LAUSR

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common diverse X-linked human enzymopathy genetic trait. Males are either G6PD-deficient or normal, but females exhibit a broader range of G6PD deficiency ranging from severe deficiency to normal. An estimated 400 million people are affected by G6PD deficiency globally, and ~160 identified amino acid missense variants cause G6PD deficiency, which is more prevalent in the African continent, Middle East, and South and Southeast Asia. Both male hemizygotes and female homozygotes with G6PD gene deficiency manifest show significantly reduced G6PD enzyme activity, while 80% of female heterozygotes show moderately reduced G6PD enzyme activity. G6PD deficiency risk in females is poorly understood and perhaps often underestimated, and there is a long-standing gender disparity in terms of G6PD deficiency data. In previous studies, G6PD deficiency was investigated in male subjects, but in a recent and exciting cross-sectional study published in Hypertension Research, Zhao et al. [1] showed that 154,917 G6PD-deficient females aged 20–49 had a higher risk of elevated blood pressure and hypertension during prepregnancy and pregnancy periods. In addition, they showed that G6PD deficiency was more obviously associated with systolic blood pressure. Emerging evidence has shown that G6PD deficiency is associated with an increased incidence of CVD among US military personnel and civilians [2, 3]. Recently, a propensity score-matched study performed in a large cohort (9604) in Northern Sardinia, where the population prevalence of G6PD deficiency is the highest in the Mediterranean area, showed a link between G6PD deficiency and the risk of cardiovascular disease (CVD) [4]. Five classifications of G6PD deficiency exist based on enzyme activity levels, as recommended by the WHO. The G6PD A variant is associated with mild to moderate enzyme deficiency (class III) with residual enzyme activity (10–60%) and is found predominately in African Americans (AA). Furthermore, the incidence of G6PD deficiency among AA is 11–14%, compared with only 1% in Caucasians, and AA also show the highest incidence of CVD and a twoto threefold increased risk of stroke compared with other ethnic groups [5]. The high prevalence of hypertension and diabetes in Afro-Caribbeans in the West could be directly related to the incidence of G6PD deficiency in those populations [6]; G6PD deficiency is more severe in AA, as they tend to develop these conditions earlier in life. Impaired redox homeostasis contributes to oxidative stress (OS). G6PD-deficient AA subjects showed elevated levels of OS and decreased levels of glutathione (GSH) [7]. A recent meta-analysis and epidemiological studies have shown that affected individuals can have an increased risk of developing diabetes and CVD [2, 4]. Various G6PD deficiency models have shown the principal role of G6PD deficiency in altering redox homeostasis and the progression of CVD, which predisposes the system to defective vasodilation [6]. In humans, the role of G6PD deficiency and hemolysis has been well documented, and the antioxidant nature of G6PD has underscored its protective effects against the development of a variety of other pathologies, including diabetes and CVD. CVD remains the principal cause of death and disability among patients with diabetes mellitus. Diabetes exacerbates mechanisms underlying atherosclerosis and heart failure. G6PD catalyzes the rate-limiting step in the pentose phosphate pathway, which provides nucleotide precursors for DNA replication as well as cytosolic reducing equivalents of the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH). NADPH contributes to * Sushil K. Jain [email protected]