 30% (grey, dashed) G6PD activity. Homozygotes are indicated on the left panel using hollow points.