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Articles by K. R. Owen
Total Records ( 3 ) for K. R. Owen
  E. L. Edghill , A. Khamis , M. N. Weedon , M. Walker , G. A. Hitman , M. I. McCarthy , K. R. Owen , S. Ellard , A. T Hattersley and T. M. Frayling
  Aim  Genome-wide association studies have identified > 30 common variants associated with Type 2 diabetes (> 5% minor allele frequency). These variants have small effects on individual risk and do not account for a large proportion of the heritable component of the disease. Monogenic forms of diabetes are caused by mutations that occur in < 1:2000 individuals and follow strict patterns of inheritance. In contrast, the role of low frequency genetic variants (minor allele frequency 0.1-5%) in Type 2 diabetes is not known. The aim of this study was to assess the role of low frequency PDX1 (also called IPF1) variants in Type 2 diabetes.

Methods  We sequenced the coding and flanking intronic regions of PDX1 in 910 patients with Type 2 diabetes and 878 control subjects.

Results  We identified a total of 26 variants that occurred in 5.3% of individuals, 14 of which occurred once. Only D76N occurred in > 1%. We found no difference in carrier frequency between patients (5.7%) and control subjects (5.0%) (P = 0.46). There were also no differences between patients and control subjects when analyses were limited to subsets of variants. The strongest subset were those variants in the DNA binding domain where all five variants identified were only found in patients (P = 0.06).

Conclusion  Approximately 5% of UK individuals carry a PDX1 variant, but there is no evidence that these variants, either individually or cumulatively, predispose to Type 2 diabetes. Further studies will need to consider strategies to assess the role of multiple variants that occur in < 1 in 1000 individuals.

  S. A. Mughal , R. Park , N. Nowak , A. L. Gloyn , F. Karpe , H. Matile , M. T. Malecki , M. I. McCarthy , M. Stoffel and K. R. Owen
 

Aims

Missed diagnosis of maturity-onset diabetes of the young (MODY) has led to an interest in biomarkers that enable efficient prioritization of patients for definitive molecular testing. Apolipoprotein M (apoM) was suggested as a biomarker for hepatocyte nuclear factor 1 alpha (HNF1A)-MODY because of its reduced expression in Hnf1a-/- mice. However, subsequent human studies examining apoM as a biomarker have yielded conflicting results. We aimed to evaluate apoM as a biomarker for HNF1A-MODY using a highly specific and sensitive ELISA.

Methods

ApoM concentration was measured in subjects with HNF1A-MODY (= 69), Type 1 diabetes (= 50), Type 2 diabetes (= 120) and healthy control subjects (= 100). The discriminative accuracy of apoM and of the apoM/HDL ratio for diabetes aetiology was evaluated.

Results

Mean (standard deviation) serum apoM concentration (μmol/l) was significantly lower for subjects with HNF1A-MODY [0.86 (0.29)], than for those with Type 1 diabetes [1.37 (0.26), = 3.1 x 10-18) and control subjects [1.34 (0.22), = 7.2 x 10-19). There was no significant difference in apoM concentration between subjects with HNF1A-MODY and Type 2 diabetes [0.89 (0.28), = 0.13]. The C-statistic measure of discriminative accuracy for apoM was 0.91 for HNF1A-MODY vs. Type 1 diabetes, indicating high discriminative accuracy. The apoM/HDL ratio was significantly lower in HNF1A-MODY than other study groups. However, this ratio did not perform well in discriminating HNF1A-MODY from either Type 1 diabetes (C-statistic = 0.79) or Type 2 diabetes (C-statistic = 0.68).

Conclusions

We confirm an earlier report that serum apoM levels are lower in HNF1A-MODY than in controls. Serum apoM provides good discrimination between HNF1A-MODY and Type 1 diabetes and warrants further investigation for clinical utility in diabetes diagnostics.

  K. R. Owen
  Assigning the correct aetiology in diabetes is important for treatment, understanding prognosis and for follow-up of family members. Despite these benefits, many are missing out on the opportunity to have testing for monogenic forms of diabetes. This review gives the clinical features of the commoner forms of monogenic diabetes and examines which clinical and biological markers can be used to identify those at highest risk of having Maturity onset diabetes of the young (MODY). MODY is characterised by young-onset, familial diabetes which is C-peptide positive, β-cell antibody negative and not associated with metabolic syndrome. Differentiating from type 1 and type 2 diabetes can be challenging due to the overlap of clinical features. In type 1 diabetes, insulin production ceases after the honeymoon period. Thus C-peptide can be used to detect those with persisting insulin secretion who might have a different cause for their diabetes. In type 2 diabetes, most have insulin resistance, so absence of metabolic syndrome could be used to identify those most likely to have MODY. Another approach is to look for non-pancreatic features associated with mutations in MODY genes. Following results from Genome-wide association studies, we have shown that those with HNF1A mutations (the commonest form of MODY) have decreased serum levels of highly-sensitive C-reactive protein (hsCRP) and altered patterns of plasma protein fucosylation. These features can differentiate HNF1A-MODY from common forms of diabetes with a high degree of discriminative accuracy. Using combinations of clinical features and new biomarkers in diagnostic pathways will help increase diagnosis rates of MODY.
 
 
 
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