Evidence of a novel gene locus <i>ARHGAP44</i> 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 (ΔHbA1c) is also associated with aging processes, cognitive performance, and mortality. We analyzed ΔHbA1c in 1,886 nondiabetic Europeans from the Long Life Family Study (LLFS) to uncover gene loci influencing ΔHbA1c. Using growth curve modeling adjusted for multiple covariates, we derived ΔHbA1c and conducted linkage-guided sequence analysis. Our genome-wide linkage scan identified a significant locus on <i>17p12</i>. In-depth analysis revealed a gene locus <i>ARHGAP44</i> (rs56340929, explaining 27% of the linkage peak) that was significantly associated with ΔHbA1c. Interestingly, RNA transcription of <i>ARHGAP44</i> was also significantly associated with ΔHbA1c 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 <i>ARHGAP44</i> for ΔHbA1c in family members without T2D. Further follow-up studies using longitudinal omics data in large independent cohorts are warranted.<b>NEW & NOTEWORTHY</b> HbA1c is clinically used in T2D diagnosis and monitoring. Its longitudinal change (ΔHbA1c) 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 <i>ARHGAP44</i> for ΔHbA1c 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.