Mortality in a Cohort of Men Expressing the Glucose-6-Phosphate Dehydrogenase Deficiency

Abstract

The objective of this study was to test the hypothesis of a lower mortality from cancer and cardiovascular diseases among men expressing glucose-6-phosphate dehydrogenase (G6PD) deficiency. We designed a mortality study based on death certificates from January 1, 1982 through December 31, 1992 in a cohort of G6PD-deficient men. Cohort members were 1,756 men, identified as expressing the G6PD-deficient phenotype during a 1981 population screening of the G6PD polymorphism. The setting was the island of Sardinia, Italy. Outcome measures were cause-specific standardized mortality ratios (SMRs), which were computed as 100 times the observed/expected ratio, with the general Sardinian male population as the reference. Deaths from all causes were significantly less than expected due to decreased SMRs for ischemic heart disease (SMR, 28; 95% confidence interval [CI], 10 to 62), cerebrovascular disease (SMR, 22; 95% CI, 6 to 55), and liver cirrhosis (SMR, 12; 95% CI, 0 to 66), which explained 95.6% of the deficit in total mortality. All cancer mortality was close to the expectation, with a significant increase in the SMR for non-Hodgkin's lymphoma (SMR, 545; 95% CI, 147 to 1,395). A decrease in mortality from cardiovascular diseases was one of the study hypotheses, based on an earlier human report and experimental evidence. However, selection bias is also a likely explanation. Further analytic studies are warranted to confirm whether subjects expressing the G6PD-deficient phenotype are protected against ischemic heart disease and cerebrovascular disease. This cohort study is consistent with more recent case-control studies in rejecting the hypothesis of a decreased cancer risk among G6PD-deficient subjects. The observed increase in mortality from non-Hodgkin's lymphoma and decrease in mortality from liver cirrhosis were not previously reported.

Impact of glucose-6-phosphate dehydrogenase deficiency on the severity of coronary atherosclerosis in patients with acute coronary syndromes

“…It is noteworthy that our results do not confirm the results of previous investigations, which supported a significant protective effect of G6PD deficiency against cardiovascular diseases. 8,12,13 However, the differences in terms of results may be partly accounted for by different designs and methods. Our findings should be evaluated in light of some limitations.…”

Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency and Long-Term Risk of Immune-Related diseases

“…Associations were found between G6PD deficiency and cardiovascular risk (Cocco et al, 1998;Dore et al, 2021;Meloni et al, 2008;Pes et al, 2019) in conflicting directions. Regarding cancer, some studies found lower rate of cancer in G6PD deficient patients, while others found no difference (Cocco, 1987;Dore et al, 2016;Ferraris et al, 1988).…”

“…Several studies have suggested that G6PD-deficient individuals may be more predisposed to specific autoimmune diseases (Dore et al, 2023; Saha et al, 1982), infections (Abu-Osba et al, 1989; Mondal et al, 2022; Rostami-Far et al, 2016) and diabetes mellitus (Lai et al, 2017; Saha, 1979). Associations were found between G6PD deficiency and cardiovascular risk (Cocco et al, 1998; Dore et al, 2021; Meloni et al, 2008; Pes et al, 2019) in conflicting directions. Regarding cancer, some studies found lower rate of cancer in G6PD deficient patients, while others found no difference (Cocco, 1987; Dore et al, 2016; Ferraris et al, 1988).…”

Studies in CRISPR-generated Mediterranean G6PD variant rats reveal G6PD orchestrates genome-wide DNA methylation and gene expression in vascular wall

“…In addition, epidemiological studies suggest that individuals in the Mediterranean region carrying a loss-of-function G6PD variant are less susceptible to cardiovascular disease 14,15 . DNMTs and TETs affect gene expression under both normal physiological and disease conditions.…”

“…At the same time, DNA hypomethylation and upregulated expression of nitric oxide synthase 3 (NOS3) and superoxide dismutase were observed in the G6PD S188F rats. In addition, epidemiological studies suggest that individuals in the Mediterranean region carrying a loss-of-function G6PD variant are less susceptible to cardiovascular disease 14,15 . DNMTs and TETs affect gene expression under both normal physiological and disease conditions.…”