Papers

Role of C282Y mutation in haemochromatosis gene in development of type 2 diabetes in healthy men: prospective cohort study

Jukka T Salonen, professor of epidemiology ^a, Tomi-Pekka Tuomainen, research fellow ^b, Kimmo Kontula, professor of molecular medicine ^c. 

^a Research Institute of Public Health and the Department of Public Health and General Practice, University of Kuopio, PO Box 1627, 70211 Kuopio, Finland, ^b Research Institute of Public Health, University of Kuopio, Kuopio, Finland, ^c Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland

Correspondence to: J T Salonen jukka.salonen{at}uku.fi

Type 2 diabetes mellitus is a common complication of iron overload diseases such as hereditary haemochromatosis.¹ A gene mutation (HFE C282Y) has recently been identified that strongly predisposes to haemochromatosis when present in homozygous form.² Because of the notable prevalence of this gene mutation (10.9% in the United Kingdom),³ any disorder related to it has public health importance. We tested the hypothesis that a carrier status for the C282Y mutation predicts the development of type 2 diabetes.

	Participants, methods, and results

Top Participants, methods, and... Comment References

We conducted a population based, prospective, four year follow up study of men aged 54 or 60 in the Kuopio ischaemic heart disease risk factor study, a population study in eastern Finland.⁴ Of 633 eligible men, 555 (88%) participated in the four year follow up. Of these, 508 were not diabetic (fasting blood glucose concentration <6.7 mmol/l and no treatment for diabetes) at baseline. A participant was defined diabetic at the end of the follow up if he had a fasting blood glucose concentration 6.7 mmol/l, a blood glucose concentration of 10.0 mmol/l two hours after a glucose load, or clinical diagnosis of diabetes requiring dietary, oral, or insulin treatment.

The G to A transition at nucleotide 845 of the HFE cDNA, resulting in a substitution of tyrosine for cysteine at codon 282, was assayed by a solid phase minisequencing technique.⁵ The other strongest predictors of diabetesblood glucose and serum fatty acid concentration,⁴ maximal oxygen uptake, and body mass indexwere assessed with standard methods. We estimated odds ratios for developing diabetes with adjustment for risk factors using multivariate logistic regression models. All tests of significance were two sided.

We found one homozygote and 34 heterozygotes for the HFE C282Y mutation, giving a carrier frequency of 6.9% (including the homozygote). Four (11%) of the carriers and 23 (5%) of the 473 non-carriers developed diabetes during the four year follow up. In a multivariate logistic model, significant predictors of diabetes, assessed at baseline, were high body mass index, high ratio of saturated to the sum of polyunsaturated and monounsaturated fatty acids in serum, and the occurrence of the C282Y mutation (table). The Tyr282 allele carriers had an odds ratio of over 3.5 (95% confidence interval 1.02 to 12.1, P=0.047) for developing diabetes, compared with non-carriers.

	Comment

Top Participants, methods, and... Comment References

Our prospective cohort study suggests an association between the common HFE gene mutation and the incidence of type 2 diabetes. Although our study was relatively small, our data support the theory that abnormalities of iron homeostasis contribute to the development of type 2 diabetes. If the observed association were causal, the C282Y mutation would account for as much as 15% of the incidence of type 2 diabetes in northern European populations with a carrier frequency of 7%. As the incidence of diabetes in northern Europe is among the highest in the world and rising, screening for C282Y mutation by DNA analysis, monitoring of iron status, and iron depleting treatment could potentially constitute new important measures in the primary prevention of diabetes. The C282Y mutation also predisposes to coronary heart disease.⁵ It may therefore prove especially important to find out whether the C282Y mutation increases the risk of myocardial infarction in people with type 2 diabetes.

	Acknowledgments

   Contributors: JTS, the principal investigator of the Kuopio ischaemic heart disease study, initiated and coordinated the research, formulated the primary study hypothesis, performed the data analysis, and drafted the manuscript. He is also the guarantor of the study. T-PT discussed core ideas and participated in writing the paper. KK supervised the genotypings, discussed core ideas, and participated in writing the paper.

	Footnotes

Funding: This work was supported by the Academy of Finland (grants for projects #41471, 1041086, 2041022 to JTS and #35313 to KK) and by the United States National Heart, Lung, and Blood Institute (grant HL44199 to George A Kaplan for the Kuopio ischaemic heart disease study four year follow up study).

Competing interests: None declared.

	References

Top Participants, methods, and... Comment References

1.	Yaouanq JM. Diabetes and haemochromatosis: current concepts, management and prevention. Diabetes Metab 1995; 21: 319-329.
2.	Feder JN, Gnirke A, Thomas W, Tsuchihashi Z, Ruddy DA, Basava A, et al. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nature Genet 1996; 13: 399-408[CrossRef][Medline].
3.	Merryweather-Clarke AT, Pointon JJ, Shearman JD, Robson KJ. Global prevalence of putative haemochromatosis mutations. J Med Genet 1997; 34: 275-278[Abstract/Free Full Text].
4.	Salonen JT, Nyyssönen K, Tuomainen T-P, Mäenpää PH, Korpela H, Kaplan GA, et al. Increased risk of non-insulin dependent diabetes mellitus at low plasma vitamin E concentrations: a four year follow up study in men. BMJ 1995; 311: 1124-1127[Abstract/Free Full Text].
5.	Tuomainen T-P, Kontula K, Nyyssönen K, Lakka TA, Heliö T, Salonen JT. Increased risk of acute myocardial infarction in carriers of the hemochromatosis gene Cys282Tyr mutation: a prospective cohort study in men in eastern Finland. Circulation 1999; 100: 1274-1279[Abstract/Free Full Text].

(Accepted 24 February 2000)