Evidence of a novel gene locus ARHGAP44 for longitudinal change in hemoglobin A1c levels among subjects without diabetes from the Long Life Family Study

Glycated hemoglobin A1c (HbA1c) indicates average glucose levels over 3 mo and is associated with insulin resistance and type 2 diabetes (T2D). Longitudinal change in circulating HbA1c (∆HbA1c) is also associated with aging processes, cognitive performance, and mortality. We analyzed ∆HbA1c in 1,886 nondiabetic Europeans from the Long Life Family Study (LLFS) to uncover gene loci influencing ∆HbA1c. Using growth curve modeling adjusted for multiple covariates, we derived ∆HbA1c and conducted linkage-guided sequence analysis. Our genome-wide linkage scan identified a significant locus on 17p12. In-depth analysis revealed a gene locus ARHGAP44 (rs56340929, explaining 27% of the linkage peak) that was significantly associated with ∆HbA1c. Interestingly, RNA transcription of ARHGAP44 was also significantly associated with ∆HbA1c in the LLFS, and this discovery was replicable on the gene locus level in the Framingham Offspring Study (FOS). Taking together, we successfully identified a novel gene locus ARHGAP44 for ∆HbA1c in family members without T2D. Further follow-up studies using longitudinal omics data in large independent cohorts are warranted. NEW & NOTEWORTHY HbA1c is clinically used in T2D diagnosis and monitoring. Its longitudinal change (∆HbA1c) is associated with T2D-related aging processes and mortality. Targeted association tests under significant linkage peaks in extended families permit identification of unique gene loci. We uncovered a novel gene locus ARHGAP44 for ∆HbA1c with gene-level validations from the FOS and RNAseq data in the LLFS. The finding provides genetically informed biological insight into mechanistic inference of glycemia/HbA1c homeostasis and potential T2D pathophysiology.