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HNF1A gene p.I27L is associated with early-onset, maturity-onset diabetes of the young-like diabetes in Turkey.

ABSTRACT: BACKGROUND:The molecular basis of the Turkish population with suspected maturity-onset diabetes of the young (MODY) has not been identified. This is the first study to investigate the association between HNF1A-gene single-nucleotide polymorphisms (SNPs) and having early-onset, MODY-like diabetes mellitus in the Turkish population. METHODS:All diabetic patients (N?=?565) who presented to our clinic between 2012 and 2015 with a clinical suspicion of MODY were included in the study. Analysis of HNF1A, HNFB, HNF4A, GCK gene mutations was performed using real-time polymerase chain reaction sequencing. After genetic analysis, diabetics (n?=?46) with HNF1A, HNF1B, HNF4A, GCK gene mutations (diagnosed as MODY) and diabetics (n?=?30) with HNF1B, HNF4A, GCK gene SNPs were excluded. Patients with early-onset, MODY-like diabetes (n?=?486) and non-diabetic controls (n?=?263) were included. Genetic analyses for the HNF1A gene p.S487?N (rs2464196), p.A98V (rs1800574) and p.I27L (rs1169288) SNPs were performed using Sanger-based DNA sequencing among the control group. RESULTS:p.S487?N and p.A98V was similar between the diabetics and controls in dominant and recessive models with no association (each, p?>?0.05). p.I27L GT/TT carriers (GT/TT vs. GG, OR?=?1.68, 95% CI: [1. 21-2.13]; p?=?0.035) and p.I27L TT carriers had increased risk of having MODY-like diabetes (GT/GG vs. TT, OR?=?1.56, 95% CI: [1. 14-2.57]; p?=?0.048). Family inheritance of diabetes was significantly more common in patients with the p.I27L TT genotype. The p.I27L SNP was modestly associated with having diabetes after adjusting for body mass index and age (??=?1.45, 95% CI: [1. 2-4.2]; p?=?0.036). CONCLUSIONS:The HNF1A gene p.I27L SNP was modestly associated with having early-onset, MODY-like diabetes in the Turkish population. HNF1A gene p.I27L SNP might contribute to age at diabetes diagnosis and family inheritance.

SUBMITTER: Beysel S

PROVIDER: S-EPMC6528345 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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HNF1A gene p.I27L is associated with early-onset, maturity-onset diabetes of the young-like diabetes in Turkey.

Beysel Selvihan S Eyerci Nilnur N Pinarli Ferda Alparslan FA Kizilgul Muhammed M Ozcelik Ozgur O Caliskan Mustafa M Cakal Erman E

BMC endocrine disorders 20190520 1

<h4>Background</h4>The molecular basis of the Turkish population with suspected maturity-onset diabetes of the young (MODY) has not been identified. This is the first study to investigate the association between HNF1A-gene single-nucleotide polymorphisms (SNPs) and having early-onset, MODY-like diabetes mellitus in the Turkish population.<h4>Methods</h4>All diabetic patients (N = 565) who presented to our clinic between 2012 and 2015 with a clinical suspicion of MODY were included in the study. ...[more]

PMID: 31109344

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Project description:OBJECTIVE:Inactivating heterozygous mutations in the GCK gene are a common cause of MODY and result in mild fasting hyperglycaemia, which does not require treatment. We aimed to identify the frequency, clinical and molecular features of GCK mutations in a Turkish paediatric cohort. DESIGN AND PATIENTS:Fifty-four unrelated probands were selected based on the following criteria: age of diagnosis ?17 years, family history of diabetes in at least two generations, anti-GAD/ICA negative, BMI<95.p and follow-up with diet, oral antidiabetic drug or low-dose insulin treatment (?0·5U/kg/d). A MODY probability score (www.diabetesgenes.org) was calculated and 21 patients with a score ?75%, HbA1c levels ?7·5% (58·5 mmol/mol) and fasting blood glucose (FBG) levels 99-145 mg/dl (5·5-8·0 mmol/l) were selected for Sanger sequencing of the GCK gene. Targeted next-generation sequencing for all known monogenic diabetes genes was undertaken for any patient without a GCK gene mutation. RESULTS:GCK gene mutations (pathogenic or likely pathogenic variants) and a novel intronic variant of uncertain significance (c.208 + 3A>T) were identified in 13/54 probands (24%). Twelve of these patients had a MODY probability score ?75%. FBG level and 2-h glucose level in OGTT were 123 ± 14 mg/dl (6·8 ± 0·7 mmol/l) (107-157 mg/dl) and 181 ± 30 mg/dl (10·1 ± 1·6 mmol/l) (136-247 mg/dl), respectively. Average of glucose increment in OGTT was 58 ± 27 mg/dl (3·2 ± 1·5 mmol/l) (19-120 mg/dl), and mean HbA1c level was 6·5 ± 0·5% (47·5 ± 5·5 mmol/mol) (5·9-7·6%). Five novel missense mutations were identified (p.F123S, p.L58P, p.G246A, p.F419C, and p.S151C). Two patients treated with low-dose insulin before the molecular analysis were able to stop treatment. CONCLUSIONS:Approximately 1 in 4 MODY cases in this Turkish paediatric cohort have a GCK mutation. Selection of patients for GCK gene analysis using the MODY probability score was an effective way of identifying most (11/12) patients with a GCK mutation.

Dataset Information

HNF1A gene p.I27L is associated with early-onset, maturity-onset diabetes of the young-like diabetes in Turkey.

Publications

HNF1A gene p.I27L is associated with early-onset, maturity-onset diabetes of the young-like diabetes in Turkey.

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