1. The Common Variant I27L Is a Modifier of Age at Diabetes Diagnosis in Individuals With HNF1A-MODY.
- Author
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Locke, Jonathan M., Saint-Martin, Cécile, Laver, Thomas W., Patel, Kashyap A., Wood, Andrew R., Sharp, Seth A., Ellard, Sian, Bellanné-Chantelot, Christine, Hattersley, Andrew T., Harries, Lorna W., and Weedon, Michael N.
- Subjects
METABOLIC disorders ,CARBOHYDRATE intolerance ,ENDOCRINE diseases ,NUTRITION disorders ,OBESITY ,GLUCOSE metabolism disorders ,TYPE 2 diabetes ,PROTEIN metabolism ,AGE factors in disease ,ALLELES ,AMINO acids ,DATABASES ,DISEASE susceptibility ,GENES ,GENETIC polymorphisms ,GENETIC techniques ,LONGITUDINAL method ,META-analysis ,GENETIC mutation ,PROTEINS ,RESEARCH evaluation ,SEQUENCE analysis - Abstract
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. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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