[note from Dr. J. Sullivan]
The following abstract (see below) by Jukka Salonen's group in Finland will be presented at the American Heart Association meeting in Dallas on November 10. These findings, together with the very similar results presented in July by JJM Marx and colleagues in the Netherlands (see below), provide strong new support for the "iron hypothesis."
The findings also specifically support the corollary hypothesis that heterozygous hemochromatosis is associated with excess myocardial infarction (Sullivan JL. Heterozygous hemochromatosis as a risk factor for premature myocardial infarction. Medical Hypotheses 1990;31:1-5).
One of the implications is that the 10-13% of the general population who are carriers will now have a non-altruistic reason for donating blood. Will the Blood Bank community now refuse to use their blood because of the cloud upon their motivation to donate? I cannot believe that they will. The number of people willing to donate has slowly but steadily fallen for years and we are always on the brink of a shortage of blood. The Blood Bank community cannot afford to turn away 1 in 8 qualified donors simply because they want to give blood to avoid a heart attack. I hope that these studies together will compel Blood Bankers to rethink their opposition to using blood from hemochromatosis patients. Something "radical" may come from this, eg universal screening of blood donors for HH. Or, just maybe, universal screening of the general population!
Jerome L. Sullivan, MD, PhD
Hemochromatosis gene HFE Cys282Tyr polymorphism is associated with two-fold increased risk at acute myocardial infarction in men.
Tuomainen T-P, Kontula K, Nyyssonen K, Lakka TA, Salonen JT.
Circulation 1998;98(Supplement: Abstract 2417):I-459.
A gene located in the major histocompatibility complex, designated as HLA-H or HFE, was recently found to carry a Cys282Tyr mutation in the majority of patients with hereditary hemochromatosis. We studied whether this relatively common mutation that is proposed to result in excess iron in the body is associated with the risk of the first acute myocardial infarction (AMI) in middle-aged men in Eastern Finland. The subjects of this study were the participants of the prospective population-based Kuopio Ischemic Heart Disease Risk Factor Study (KIHD) (n = 2682), who at entry had no prior ischemic heart disease
and for whom a DNA sample was available (n = 1135, mean age 52.0 years). The follow-up time was from March 1984 to December 1996 (mean, 9.1 years). AMIs were collected using WHO MONICA criteria and determination of the HFE gene Cys282Tyr polymorphism was carried out by a solid-phase minisequencing technique. One (0.1%) subject was homozygous and 75 (6.6%) heterozygous for the HFE 282Tyr allele.
During the follow-up, 67 men experienced an AMI; eight of them were carriers of the 282Tyr allele while 59 were non-carriers. In a forward step-up Cox proportional hazards model adjusting for multiple risk factors, carriers of the HFE 282Tyr allele had a more than two-fold risk of AMI, compared with the non-carriers (Odds ratio 2.3, 95% Cl 1.1 to 4.7, P 0.032). Other statistically significant predictors of AMI were serum apolipoprotein B concentration, 24-hour urinary excretion of nicotine metabolites, ischemic ECG finding in the baseline exercise test and waist-to-hip circumference ratio. These data suggest that HFE gene Cys282Tyr substitution is an independent risk factor for AMI. This finding supports the assumption that increased body iron contributes to the development of AMI.
The HFE CYS282Tyr polymorphism is associated with cardiovascular mortality.
Roest M, Schouw Yvd, B. de Valk BD, Marx JJM, Tempelman M, de Groot P, Sixma J, Banga JD. Presented at the July 1998 meeting of the European Iron Club.
Background: The genetic background of hereditary hemochromatosis (HH) is homozygosity for a Cysteine to Tyrosine transition at position 282 in the HFE-gene. Heterozygosity for HH is associated with moderately increased iron levels and is therefore a candidate risk factor for cardiovascular mortality.
Objective: To study the relationship between HH heterozygosity and cardiovascular mortality. Methods: 12,239 women, aged between 51 an 69 years were followed for 16-18 years (182,976 follow up years) on cardiovascular mortality. Within this cohort 531 women died of a cardiovascular event. These woman were compared with a random sample of the same cohort of 555 women who did not die of cardiovascular disease. HH genotype was determined in DNA obtained from overnight urine samples.
Results: The allele frequency of the HH gene in the reference group was 4.0 (95% confidence interval; CI: 2.9-5.4). The incidence rate ratios of HFE heterozygosity were 1.5 (95% CI: 1.3-3.5) for mortality by myocardial infarction, 2.4 (95% CI: 1.3-3.5) for cerebrovascular mortality and 1.6 (95% CI: 1.1-2.4) for total cardiovascular mortality. The population attributable risks of HH heterozygosity for myocardial infarction, cerebrovascular mortality and total cardiovascular mortality were 3.3%, 8.8% and 4.0% respectively. The effect of the HH gene is more prominent in hypertensive smokers.
Conclusions: Heterozygosity for HH is associated with increased risk of cerebrovascular and total cardiovascular mortality, in particular in combination with hypertension and smoking. Long term exposure to minimal iron overload may enhance atherosclerosis.