Novel gene variants associated with hba1c changes over time among nondiabetic subjects in the long life family study

Abstract Longitudinal changes in HbA1c (ΔHbA1c) are associated with insulin resistance, aging, cognition, and mortality. To identify novel gene variants underlying ΔHbA1c, we conducted linkage-guided sequence analysis on 17p12 (LODs=3.59) in the Long Life Family Study, a study with familial clustering of exceptional longevity in the US and Denmark. Subjects with clinical diagnosis of diabetes or diabetes treatment and undiagnosed diabetes cases whose fasting glucose ≥ 126 mg/dl or HbA1c ≥ 6.5% were excluded. ΔHbA1c, collected from two exams 7 years apart, was derived using growth curve modeling, adjusting for age, sex, BMI, smoking, field centers and PCs, and was blom-transformed to approximate normality. We identified a significant variant under the linkage peak (ARHGAP44 rs56340929, p=1.77E-06, MAF=6%, accounting for linkage=26.5%). Taking advantage of our currently available RNAseq data, we found a significant association between quantification of ARHGAP44 RNA transcript and adjusted ΔHbA1c using 16 linkage enriched families (n=176, β = -0.24, SE=0.09, p=0.01). We also assessed currently available lipidomics data (188 metabolites, 13 compound classes) and found phosphatidylcholine (p=0.025) and lysophosphatidylcholine (p=0.02) were marginally associated with adjusted ΔHbA1c. ARHGAP44 is reportedly associated with glycemic traits and is mainly expressed in the brain. Further complete omics-data analyses in the LLFS and a replication study using the Framingham Offspring Study are underway.