Genetics of Circulating HbA1c Long-Term Change over Time in Nondiabetic Subjects—The Long Life Family Study

HbA1c is a stable index of chronic glycemic status and hyperglycemia associated with progressive development of insulin resistance and frank T2D. Trajectories of repeated HbA1c measurements over years are also associated with aging, cognitive performance and mortality. To identify genomic regions and loci for long term change in HbA1c, we conducted genome-wide linkage (GWLS) and association (GWAS) studies in the Long Life Family Study (LLFS), a study with familial clustering of exceptional longevity in the U.S. and Denmark. We performed GWLS/GWAS in 1902 non-T2D participants of European ancestry who had complete data from two exams collected 7 years apart. HbA1c change over time was derived using growth curve modeling, and was adjusted for age, sex, BMI, smoking, centers and PCs, and blom-transformed to approximate normality. SNPs imputed using the HRC all-Caucasian reference panel were analyzed. LOKI/SOLAR were used for GWLS. EPACTS with make-kin and emmax options for familial clustering assuming additive genetic effects were used for GWAS. Lods > 3 for GWLS and p < 5e-8 for GWAS were used to declare significance. Heritability for HbA1c change over time reached 38% (p = 8e-10). GWLS yielded a significant region on 17p12 (Lods 3.5, 13 Mb). Two previous reports highlighted this region for fasting glucose and metabolic syndrome. From the GWAS, one SNP on 10q22.1 was significant (HK1-rs16926246, p = 4e-8, MAF = 0.14, β = -0.26). HK1 encodes hexokinase 1, which phosphorylates glucose to produce G6P, the first step in glycolysis. HK1-rs16926246 is a SNP previously associated with baseline HbA1c, erythrocyte traits, hematocrit and hemoglobin. Together, we identified 17p12 and HK1-rs16926246 as candidate loci for longitudinal change in HbA1c among non-T2D subjects in the LLFS. This analysis yields new information about the genetic regulation of HbA1c among nondiabetic individuals selected for exceptional survival and healthy aging. Replication in the external datasets is underway.