Screening of HNF1A and HNF4A mutation and clinical phenotype analysis in a large cohort of Chinese patients with maturity-onset diabetes of the young
- 34 Downloads
The study aimed to screen the HNF1A and HNF4A mutation in a large Chinese cohort of high clinical suspicion of maturity-onset diabetes of the young (MODY) patients and characterize the clinical features of those patients. The performance of hsCRP as a biomarker to differentiate MODY3 from early onset T2DM was also evaluated.
A total of 74 patients with a strong clinical suspicion of MODY from 59 families and 33 newly diagnosed early-onset T2DM were included. HNF1A and HNF4A mutations were analyzed by Sanger sequencing. ROC curves were used to identify the optimal cutoff of hsCRP.
One novel (c.864_865insG) and six recurrent HNF1A mutations (R203H, R263H, P379T, L422P, P519L and c.873delC) in 17 patients from 8 families (13.6%), as well as one novel HNF4A (R331H) mutation were identified. Nonspecific clinical presentations were observed in MODYX compared to MODY3 patients. MODY3 subjects exhibited with younger, lower BMI, TG, fasting and postprandial C-peptide, higher HDL than T2DM. Particularly, we confirmed serum hsCRP was lower in MODY3 than T2DM. ROC curve showed a good discrimination with an AUC of 0.852 and identified a cutoff hsCRP of 0.79 (75% sensitivity and 83% specificity). Good glycemic control was observed in all identified patients after switching to glimepiride therapy.
The prevalence of HNF1A mutation was relatively lower in Mainland China and HNF4A mutation was rare. Serum hsCRP concentrations performed well in discriminating MODY3 from T2DM. Molecular diagnosis of MODY3/1 did transform management in clinical practice and facilitated the glycemic control.
KeywordsMaturity-onset diabetes of the young HNF1A HNF4A CRP Mutation
The study was funded by research grants from the National Key R&D program of China (2017YFC1309603), National Key research and Development Program of China (2016YFA0101002), National Natural Science Foundation of China (NO. 81170736, 81570715), and Beijing science and technology project (D141107005314002). We thank all the subjects in this study.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
All procedures performed in this study involving human participants were in accordance with the ethical standards of the Peking Union Medical College Hospital Ethics Committee.
Human and animal rights
The study was conducted in accordance with the principles of the Declaration of Helsinki of 1975, as revised in 2008.
Informed consent was obtained from all patients for being included in the study.
- 15.Pihoker C, Gilliam LK, Ellard S, Dabelea D, Davis C, Dolan LM et al (2013) Prevalence, characteristics and clinical diagnosis of maturity onset diabetes of the young due to mutations in HNF1A, HNF4A, and glucokinase: results from the SEARCH for diabetes in youth. J Clin Endocrinol Metab 98:4055–4062CrossRefGoogle Scholar
- 16.Harries LW, Ellard S, Stride A, Morgan NG, Hattersley AT (2006) Isomers of the TCF1 gene encoding hepatocyte nuclear factor-1 alpha show differential expression in the pancreas and define the relationship between mutation position and clinical phenotype in monogenic diabetes. Hum Mol Genet 15:2216–2224CrossRefGoogle Scholar
- 17.Schober E, Rami B, Grabert M, Thon A, Kapellen T, Reinehr T et al (2009) Phenotypical aspects of maturity-onset diabetes of the young (MODY diabetes) in comparison with type 2 diabetes mellitus (T2DM) in children and adolescents: experience from a large multicentre database. Diabet Med 26:466–473CrossRefGoogle Scholar