The Common HNF1A Variant I27L Is a Modifier of Age at Diabetes Diagnosis in Individuals With HNF1A-MODY
Copyright policy )The Common HNF1A Variant I27L Is a Modifier of Age at Diabetes Diagnosis in Individuals With HNF1A-MODY
There is wide variation in the age at diagnosis of diabetes in individuals with maturity-onset diabetes of the young (MODY) due to a mutation in the HNF1A gene. We hypothesized that common variants at the HNF1A locus (rs1169288 [I27L], rs1800574 [A98V]), which are associated with type 2 diabetes susceptibility, may modify age at diabetes diagnosis in individuals with HNF1A-MODY. Meta-analysis of two independent cohorts, comprising 781 individuals with HNF1A-MODY, found no significant associations between genotype and age at diagnosis. However after stratifying according to type of mutation (protein-truncating variant [PTV] or missense), we found each 27L allele to be associated with a 1.6-year decrease (95% CI −2.6, −0.7) in age at diagnosis, specifically in the subset (n = 444) of individuals with a PTV. The effect size was similar and significant across the two independent cohorts of individuals with HNF1A-MODY. We report a robust genetic modifier of HNF1A-MODY age at diagnosis that further illustrates the strong effect of genetic variation within HNF1A upon diabetes phenotype.
- Assistance Publique -Hopitaux De Paris France
- Pitié-Salpêtrière Hospital France
- Sorbonne University France
- University of Exeter United Kingdom
- Sorbonne Paris Cité France
Male, Paris, DNA Mutational Analysis, Mutation, Missense, Reproducibility of Results, Polymorphism, Single Nucleotide, Cohort Studies, Amino Acid Substitution, Diabetes Mellitus, Type 2, England, Gene Frequency, Databases, Genetic, Humans, Female, Genetic Predisposition to Disease, Hepatocyte Nuclear Factor 1-alpha, Age of Onset, Alleles, Genetic Association Studies, Genome-Wide Association Study
Male, Paris, DNA Mutational Analysis, Mutation, Missense, Reproducibility of Results, Polymorphism, Single Nucleotide, Cohort Studies, Amino Acid Substitution, Diabetes Mellitus, Type 2, England, Gene Frequency, Databases, Genetic, Humans, Female, Genetic Predisposition to Disease, Hepatocyte Nuclear Factor 1-alpha, Age of Onset, Alleles, Genetic Association Studies, Genome-Wide Association Study
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