The Common <i>HNF1A</i> Variant I27L Is a Modifier of Age at Diabetes Diagnosis in Individuals With HNF1A-MODY

Locke, Jonathan M.; Saint‐Martin, Cécile; Laver, Thomas W; Patel, Kashyap; Wood, Andrew R.; Sharp, Seth A.; Ellard, Sian; Bellanné‐Chantelot, Christine; Hattersley, Andrew T.; Harries, Lorna W.; Weedon, Michael N.

doi:10.2337/db18-0133

Cited by 16 publications

(16 citation statements)

References 23 publications

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“…A German-Austrian study reported that age at onset of diabetes (10.9 years) was found to be younger in p.I27L + p.S487 N ± p.A98V carriers, as compared with HNF1A mutation (14 years). Locke et al reported that each p.I27L allele was associated with a 1.6-year decrease in age at diagnosis in patients with HNF1A-MODY [30]. Our study reported early onset of diabetes (24.08 ± 4.82 year) with no differences between HNF1A gene SNPs.…”

Section: Discussionsupporting

confidence: 48%

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

et al. 2019

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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 ( β = 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. Electronic supplementary material The online version of this article (10.1186/s12902-019-0375-2) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 48%

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

et al. 2019

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“…The effect of cohort ascertainment on penetrance is likely due to environmental or/and genetic modifiers 25 . We have previously shown that the presence of the common variant HNF1A p.(I27L) reduces the age of diagnosis of HNF1A MODY 32 . Recent studies of monogenic cardiomyopathy, familial hypercholesterolemia and monogenic breast cancer also observed the impact of common variants on the phenotype [33][34][35] .…”

Section: Discussionmentioning

confidence: 98%

The penetrance of age-related monogenic disease depends on ascertainment context

Mirshahi

Colclough

Wright

et al. 2021

Preprint

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BACKGROUND: Accurate penetrance of monogenic disorders is often unknown due to a phenotype-first approach to genetic testing. Here, we use a genotype-first approach in four large cohorts with different ascertainment contexts to accurately estimate penetrance of the three commonest causes of monogenic diabetes, Maturity Onset Diabetes of the Young (MODY). We contrast HNF1A-MODY / HNF4A-MODY which causes an age-related progressive diabetes and GCK-MODY, which causes life-long mild hyperglycaemia. METHODS: We analysed clinical and genetic sequencing data from four different cohorts: 1742 probands referred for clinical MODY testing; 2194 family members of the MODY probands; 132,194 individuals from an American hospital-based cohort; and 198,748 individuals from a UK population-based cohort. RESULTS: Age-related penetrance of diabetes for pathogenic variants in HNF1A and HNF4A was substantially lower in the clinically unselected cohorts compared to clinically referred probands (ranging from 32% to 98% at age 40yrs for HNF1A, and 21% to 99% for HNF4A). The background rate of diabetes, but not clinical features or variant type, explained the reduced penetrance in the unselected cohorts. In contrast, penetrance of mild hyperglycaemia for pathogenic GCK variants was similarly high across cohorts (ranging from 89 to 97%) despite substantial variation in the background rates of diabetes. CONCLUSIONS: Ascertainment context is crucial when interpreting the consequences of monogenic variants for age-related variably penetrant disorders. This finding has important implications for opportunistic screening during genomic testing.

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“…Indeed, the same variant in a MODY gene can give rise to a spectrum of clinical phenotypes and exhibit variable penetrance depending on genomic (regulatory variants in cis or trans , or haplotype epistasis) and environmental (epigenomic) context which are difficult to capture in functional assessments. 29 , 30 , 31 , 32 , 33 It is also entirely possible that some of the noise in functional-clinical mapping is a reflection of the heterogeneity in the clinical phenotypic manifestation of HNF1A variants. 5 The same variant which has a mild effect on HNF1A function, and thus beta-cell function and ability to respond appropriately to a given level of glycemia, could play out differently in individuals who are already struggling to meet the insulin demand through insulin resistance and/or other genetically driven defects in their beta-cells.…”

Section: Discussionmentioning

confidence: 99%

Unsupervised Clustering of Missense Variants in HNF1A Using Multidimensional Functional Data Aids Clinical Interpretation

Althari

Najmi

Bennett

et al. 2020

The American Journal of Human Genetics

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Summary Exome sequencing in diabetes presents a diagnostic challenge because depending on frequency, functional impact, and genomic and environmental contexts, HNF1A variants can cause maturity-onset diabetes of the young (MODY), increase type 2 diabetes risk, or be benign. A correct diagnosis matters as it informs on treatment, progression, and family risk. We describe a multi-dimensional functional dataset of 73 HNF1A missense variants identified in exomes of 12,940 individuals. Our aim was to develop an analytical framework for stratifying variants along the HNF1A phenotypic continuum to facilitate diagnostic interpretation. HNF1A variant function was determined by four different molecular assays. Structure of the multi-dimensional dataset was explored using principal component analysis, k-means, and hierarchical clustering. Weights for tissue-specific isoform expression and functional domain were integrated. Functionally annotated variant subgroups were used to re-evaluate genetic diagnoses in national MODY diagnostic registries. HNF1A variants demonstrated a range of behaviors across the assays. The structure of the multi-parametric data was shaped primarily by transactivation. Using unsupervised learning methods, we obtained high-resolution functional clusters of the variants that separated known causal MODY variants from benign and type 2 diabetes risk variants and led to reclassification of 4% and 9% of HNF1A variants identified in the UK and Norway MODY diagnostic registries, respectively. Our proof-of-principle analyses facilitated informative stratification of HNF1A variants along the continuum, allowing improved evaluation of clinical significance, management, and precision medicine in diabetes clinics. Transcriptional activity appears a superior readout supporting pursuit of transactivation-centric experimental designs for high-throughput functional screens.

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The Common HNF1A Variant I27L Is a Modifier of Age at Diabetes Diagnosis in Individuals With HNF1A-MODY

Cited by 16 publications

References 23 publications

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

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

The penetrance of age-related monogenic disease depends on ascertainment context

Unsupervised Clustering of Missense Variants in HNF1A Using Multidimensional Functional Data Aids Clinical Interpretation

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