**The CommonHNF1AVariant 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 A.
Wood, Andrew R.
Sharp, Seth A.
Ellard, Sian
Bellanné-Chantelot, Christine
Hattersley, Andrew T.
Harries, Lorna W.
Weedon, Michael N.

¹Institute of Biomedical and Clinical Science, University of Exeter Medical School, University of Exeter, Exeter, U.K.
²Department of Genetics, Pitié-Salpétrière Hospital, Assistance Publique-Hôpitaux de Paris, and Pierre et Marie Curie University, Paris, France

Corresponding author: Jonathan M. Locke, e-mail; [email protected].

L.W.H. and M.N.W. contributed equally to this work.

Received January 29, 2018; Accepted June 05, 2018; previously published online June 12, 2018

Diabetes 67(9):p 1903-1907, September 2018. | DOI: 10.2337/db18-0133

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 theHNF1Agene. We hypothesized that common variants at theHNF1Alocus (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 withinHNF1Aupon diabetes phenotype.