Human Molecular Genetics

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Human Molecular Genetics, 2003, Vol. 12, No. 12 1361-1365
DOI: 10.1093/hmg/ddg149
© 2003 Oxford University Press

Typical type 2 diabetes mellitus and HFE gene mutations: a population-based case – control study

David J. Halsall^1,*, Ian McFarlane¹, Jian'an Luan², Timothy M. Cox³ and Nicholas J. Wareham²

¹Department 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

Received March 12, 2003; Accepted April 3, 2003

	ABSTRACT

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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 over-represented 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

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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 ß₂-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

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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 (GT) was higher in the diabetic cohort possibly as a result of increased steatosis that is associated with this condition. An increase in GT 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.

View this table: [in this window] [in a new window]   Table 1. Characteristics of the case and control subjects

 
Allele frequencies
The C282Y allele frequencies were in Hardy–Weinberg equilibrium for both the individuals with diabetes and the non-diabetic controls (P=0.07, log-likelihood ² 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=0.48).

Meta analysis
Nine papers were identified by a literature search and included in the meta analysis (7,9–16) (Fig. 1). The results of the meta-analysis suggest that the C282Y mutation was not found more frequently in patients with T2DM compared with controls. The adjusted overall odds ratio for carriers was 1.085, 95% confidence interval 0.911–1.292, P=0.3609. The most extreme association was found in the study by Moczulski et al. (7). With this study included, the ² for heterogeneity between studies was 19.44 (10 degrees of freedom, P=0.035). However, when this study was excluded, the ² value fell to 11.9 and was not statistically significant (9 degrees of freedom, P=0.219).

View larger version (12K): [in this window] [in a new window]   Figure 1. Meta-analysis of C282Y gene frequency in type 2 diabetes mellitus. The studies, indicated by first author are: Behn et al. (8); Braun et al. (9); Dubois-Laforgue et al. (10); Frayling et al. (13); Kwan et al. (14); Fernandez-Real et al. (11); Florkowski et al. (12); Sampson et al. (15); Moczulski et al. (7) and Njajou et al. (16).

 
Compound heterozygotes
We examined the effect of compound heterozygotes in our case–control study. As Table 2 indicates, there was no significant difference in the number of C282Y homozygotes (HHYY) detected, nor was there any significant difference in the frequency of compound heterozygotes for C282Y and H63D (HDCY), a mutation in trans with the C282Y mutation, which has also been related to hereditary haemochromatosis. H63D and C282Y are in linkage disequilibrium (19).

View this table: [in this window] [in a new window]   Table 2. Compound heterozygote frequencies in type 2 diabetes patients and control group

 
Anthropometric and biochemical studies
Finally we examined the association of genotype with anthropometric and biochemical variables within cases and controls separately (Table 3). We saw no effect of genotype on levels of HbA_1c in either cases or controls, suggesting that these HFE alleles are unlikely to have a marked effect on glucose tolerance or glycaemic control. Although among the cases insulin use was higher in gene carriers, this did not reach significance. Serum GT, which has the potential to be increased by iron-induced liver disease, was not associated with HFE genotype in either group. In the cases men who carried the HFE allele were heavier and women carriers had an increased fat percentage. However, the statistical significance of these findings was marginal and the results should be treated with caution given the post hoc nature of these comparisons.

View this table: [in this window] [in a new window]   Table 3. Anthropometric and biochemical characteristics of the cases and controls by C282Y genotype

 

	DISCUSSION

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By itself, this study suggests that the C282Y gene frequency, 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- and sex-matched non-diabetic controls. In combination with data from all other previous studies, we are confident that there is no overall association as the odds ratio is 1.1 with very narrow confidence intervals (0.9–1.3), excluding the possibility that this allele is strongly associated with diabetes as defined in these studies.

The most extreme study in the meta-analysis is that of Moczulski et al. (7) in Polish subjects. Previous studies have suggested a gradient across Europe in the frequency of C282Y (3,20), with the Y282 allele being more prevalent in northwest Europe (gene frequency of 11% in Ireland compared with 1.6% in southern Italy), perhaps reflecting the Celtic origin of this allele. Although the Polish cases have a C282Y frequency similar to that of the other European studies, the unusually high odds ratio arises because the frequency of the allele is so low in their controls (0.7%). Whether this is a true result, a chance finding because of the small number of controls or is a function of selection bias is uncertain.

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, a case definition that is typical of studies that attempt to include cases of T2DM. Increasingly this is a diagnosis of exclusion, with disorders of glucose metabolism of known aetiology being classified by the World Health Organization (21) into a separate group (group 3). Although our study suggests that the HFE gene is not associated with typical T2DM, this is not equivalent to suggesting it is not associated with diabetes. Indeed, our case definition may have excluded those very cases of diabetes that are associated with HH. Since the iron overload present in haemochromatosis is likely to lead to both impaired pancreatic function and also insulin resistance, 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. To examine this question Ellervik and colleagues (22) selected Danish patients who presented with insulin-requiring DM after the age of 30. A greater number of these patients were homozygous for C282Y than non-diabetic controls (odds ratio 4.6; 95% CI 2.0–10.1; P=0.0001). These data would suggest that this genotype is associated with a specific diabetic phenotype that is not typical of type 2 diabetes, and may, as is the case in our study, have been selectively excluded.

Another explanation for heterogeneity between studies is the degree to which diabetes was excluded from the controls. In our study DM was excluded from the control group on the basis of HbA_1c measurements. Of all the other studies, only Frayling et al. (13) excluded diabetes in the control group using biochemical criteria. Others used self-reported diabetes (15) or a family history of diabetes (9) as the basis for exclusion. However as undiagnosed T2DM is uncommon, failure to diagnose diabetes is unlikely to seriously bias estimation of the overall association.

The C282Y mutation is almost always associated with increased iron indices (4–6), but controversy remains as to whether increased body iron stores contribute to the development of diabetes. 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), which would explain the lack of success for screening for haemochromatosis in T2DM cohorts using biochemical markers (24,25). Reducing iron stores in overloaded non-C282Y diabetics may, however, improve glycaemic control (26).

We were unable to replicate the findings of Dubois-Laforgue et al. (27), 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. Indeed we have weak evidence for the opposite effect. We saw no relationship between genotype and HbA_1c levels in either the cases or controls and saw no effect of genotype on serum GT levels. Whilst the C282Y allele clearly disposes to iron overload, the mechanism by which this overload leads to pancreatic failure or any other end-organ damage associated with HH, or insulin resistance remains obscure. In conclusion, C282Y genotyping has no value in population screening to predict risk of typical type 2 diabetes, but this may not preclude its utility in identifying disease aetiology in people with a specific phenotype characterized by onset after 30 years with early requirement for insulin.

	MATERIALS AND METHODS

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A total of 552 patients aged 45–76 years with T2DM were randomly selected from general practitioner diabetes registers in Cambridgeshire, UK and were invited to join this study. The Presence of T2DM was based on clinical criteria: onset of diabetes after the age of 30 years without treatment with insulin in the first year after diagnosis (28). The controls were recruited at random from the same population sampling frames, and were individually matched to cases for age, sex and GP practice. Diabetes was excluded in controls by medical record search and by a HbA_1c measurement of less than 6%. Anthropometric measurements were taken with participants dressed in light clothing and no shoes. Height was measured to the nearest 0.1 cm using a stadiometer and weight was measured to the nearest 100 g using Salter scales. Body mass index (BMI) was calculated as the weight (kg) divided by the height (m) squared. Waist circumference was measured at the midpoint between the inferior border of the coastal margin and the anterior superior iliac crest and hip circumference at the level of the greater trochanter. Fat percentage was measured using a Bodystat impedance monitor. A sample of EDTA-anticoagulated blood was taken for HbA_1c measurement using high-performance liquid chromatography on a Bio-Rad Diamat (Richmond, CA, USA). The study received ethical approval from the Cambridge Local Research Ethics Committee, and participants provided informed consent. The study was powered to detect an odds ratio of 1.9 at 5% significance and 90% power assuming a C282Y gene frequency of 6% (29).

DNA was extracted from EDTA-anticoagulated blood collected from the above patients using standard methods. HFE C282Y genotyping was performed using a PCR-based restriction digestion method (30) using modified oligonucleotide primers sequence to improve allelic discrimination (5'-CTA CCA GGG CTG GAT AAC CTT G and 5'-TGG CTC TCA TCA GTC ACA TAC C). H63D genotyping was performed similarly as described above. Genotyping was undertaken blinded to case–control assignation.

Anthropometric characteristics of the cases and controls, and of the HFE genotypes were compared by t-test for continuously distributed data, by comparison of proportions for categorical data, and by Mann–Whitney and Wilcoxon test for alcohol intake data. Genotype frequencies in cases and controls were tested separately for Hardy–Weinberg equilibrium. HFE allele frequencies between cases and controls were compared by a test of proportions and odds ratio calculated.

An Entrez ‘Pub Med’ (NCBI) search for ‘Diabetes’ and ‘Haemochromatosis’ was performed between November 2002 and August 1996, when the cloning of the HFE gene was first reported (19). Publications where C282Y gene frequencies were compared in patients with T2DM and controls were included and citations within these records were hand searched. Meta-analysis was performed using SAS procedure LOGISTIC. The pooled odds ratio and the test for heterogeneity were calculated by using Mantel–Haenszel method (31).

	ACKNOWLEDGEMENTS

 
Financial support for this study was provided by an European Union Quality of Life and Management of Living Resources Grant.

	FOOTNOTES

 
^* To whom correspondence should be addressed. Tel: +44 1223217156; Fax: +44 1223216862; Email: djh44{at}hermes.cam.ac.uk

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