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The Role of Hemochromatosis C282Y and H63D Gene Mutations in Type 2 Diabetes

Findings from the Rotterdam Study and meta-analysis

¹ Genetic Epidemiology Unit, Department of Epidemiology & Biostatistics, Rotterdam, the Netherlands
² Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, the Netherlands

Diabetes is a disease commonly found in patients with hemochromatosis (1). The hemochromatosis C282Y and H63D mutations in the HFE gene are associated with increased iron stores (2), which in turn are associated with glucose intolerance and insulin resistance (3). Whether these HFE mutations play an important role in the pathogenesis of type 2 diabetes is still a matter of controversy.

We have studied the frequencies of the C282Y and H63D mutations in 254 subjects with glucose intolerance, 220 patients with type 2 diabetes, and 595 normoglycemic individuals (control subjects), all derived from a population-based cohort study (Rotterdam Study) (4). Glucose levels were measured by the hexokinase method in fasting and postload serum samples, and participants were classified as diabetic, glucose intolerant, or normoglycemic (4). Genotyping for the C282Y and H63D mutations was carried out as previously described (5).

In our population-based sample, we observed that 26 (10.5%) subjects with glucose intolerance, 24 (11.0%) with type 2 diabetes, and 61 (10.6%) control subjects were carriers of the C282Y mutation. For the H63D mutation, 65 (26.0%) glucose-intolerant subjects, 56 (25.7%) type 2 diabetic patients, and 168 (28.5%) control subjects were carriers. Also, the number of homozygotes for the H63D mutation in glucose-intolerant patients (1.7%) and in type 2 diabetic patients (1.8%) was similar to that seen in control subjects (1.5%). There were too few homozygotes for the C282Y mutation among glucose-intolerant (n = 2) and diabetic patients (n = 1) to yield reliable results.

Because of the low frequency of the C282Y mutation, we reanalyzed all published association studies between the HFE mutations and type 2 diabetes in a meta-analysis. Our meta-analysis included 12 studies for the C282Y mutation and 8 studies for the H63D mutation. There was no evidence for heterogeneity (²= 18.5, 11, P = 0.07) between studies. Of 2,630 type 2 diabetic patients, 225 (8.6%) were carriers of the C282Y mutations compared with 327 of 3,437 control subjects (9.5%), yielding an odds ratio (OR) (95% CI) of 1.0 (0.8–1.4), suggesting no association between C282Y and the risk of diabetes. When studying the C282Y homozygosity, there was no significant association to diabetes (1.1 [0.6–2.3]). For the H63D mutation, 559 type 2 diabetic patients of 1,889 (29.6%) and 690 control subjects of 2,524 (27.3%) were carriers, yielding an OR of 1.1 (1.0–1.3). The frequency of H63D homozygosity was modestly increased (1.2 [1.1–2.3]) in type 2 diabetic patients, suggesting no major effect of the H63D mutation on type 2 diabetes.

In conclusion, there was no evidence for an increased frequency of the C282Y or H63D mutations in patients with impaired glucose intolerance or type 2 diabetes in our population-based sample or in the meta-analysis. Also, the findings of our meta-analysis suggest that the role of HFE mutations in the pathogenesis of diabetes in the general population is limited.

Footnotes

Address correspondence to Omer T. Njajou, Genetic Epidemiology Unit, Department of Epidemiology & Biostatistics, P.O. Box 1738, Rotterdam, 3000 DR, the Netherlands. E-mail: njajou{at}lycos.com.

References

1. Phelps G, Chapman I, Hall P, Braund W, Mackinnon M: Prevalence of genetic hemochromatosis among diabetic patients. Lancet 8657:233–234, 1989
   
2. Whitfield JB, Cullen LM, Jazwinska EC, Powell LW, Heath AC, Zhu G, Duffy DL, Martin NG: Effects of HFE C282Y and H63D polymorphism and polygenic background on iron stores in a large community sample of twins. Am J Hum Genet 66:1246–1258, 2000[Medline]
   
3. Tuomainen TP, Nyyssonen K, Salonen R, Tervahauta A, Korpela H, Lakka T, Kaplan GA, Salonen JT: Body iron stores are associated with serum insulin and blood glucose concentrations: population study in 1,013 eastern Finnish men. Diabetes Care 20:426–428, 1997[Abstract]
   
4. Baan CA, Stolk RP, Grobbee DE, Witteman JCM, Feskens EJM: Physical activity in elderly subjects with impaired glucose tolerance and newly diagnosed diabetes mellitus. Am J Epid 149:219–227, 1999[Abstract/Free Full Text]
   
5. Feder JN, Gnirke A, Thomas W, Tsuchihashi Z, Ruddy DA, Basava A, Dormishian F, Domingo R Jr, Ellis MC, Fullan A, Hinton LM, Jones NL, Kimmel BE, Kronmal GS, Lauer P, Lee VK, Loeb DB, Mapa FA, McClelland E, Meyer NC, Mintier GA, Moeller N, Moore T, Morikang E, Wolff RK, et al: A novel MHC class I-like gene is mutated in patients with hereditary hemochromatosis. Nat Genet 13: 399–408, 1996
   

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