Human Molecular Genetics, 2003, Vol. 12, No. 12 DOI: 10.

1093/hmg/ddg149

1361–1365

Typical type 2 diabetes mellitus and HFE gene mutations: a population-based case – control study
David J. Halsall1,*, Ian McFarlane1, Jian’an Luan2, Timothy M. Cox3 and Nicholas J. Wareham2
1

Department of Clinical Biochemistry, Addenbrooke’s NHS Trust, Cambridge CB2 2QR, UK, 2Department of Public Health and Primary Care, Institute of Public Health, Cambridge University, Cambridge, UK and 3Department of Medicine, Addenbrooke’s NHS Trust, Hills Road, Cambridge CB2 2QR, UK
Downloaded from http://hmg.oxfordjournals.org/ at Makerere University on May 17, 2012

Received March 12, 2003; Revised and Accepted April 3, 2003

Diabetes mellitus is a recognized consequence of hereditary haemochromatosis. Whether the common HFE mutations, that associate with this condition and pre-dispose to increases in serum iron indices, are overrepresented in diabetic populations remains controversial. We present data from the largest case–control study of the C282Y and H63D HFE allele frequencies in typical type 2 diabetes mellitus, as defined by an age of onset greater than 30 years and no requirement for insulin in the first year post-diagnosis. We also present a meta-analysis of all similar studies to date. We see no evidence for over-representation of iron loading HFE alleles in type 2 diabetes mellitus, suggesting that screening for HFE mutations in this population is of no value.

INTRODUCTION
Hereditary haemochromatosis (HH) results in excess iron absorption from the diet and deposition in body tissues (1), including the liver, joints, pancreas and pituitary gland with consequent tissue damage leading to the typical presentations of cirrhosis, arthralgia and hypogonadism. Although diabetes mellitus is a well-recognized complication of this condition (2), it is unclear what proportion of people presenting with typical type 2 diabetes mellitus (T2DM) have polymorphisms in the HFE gene. In the UK the majority of HH is associated with homozygosity for a cysteine to tyrosine mutation at amino acid position 282 (C282Y) within the HFE gene (3). The HFE gene product is an HLA-like molecule that is presented at the cell surface bound to b2-microglobulin, where it is proposed to modify the affinity of transferrin for its receptor. A second common HFE sequence variant (histidine to aspartic acid at amino acid position 63-H63D) also associates with HH in the compound heterozygous state with C282Y. Whilst the C282Y gene dose predicts serum iron indices (4–6), reports of the C282Y allele frequency in T2DM are conflicting (7–18). This paper describes the largest population-based case–control study of HFE mutations and T2DM and summarizes the magnitude of the overall association of HFE mutations and T2DM in a meta-analysis of published studies.

RESULTS
Table 1 shows the anthropometric characteristics of the case and control subjects included in this analysis. The cohorts were well matched for age and sex, but, unsurprisingly, the individuals with diabetes were more obese. Serum gamma-glutamyl transferase (gGT) was higher in the diabetic cohort possibly as a result of increased steatosis that is associated with this condition. An increase in gGT was seen in the cases even though alcohol intake was lower. This may represent true differences in alcohol intake or alternatively may be a manifestation of recall bias consequent on the provision of healthy-living advice to the cases. The percentage of patients treated with insulin and oral hypoglycaemic agents is typical of a cohort of patients of this age with T2DM diabetes in the UK. Allele frequencies The C282Y allele frequencies were in Hardy–Weinberg equilibrium for both the individuals with diabetes and the non-diabetic controls (P ¼ 0.07, log-likelihood w2 test). There was no evidence to suggest that the C282Y gene frequency was increased in patients with T2DM. The odds ratio for the association of the C282Y allele with diabetes was 1.14 (95% CI 0.78–1.68, P ¼ 0.48).

*To whom correspondence should be addressed. Tel: þ44 1223217156; Fax: þ44 1223216862; Email: djh44@hermes.cam.ac.uk

Human Molecular Genetics, Vol. 12, No. 12 # Oxford University Press 2003; all rights reserved

(15). With this study included. which has the potential to be increased by iron-induced liver disease.5 84. we are confident that there is no overall association as the odds ratio is 1. 12. The most extreme association was found in the study by Moczulski DISCUSSION By itself.47) HDCY þ HHYY 11 7 18 1.oxfordjournals.57 (0.and sex-matched nondiabetic controls. (12).4) (5.1){ (11. In combination with data from all other previous studies.01 (0.7 34.7) (0.8 0. (7).9 65.9–16) (Fig.94 7.90 5. We saw no effect of genotype on levels of HbA1c in either cases or controls.3). (7) and Njajou et al. there was no significant difference in the number of C282Y homozygotes (HHYY) detected. when this study was excluded.4 — — 5.7–7. Florkowski et al.2 0. Serum gGT. Dubois-Laforgue et al. P ¼ 0.035).52) HDCY are compound heterozygotes for the H63D allele and the C282Y allele. 95% confidence interval 0. P ¼ 0. 1).3609.9) 63.66–7.3 (4. Sampson et al. (8). Table 1.6 27. was not associated with HFE genotype in either group. Anthropometric and biochemical studies Finally we examined the association of genotype with anthropometric and biochemical variables within cases and controls separately (Table 3).08) (7.219). the statistical significance of these findings was marginal and the results should be treated with caution given the post hoc nature of these comparisons. 2012 Compound heterozygotes We examined the effect of compound heterozygotes in our case–control study.1–6. Figure 1. The adjusted overall odds ratio for carriers was 1.2){ (0.9) *P < 0.3 30. Kwan et al. data shown are mean (SD) or a geometric mean (95% confidence interval). the w2 for heterogeneity between studies was 19.56–4.6 1. (9).90) (47.1362 Human Molecular Genetics. indicated by first author are: Behn et al.7){ 450 60 2 6. (14). As Table 2 indicates. 2003. the w2 value fell to 11.3) Non-diabetic controls 508 63. Moczulski et al.44 (10 degrees of freedom.1–39. a mutation in trans with the C282Y mutation. In the cases men who carried the HFE allele were heavier and women carriers had an increased fat percentage. units/week) Weight (kg) BMI (kg/m2) Body fat (%) Waist-to-hip ratio HbA1c (%)a gGT (U/l)a C282Y CC (n) CY (n) YY (n) Frequency of Y allele (95% CI) (%) 512 63. .org/ at Makerere University on May 17. (16). HHYY are Y282 homozygotes.911–1.56–5.9 and was not statistically significant (9 degrees of freedom.6){ (4. nor was there any significant difference in the frequency of compound heterozygotes for C282Y and H63D (HDCY).6 (7.9–1. Meta analysis Nine papers were identified by a literature search and included in the meta analysis (7. Braun et al.1 with very narrow confidence intervals (0. which has also been related to hereditary haemochromatosis. excluding the possibility that this allele is strongly associated with diabetes as defined in these studies.5 (4.292.75–17. No.085. Fernandez-Real et al. (13).38) HHYY 2 4 6 0.04–3. suggesting that these HFE alleles are unlikely to have a marked effect on glucose tolerance or glycaemic control.6 29. the number of C282Y homozygotes and the number of C282Y/ H63D compound heterozygotes are unlikely to be different in people with typical T2DM than in age. Vol. Compound heterozygote frequencies in type 2 diabetes patients and control group Genotype T2DM Controls Total Odds Ratio (95% CI) n 501 501 1002 HDCY 9 3 12 3.78 50.60 37. (11).63){ (36. (10). The studies.6 (7.5 (15.2) (12.8–53. Although among the cases insulin use was higher in gene carriers. {P < 10À6.9 8.9 (13. The results of the meta-analysis suggest that the C282Y mutation was not found more frequently in patients with T2DM compared with controls.0{ 78. Downloaded from http://hmg. Frayling et al. this study suggests that the C282Y gene frequency. et al. this did not reach significance. Characteristics of the case and control subjects People with diabetes n Age (years) Percentage male (%) Percentage treated with insulin (%) Percentage treated with oral hypoglycaemics (%) Alcohol intake (median.8) 456 48 4 5.8) 63. Meta-analysis of C282Y gene frequency in type 2 diabetes mellitus. H63D and C282Y are in linkage disequilibrium (19). However. For continuous variables. However. 12 Table 2.49 (0. P ¼ 0.05.08){ (5.

7) (6.6) (43.858 0.39 40.70 40. However as undiagnosed T2DM is uncommon. The cases in our case–control study were selected to have an age of onset above 30 and not to require insulin in the first year after diagnosis.25).6 P-value 0.50 85.041 0. who suggested that the lower body mass index of the people with diabetes who had the C282Y mutation was a consequence of this mutation exacerbating disease progression.50 3.81) (33.9 52.5) (13. failure to diagnose diabetes is unlikely to seriously bias estimation of the overall association.7 (7.7–37.9) (0. and may.678 0.6) 63.70–8. the unusually high odds ratio arises because the frequency of the allele is so low in their controls (0.887 0.6 (8.9% 2.44–5. our case definition may have excluded those very cases of diabetes that are associated with HH. perhaps reflecting the Celtic origin of this allele.76–8.311 0.05) (0.75 82.29 32.7 0.5 (7.1 51.0 28. C282/Y282 heterozygous: YY.9) 64.844 — 0.94 0.6 27. Vol.6 29.64 8.7) — 10. Previous studies have suggested a gradient across Europe in the frequency of C282Y (3.73) (6.8 26.8) (7.7) (8.7) Downloaded from http://hmg.0001).1 80.06) (5.86) (38.0) (3. The C282Y mutation is almost always associated with increased iron indices (4–6). Whilst the C282Y allele clearly disposes to iron .399 0.151 0. 12. Increasingly this is a diagnosis of exclusion.49–5.725 0.7) 63.3 CY and YY (n ¼ 18/22) 62.5 0.3 27.8) (16.5) (15. We saw no relationship between genotype and HbA1c levels in either the cases or controls and saw no effect of genotype on serum gGT levels.7 49.9) — 19. The most extreme study in the meta-analysis is that of Moczulski et al.8–47.0) (9. with the Y282 allele being more prevalent in northwest Europe (gene frequency of $11% in Ireland compared with 1. 2003. as is the case in our study.50 75.4% 1.9) (47.275 — 0.9 32.6) (11.881 0.0 (6. C282 homozygous: CY.570 0.4 (7.97 33.5–66.07) (5.09) (5.5) (4.8) (4.82 0.4) (41.59 7.64) (7. P ¼ 0. Since the iron overload present in haemochromatosis is likely to lead to both impaired pancreatic function and also insulin resistance.4–42.1.0 51.563 0. a chance finding because of the small number of controls or is a function of selection bias is uncertain. Reducing iron stores in overloaded non-C282Y diabetics may.5 24.54–7.92) (26. this is not equivalent to suggesting it is not associated with diabetes.258 0.2–41.5% — 64.6) (9.7) (12.0) (44.5) (0. a case definition that is typical of studies that attempt to include cases of T2DM.07) (0.1 46. (7) in Polish subjects.6 P-value 0.048 0.377 0.75 0. improve glycaemic control (26).540 0. which would explain the lack of success for screening for haemochromatosis in T2DM cohorts using biochemical markers (24. A greater number of these patients were homozygous for C282Y than non-diabetic controls (odds ratio 4.3) (13.00 2.6.1 (7.2–54.98 5.55–5.5 31. however.3) (8.819 0. but controversy remains as to whether increased body iron stores contribute to the development of diabetes. Y282 homozoygous.9) (18. 12 1363 Table 3.242 0. Anthropometric and biochemical characteristics of the cases and controls by C282Y genotype Men CC (n ¼ 288/287) Age (years) Percentage treated with insulin Percentage treated with oral hypoglycaemic Alcohol intake (median.9) — 10.50 71.99–7.9) (17.773 0.2% 5.0% — 52.97 5.94 0.905 0. Whether this is a true result. have been selectively excluded. only Frayling et al.Human Molecular Genetics.8 0.0–10.2 (9.8) (4. Although the Polish cases have a C282Y frequency similar to that of the other European studies.5 41. Another explanation for heterogeneity between studies is the degree to which diabetes was excluded from the controls.1 28.18) (30.678 (11.185 0.60 7.80) (7. HH may be more likely to result in a phenotype in which insulin deficiency and therefore early requirement for insulin therapy is a more prominent feature than in our cases.7%). A recent critical review suggests that there is little evidence for a strong correlation between serum ferritin (as a surrogate for increased iron stores) and the development of diabetes independent of HFE status (23).1–61. 95% CI 2.20).4) (8. To examine this question Ellervik and colleagues (22) selected Danish patients who presented with insulin-requiring DM after the age of 30.575 0.9) — 7.8 (7.4 0.077 0.527 — 0.67) (7. 2012 Data are in mean (SD) or ageometric mean (95% confidence interval).0) (3.58 7.06) (0.1 27. Of all the other studies. No.3 86. (27).89 5.6 50. Others used self-reported diabetes (15) or a family history of diabetes (9) as the basis for exclusion.891 Women CC (n ¼ 168/163) 63.764 — 0. Genotypes are: CC.5) (3.6% in southern Italy).9) (0. with disorders of glucose metabolism of known aetiology being classified by the World Health Organization (21) into a separate group (group 3).2 41.6 25.199 0.08) (0.190 0.5–54. These data would suggest that this genotype is associated with a specific diabetic phenotype that is not typical of type 2 diabetes.3% — 69.144 0.org/ at Makerere University on May 17.8) (0.89 5.6 90. We were unable to replicate the findings of Dubois-Laforgue et al.06) (5.860 0.0) 63.645 0.54–5.963 0.906 0. units/week) Weight (kg) BMI (kg/m2) Body fat (%) Waist–hip ratio HbA1c (%)a gGT (U/l)a Control Diabetic Control Diabetic Control Diabetic Control Diabetic Control Diabetic Control Diabetic Control Diabetic Control Diabetic Control Diabetic Control Diabetic 63.7 28.oxfordjournals.6% — 66. In our study DM was excluded from the control group on the basis of HbA1c measurements.25 0. Indeed we have weak evidence for the opposite effect. (13) excluded diabetes in the control group using biochemical criteria.4 85. Indeed.83 0.0) (6.233 0.5% 6. Although our study suggests that the HFE gene is not associated with typical T2DM.9 CY and YY (n ¼ 34/40) 64.7) (6.

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