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Blood, Vol. 91 No. 2 (January 15), 1998:
pp. 706-709
Mortality in a Cohort of Men Expressing the Glucose-6-Phosphate
Dehydrogenase Deficiency
By
Pierluigi Cocco,
Pierfelice Todde,
Susanna Fornera,
Maria Bonaria
Manca,
Pierina Manca, and
Ana Rosa Sias
From the Istituto di Medicina del Lavoro, Università di
Cagliari, Cagliari, Italy; the Servizio di Anatomia Patologica,
Ospedale S. Michele, ASL 8, Cagliari, Italy; and the Servizio di Igiene
Pubblica, ASL n. 6, S. Gavino Monreale, Italy.
 |
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.
| |
INTRODUCTION |
GLUCOSE-6-PHOSPHATE dehydrogenase (G6PD)
is a cytoplasmic enzyme that affects the production of the reduced form
of the extramitochondrial nicotine-adenosine-dinucleotide phosphate
coenzyme (NADPH) by controlling the step from glucose-6-phosphate to
6-phospho-gluconate in the pentose phosphate pathway.1,2 In
red blood cells, defense against oxidative damage is heavily dependent
on G6PD activity, because it is the only source of NADPH, which
maintains the stability of catalase and preserves and regenerates the
reduced form of glutathione (GSH).1,2 In other tissues, and
particularly in liver cells, NADPH is required for various cellular
functions, including fatty acid and cholesterol
synthesis,3,4 the ruling step of which is the
NADPH-dependent reduction of  -hydroxy--methyl-glutaryl-coenzyme A
(HMG-CoA) to mevalonate. Also, cytochrome P-450 isoenzymes
capture electrons from the reduced coenzymes nicotinamide adenine
dinucleotide (NADH) and NADPH during the cyclic redox processes
activating many xenobiotics.5,6 NADPH, and therefore G6PD
activity, may be also implicated for the ready availability of GSH to
support the phase two metabolism of carcinogens operated by
glutathione-S-transferase isoenzymes by catalyzing the conjugation of
hydrophobic electrophiles to GSH.7
The gene encoding G6PD is located in the telomeric region of the long
arm of the X chromosome (band Xq28).1 More than 300 alleles
have been identified that are related to point mutations in the base
sequence of the G6PD gene.1,2 One of these alleles, the
Gd-Mediterranean allele, is mostly frequent among the male population
in Sardinia, Italy, and it is associated with levels of enzyme activity
undetectable with routine methods. This condition affects 12% to 15%
of the Sardinian male population overall,8,9 with a broad
range by communes (1% to 30%) that has been related to the past
incidence of malaria.8 G6PD deficiency is a public health
issue in Sardinia because of the seasonal occurrence of hemolytic
crises among subjects expressing the deficient phenotype after the
ingestion of fava beans (favism). In an attempt to prevent such
occurrences, the Health Department of the Regional Administration of
Sardinia launched in 1981 a program of free testing of the G6PD
polymorphism in the general population. The data from this screening
provide a unique opportunity to test early hypotheses of lower risks
for cardiovascular diseases and cancer among G6PD-deficient individuals.10-12
| |
MATERIALS AND METHODS |
The population screening of the G6PD polymorphism covered all of
1981. Blood withdrawals (1 to 2 mL) were performed for
free in numerous public health services dispersed throughout the
region. The G6PD polymorphism was assayed in erythrocytes with the
Beutler's fluorescent spot test13 in four central
laboratories. About 2% of the resident population participated in the
screening. Participation was voluntary and covered the whole region,
although the sample size ranged from 1% to 42% of the resident
population by commune. The lowest participation rates were in the
central western area, where G6PD deficiency is mostly frequent (~30%
of the male residents).9 Among the participants, 15,964 were men, 1,905 (11.9%) of whom expressed a complete enzymatic
deficiency in erythrocytes. Records were kept only for G6PD-deficient
subjects (ie, subjects showing no enzyme activity at the test) most
likely related to G6PD alleles associated with very severe reduction in
enzyme activity and for men with partial enzyme activity related to
other G6PD alleles relatively less common.1,2 These
subjects were not considered as G6PD-deficient for the purposes of this
study. Women were also excluded because of the small number of
homozygote subjects with complete lack of erythrocyte G6PD activity.
The Computer Center of the Regional Administration of Sardinia provided
a complete list of the 1,905 men diagnosed as G6PD-deficient during the
1981 screening. Available information included name, date of birth, and
complete address. Tracing was extended to all Italian territory. Vital
status was successfully determined as of December 31, 1992 for 96.8%
of the subjects at the municipalities of residence.
Table 1 shows the number of subjects
excluded from study by criteria for exclusion and the number of
subjects who entered the cohort by vital status at the end of
follow-up. Forty-three subjects who could not be identified (missing or
wrong identification data) were excluded from study. Eighteen subjects
identified and subsequently lost to follow-up contributed to
person-years up to date of last known vital status. For subjects found
to be deceased, the Public Health Departments of the Local Health Units
covering the area where death occurred provided the death certificate
upon request. Thirteen men who died in 1981 did not enter the cohort. Subjects less than 15 years of age were also excluded because regional
mortality rates were not available in computerized form for the younger
ages. Thus, an additional 93 subjects, including 91 subjects who
reached age 15 after the end of follow-up and 2 subjects who died
before age 15, were excluded from the cohort. Therefore, the cohort
comprised all men identified as G6PD-deficient during the 1981 survey,
identified as alive on January, 1 1982, and 15 years of age or more (N = 1,756). Each subject entered the cohort on January, 1 1982 or
thereafter at age 15.
One-hundred twenty-one deaths were identified, with death certificates
available for 117 (97%). Primary causes of death were coded following
the International Classification of Diseases (9th revision).14 Expected deaths were calculated by applying
the 5-year age group and 5-year period of follow-up specific mortality rates in the Sardinian general male population to the person-years of
follow-up in the correspondent strata of the study population. The
Italian National Institute of Health (Istituto Superiore di Sanità) made reference rates available in computerized form. To
preserve the same diagnostic level as in the reference population, we
did not make attempts to confirm the accuracy of the causes of death
reported on the death certificates. The measure of association between
the G6PD-deficient phenotype and cause-specific mortality was the
standardized mortality ratio (SMR) computed as 100 times the ratio of
observed versus expected deaths. Ninety-five percent confidence
intervals (CIs) of SMRs were calculated according to Liddell.15 The results were considered statistically
significant when the 95% CI did not include 100.
| |
RESULTS |
The average age at entry into follow-up was 41.6 years (median, 40 years; standard deviation [SD], 18.4 years). The 1,756 cohort members
accumulated a total of 15,164.7 person-years. Average age at death was
67.9 years (median, 72 years; SD, 15.0 years). Only 2 deaths, 1 from
bronchopneumonia and another from accidental death, occurred among the
93 subjects excluded from follow-up because of the age criterion.
Results of the mortality analysis are reported in
Table 2. Mortality from all causes was
significantly reduced among cohort members (SMR, 76). Mortality from
cardiovascular diseases was about half the expectation (SMR, 46),
mostly due to a decrease in deaths from ischemic heart disease (SMR,
28) and cerebrovascular disease (SMR, 22). Digestive diseases also
showed a significant decrease in risk (SMR, 24), which was mostly due
to a significant deficit in mortality from liver cirrhosis (SMR, 12).
Nonmalignant respiratory diseases were also less than expected, but the
SMR was not statistically significant. The deficit in mortality from ischemic heart disease, cerebrovascular disease, and liver cirrhosis (15.1 + 14.6 + 7.4 = 37.1) accounted for 95.6% of the
deficit in total mortality (37.1/38.8).
Mortality from all cancers combined was nearly identical to the
expectation, with a nonsignificant reduction in lung cancer. Nonsignificant excess risks were observed for oral and pharyngeal cancer, prostate cancer, and cancer of the lymphatic and hematopoietic system. The excess of lymphatic and hematopoietic cancer was entirely due to a significant increase in mortality from non-Hodgkin's lymphoma
(SMR, 545; based on 4 deaths).
| |
DISCUSSION |
In this mortality follow-up study of G6PD-deficient individuals, we
found a decrease in deaths from ischemic heart disease, cerebrovascular
disease, and liver cirrhosis and a significant 5.4-fold increase in
mortality from non-Hodgkin's lymphoma.
In an early cross-sectional study, 7.2% of patients affected by
coronary artery disease carried the A-G6PD phenotype (associated with
partially deficient enzyme activity), whereas they accounted for 14.1%
of all other patients, although the frequency of hypertensive disease
did not vary by G6PD phenotype.10 On the other
hand, higher blood pressure levels were reported among African-American men with the G6PD A-allele in another study.16 To the best
of our knowledge, no other studies have explored the hypothesis of a
decreased risk for cardiovascular diseases among subjects expressing G6PD deficiency. A large body of experimental evidence linking G6PD
activity, cholesterol synthesis, and cell growth has accumulated in
recent years.17 However, despite their genetic condition, G6PD-deficient individuals grow normally.18 It is plausible that alternative sources of NADPH, such as the extramitochondrial isocitrate dehydrogenase enzyme and the malic enzyme, provide enough
NADPH to support the endogenous cholesterol synthesis required for
normal cell replication.17 Data on the consistency in
deficient enzyme activity across different tissues from the same
individual expressing erythrocyte G6PD deficiency have been
published,19-22 but a Medline search from 1966 onwards did
not list any study providing data specifically for endothelial cells.
Therefore, the hypothesis that G6PD-deficient individuals might be less
susceptible to ischemic heart diseases and cerebrovascular diseases,
because of difficulties in providing enough NADPH for the intima cell proliferation during the formation of the atheroma,23 is
only speculative.
Balance between nitric oxide (NO) synthase activity, which is
NADPH-dependent,24 and levels of GSH, a physiological
scavenger of NO,25 might also be an important factor in
preventing the occurrence of cardiovascular diseases. It is unknown
whether the two factors balance out in G6PD-deficient individuals. NO
itself and/or its S-nitrosocysteine adduct are powerful
vasodilators,26 and its other properties that are relevant
for the cardiovascular homeostasis include acting as a scavenger of
superoxide radicals abrogating their toxicity27 and
preventing the oxidation of low-density lipoproteins
(LDL)28 and inhibiting platelet aggregation, leukocyte
adhesion, and vascular smooth muscle proliferation.29
Early suggestions of a decrease in cancer risk among G6PD-deficient
individuals11,12 were not supported by more recent case-control studies.30,31 The present cohort study
confirms that G6PD-deficient subjects do not differ from the general
population in terms of mortality from all cancers combined. Among
single cancer sites, non-Hodgkin's lymphoma showed a 5.4-fold
increase. However, this was generated by 4 deaths only, and previous
studies did not find a higher proportion of G6PD-deficient subjects
among patients with non-Hodgkin's lymphoma.32,33 Most of
the decrease in mortality from all digestive diseases observed in the
present study was due to a deficit in deaths from liver cirrhosis,
which was not previously described.
There are limitations that must be considered. The selection of the
surveyed sample (~2% of the total Sardinian male population) was not
random. Subjects who volunteered for the test were presumably unaware
of their G6PD status. However, because the proportion of G6PD-deficient
subjects in the screened population (11.9%) was smaller than
previously reported for the Sardinian general male
population,8 it does not seem likely that a positive family history of favism was an important factor in the decision of
volunteering for the test. It is plausible that individuals who
participated were more concerned about their health status than were
nonparticipants. Unfortunately, no information was collected at the
time of the survey on lifestyle habits, including diet and smoking, of
the individuals who were screened, and no records were kept of the individuals who were found to carry the wild-type G6PD phenotype. As it
may be derived from the mean age at entry in the follow-up among cohort
members, a large proportion of the cohort consisted of men who reached
adulthood or even became elderly without awareness of their G6PD
phenotype. This implies that they did not suffer negative health
effects from their genetic condition. On the other hand, one cannot
exclude a priori that the genetic condition of G6PD deficiency itself
contributed to a hypothetical healthier condition among these subjects.
Smoking-related deaths, such as lung cancer and nonmalignant
respiratory diseases, were below the expectation in this cohort, although the respective SMRs were not statistically significant. Indeed, in a case-control study of cancer risk by G6PD phenotype, G6PD-deficient individuals were found to smoke less frequently than
subjects with the wild-type phenotype (53.8% v 70.7%,
respectively).30 However, observed and expected deaths from
smoking-related cancer sites other than the lung (oral cavity,
pancreas, larynx, bladder, and kidney) combined were similar (8 observed deaths v 8.4 expected). Also, we estimated the number
of deaths from cardiovascular diseases, which would have been expected
if the proportion of smokers in the general population (~70%) were
the same as among G6PD-deficient subjects (53.8%)33 and
obtained a corrected SMR of 49 (95% CI, 33 to 71), which is still
significant. This finding suggests that smoking was unlikely to greatly
bias our results. No information is available on consumption of
alcoholic beverages among G6PD-deficient individuals to assess the
proportion of decrease in mortality from liver cirrhosis that could be
explained by an alcohol consumption lower than the average in the
Sardinian general male population. Also, whether alcohol metabolism is
affected by the G6PD-deficient condition is unclear, because NAD+ and
not NADP+ binds the alcohol dehydrogenase isoenzymes receiving the
hydrogen ion from alcohol.34
In conclusion, selection bias is a likely explanation for our finding
of a decrease in deaths from ischemic heart disease and cerebrovascular
disease among G6PD-deficient individuals. However, these results are
partially consistent with an early report and are corroborated by
experimental studies. Future studies of long-term health outcomes
associated with the G6PD polymorphism should include information on
diet, smoking, and health history to evaluate the impact of the
informational programs and any subsequent lifestyle changes on disease
risk.
| |
FOOTNOTES |
Submitted July 1, 1997;
accepted September 22, 1997.
Supported by the Assessorato alla Sanita', Regione Autonoma della
Sardegna (progetti finalizzati).
Address reprint requests to Pierluigi Cocco, MD, Istituto di Medicina
del Lavoro, Università di Cagliari, via S. Giorgio 12, 09124 Cagliari, Italy.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. section 1734 solely
to indicate this fact.
| |
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[Abstract]
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T. Efferth, U. Fabry, and R. Osieka
DNA damage and apoptosis in mononuclear cells from glucose-6-phosphate dehydrogenase-deficient patients (G6PD Aachen variant) after UV irradiation
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Abstract
Introduction
Abstract