Abstract P263: Resequencing Study Identifies Renin-Angiotensin-Aldosterone System Genes and Novel Low Frequency Variants Associated with Blood Pressure Salt-sensitivity
Authors: Anderson Christopher E , Li Changwei , He Jiang , Rao Dabeeru C , Hixson James E , Gu Dongfeng , Shimmin Lawrence C , Huang Jianfeng , Rice Treva K , Chen Jichun , Li Jianxin , Kelly Tanika N 
Published: March 2022

Christopher E. Anderson, Changwei Li, Jiang He, Dabeeru C. Rao, James E. Hixson, Dongfeng Gu, Lawrence C. Shimmin, Jianfeng Huang, Treva K. Rice, Jichun Chen, Jianxin Li, Tanika N. Kelly

Genetic association studies have identified significant associations between common variants from the renin-angiotensin-aldosterone system (RAAS) genes and blood pressure responses to dietary sodium interventions. The role of low-frequency and rare RAAS variants in salt-sensitivity remains largely unexplored. We hypothesized that low-frequency and rare RAAS variants are associated with BP salt-sensitivity. To test this hypothesis, we conducted a RAAS candidate gene resequencing study among participants in the Genetic Epidemiology Network of Salt-Sensitivity (GenSalt) study. The GenSalt study was conducted among 1,906 participants from 633 families who underwent a 7-day low-sodium (51.3 mmol sodium/day) followed by a 7-day high-sodium (307.8 mmol sodium/day) feeding-study. We chose the 300 GenSalt subjects with the highest and 300 GenSalt subjects with the lowest mean arterial pressure responses to the high sodium intervention to participate in the current resequencing study. Functional regions of seven RAAS genes (ACE2, APLN, AGTR1, HSD11B1, HSD11B2, NR3C2 and RENBP) were resequenced using the VariantSEQr
TM
system (Applied Biosystems; Foster City, CA). For gene-based analyses, variants with MAF less than 5% were first collapsed within each RAAS gene. The collapsed indicator variable was then tested for association with BP salt-sensitivity using generalized estimating equations (GEE) to accommodate correlation of genotypes due to family structure. Single variant analyses were performed for all low-frequency variants with a minor allele frequency (MAF) greater than 1% and less than 5%, again using GEE to accommodate

family structure. In gene-based, we identified significant associations between rare and low-frequency variants in
APLN
and
AGTR1
, and a borderline significant association of
HSD11B2
with BP salt-sensitivity, with respective p-values of 0.03, 0.05 and 0.06. Eight percent of GenSalt participants with high salt-sensitivity carried at least one of the rare or low-frequency
APLN
variants, while 4% of salt-resistant participants were carriers. Seventeen percent of participants with high salt-sensitivity were carriers of rare or low-frequency
AGTR1
variants compared to 11% of salt-resistant subjects. Eight percent of those with high salt-sensitivity were carriers of a rare or low-frequency
HSD11B2
variant, compared to 4% of salt-resistant subjects. In single variant analyses, only one low-frequency variant,
AGTR1
variant rs75367686, was marginally associated with the BP salt-sensitivity phenotype, with a p-value of 0.06. In aggregate, these findings provide promising evidence for a role of low-frequency and rare RAAS variants in BP salt-sensitivity.