QJM Advance Access originally published online on December 26, 2007
QJM 2008 101(2):161-163; doi:10.1093/qjmed/hcm129
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Subjects expressing the glucose-6-phosphate dehydrogenase deficient phenotype experience a lower cardiovascular mortality
Sir,In a recent mortality follow-up study of lead smelters in southwestern Sardinia, Italy, whose glucose-6-phosphate dehydrogenase (G6PD) phenotype was part of the pre-employment screening program, workers expressing the G6PD deficient (G6PD–) phenotype showed a substantial reduction in cardiovascular mortality.1 The same result was previously reported in a follow-up study of G6PD– subjects who voluntarily participated in a population screening,2 as well as in a US cross-sectional study of hospitalized patients.3 Interpretation of those earlier findings was limited by possible selection bias,2 and the cross-sectional study design.3 For further inquiry on the deficit of cardiovascular deaths among G6PD– subjects, we combined the lead exposed and lead unexposed employees of the same smelting plant, and re-analyzed the data changing the focus from lead susceptibility to cardiovascular mortality by the G6PD phenotype. The study population consisted of 1226 male subjects, including 993 subjects expressing the wild-type G6PD (wtG6PD) phenotype and 233 expressing the mutant G6PD– phenotype. Follow-up of vital status was 99.5% successful, and the cause of death was retrieved for all the 121 deceased cohort members. We compared the observed deaths for cardiovascular diseases and myocardial infarction in the G6PD– subcohort with the directly age-standardized expectation calculated from the mortality rates in the wtG6PD subcohort. The chance probability associated with the observed result was tested based on the Poisson distribution. We also analyzed survival from cardiovascular diseases by the G6PD phenotype from 1 January 1973 to 31 December 2003, using Cox's proportional hazard modeling, adjusting by age.
Three deaths from cardiovascular diseases and none from ischemic heart disease occurred among the G6PD– subcohort vs. 6.4 (p = 0.07) and 2.8 (p = 0.06) expected, respectively. The deficit in cardiovascular mortality of the G6PD– subcohort concentrated among subjects dying at age 50 or older (2 observed vs. 5.5 expected; p = 0.09). No such deficit occurred at age below 50 (p = 0.77). Mortality from diseases other than cardiovascular did not differ between the two subcohorts. Although not statistically significant because of the small size of the G6PD– subcohort, survival from cardiovascular diseases was prolonged among this subcohort (hazard ratio = 0.5; 95% confidence interval 0.2–1.7) (Figure 1), supporting the hypothesis that subjects expressing the G6PD deficient phenotype might be less prone to cardiovascular death. The universal pre-employment application of the test generated an unbiased study population, thus overcoming limitations in the earlier studies.2,3 However, awareness of their genetic susceptibility to specific diseases might have lead to a healthier life style among these subjects. In fact, a decrease in mortality from smoking-related illnesses, such as lung cancer and nonmalignant respiratory diseases (data not shown), was also observed, indirectly suggesting a lesser smoking prevalence among the G6PD– subcohort. Whether this might entirely explain the reduction in cardiovascular mortality we observed seems unlikely.
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A deficient G6PD activity results from mutation in the untranslated region in the splice site of the G6PD gene, located in Xq28.4 Such mutations are specially frequent in the Mediterranean island of Sardinia, our study area.5 An experimental study on G6PD– mice showed less aortic medial hypertrophy and reduced 3-O-nitrotyrosine staining and superoxide anion production following infusion with angiotensin II for 6 days.6 Such findings were replicated in Apo E–/– mice bearing the G6PD– mutation and fed a high-fat western diet, compared to Apo E–/– mice with wtG6PD, also showing reduced VCAM-1 aortic expression, a measure of vascular inflammation.7 In the G6PD– mice, the atherosclerotic lesion area was reduced 50% and serum cholesterol was also significantly lower (11%), but the lesion area reduction was independent on serum cholesterol level. Overall, these results suggest resistance to atherosclerosis development in these animals. Dehydroepiandrosterone (DHEA) is a potent uncompetitive inhibitor of mammalian G6PD.8,9 A negative association between plasma DHEA-sulfate level and mortality has been reported in elderly humans,10,11 and DHEA treatment in animals with12 or without13 balloon-induced severe aortic endothelial injury, fed a high-cholesterol diet, significantly inhibited aortic atherosclerotic plaque and fatty streak formation. Lastly, DHEA administration inhibited coronary artery stenosis by 50% in both the transplanted and nontransplanted hearts,14 without any apparent effect on cholesterol level.
Follow-up studies of larger cohorts would be required to properly test the hypothesis that expressing the G6PD– phenotype protects against cardiovascular mortality, and to understand whether the elevated prevalence of this genetic trait is a plausible explanation for the exceptional proportion of male centenarians among the Sardinian population.15 However, we are not aware of other unbiased population cohorts world wide with the G6PD phenotype available. Therefore, to date, case-control studies are the only methodological alternative. If confirmed, the decrease in cardiovascular risk in relation to the G6PD polymorphism would imply the intriguing possibility of pharmacological inhibition of G6PD as a rational approach to reduce the development of atherosclerosis and cardiovascular disease.16
Department of Public Health
Occupational Health Section
University of Cagliari
Italy
email: coccop{at}pacs.unica.it
FELS Institute
Temple University School of Medicine
Philadelphia
USA
References
1. Cocco P, Fadda D, Atzeri S, Avataneo G, Meloni M, Flore C. Causes of death among lead smelters in relation to the glucose-6-phosphate dehydrogenase polymorphism. Occup Environ Med (2007) 64:414–6.
2. Cocco P, Todde PF, Fornera S, Manca MB, Manca P, Sias AR. Mortality in a cohort expressing the glucose-6-phosphate dehydrogenase deficiency. Blood (1998) 91:706–9.
3. Long WK, Wilson SW, Frenkel EP. Association between red cell glucose 6-phosphate variants and vascular disease. Am J Human Genet (1967) 19:35–53.[Web of Science][Medline]
4. Sanders S, Smith DP, Thomas GA, Williams ED. A glucose-6-phosphate dehydrogenase (G6PD) splice site consensus sequence mutation associated with G6PD enzyme deficiency. Mutat Res (1997) 374:79–87.[Web of Science][Medline]
5. Cocco P, Manca P, Dessì S. Preliminary results of a geographic correlation study on G6PD-deficiency and cancer. Toxicol Pathol (1987) 15:106–8.
6. Matsui R, Xu S, Maitland KA, Hayes A, Leopold JA, Handy DE, et al. Glucose-6-phosphate dehydrogenase deficiency decreases the vascular response to angiotensin II. Circulation (2005) 112:257–63.
7. Matsui R, Xu S, Maitland KA, Mastroianni R, Leopold JA, Handy DE, et al. Glucose-6-phosphate dehydrogenase deficiency decreases vascular superoxide and atherosclerotic lesions in apolipoprotein E(–/–) mice. Arterioscler Thromb Vasc Biol (2006) 26:910–6.
8. Raineri R, Levy HR. On the specificity of steroid interaction with mammary gland glucose-6-phosphate dehydrogenase. Biochemistry (1970) 9:2233–43.[CrossRef][Web of Science][Medline]
9. Gordon G, Mackow MC, Levy HR. On the mechanism of interaction of steroids with human glucose 6-phosphate dehydrogenase. Arch Biochem Biophys (1995) 318:25–9.[CrossRef][Web of Science][Medline]
10. Glei DA, Goldman N. Dehydroepiandrosterone sulfate (DHEAS) and risk for mortality among older Taiwanese. Ann Epidemiol (2006) 16:510–5.[CrossRef][Web of Science][Medline]
11. Trivedi DP, Khaw KT. Dehydroepiandrosterone sulfate and mortality in elderly men and women. J Clin Endocrinol Metab (2001) 86:4171–7.
12. Gordon GB, Bush DE, Weisman HF. Reduction of atherosclerosis by administration of dehydroepiandrosterone. J Clin Invest (1988) 82:712–20.[Web of Science][Medline]
13. Arad Y, Badimon JJ, Badimon L, Hembree WC, Ginsberg HN. Dehydroepiandrosterone feeding prevents aortic fatty streak formation and cholesterol accumulation in cholesterol-fed rabbit. Arteriosclerosis (1989) 9:159–66.
14. Eich DM, Nestler JE, Johnson DE, Dworkin GH, Ko D, Wechsler AS, et al. Inhibition of accelerated atherosclerosis with dehydroepiandrosterone in the heterotropic rabbit model of cardiac transplantation. Circulation (1993) 87:261–9.
15. Koenig R. Sardinia's mysterious male methuselahs. Science (2001) 291:2074–6.
16. Schwartz AG, Pashko LL. Dehydroepiandrosterone, glucose-6-phosphate dehydrogenase, and longevity. Ageing Res Rev (2004) 3:171–87.[CrossRef][Web of Science][Medline]
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