A Novel Gene ARHGAP44 for Longitudinal Changes in Glycated Hemoglobin (HbA1c) in Subjects without Type 2 Diabetes: Evidence from the Long Life Family Study (LLFS) and the Framingham Offspring Study (FOS)
Wang, S.; Lenzini, P.; Thygarajan, B.; Lee, J. H.; Vardarajan, B. N.; Yashin, A.; Miljkovic, I.; Daw, E. W.; Lin, S. J.; Patti, G.; Brent, M.; Zmuda, J. M.; Perls, T. T.; Christensen, K.; Province, M. A.; An, P.
Show abstract
Glycated hemoglobin (HbA1c) indicates average glucose levels over three months and is associated with insulin resistance and type 2 diabetes (T2D). Longitudinal changes in HbA1c ({Delta}HbA1c) are also associated with aging processes, cognitive performance, and mortality. We analyzed {Delta}HbA1c in 1,886 non-diabetic Europeans from the Long Life Family Study to uncover gene variants influencing {Delta}HbA1c. Using growth curve modeling adjusted for multiple covariates, we derived {Delta}HbA1c and conducted linkage-guided sequence analysis. Our genome-wide linkage scan identified a significant locus on 17p12. In-depth analysis of this locus revealed a variant rs56340929 (explaining 27% of the linkage peak) in the ARHGAP44 gene that was significantly associated with {Delta}HbA1c. RNA transcription of ARHGAP44 was associated with {Delta}HbA1c. The Framingham Offspring Study data further supported these findings on the gene level. Together, we found a novel gene ARHGAP44 for {Delta}HbA1c in family members without T2D. Follow-up studies using longitudinal omics data in large independent cohorts are warranted.
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