A regulatory SNP in AKAP13 is associated with blood pressure in Koreans

Abstract

High blood pressure contributes to more than 10 million deaths per year worldwide through stroke and ischemic heart disease. Yet, genome-wide association studies (GWASs) have identified a small fraction of its underlying genetic factors. To identify biologically important single-nucleotide polymorphisms (SNPs) that regulate variations in blood pressure, we analyzed SNPs in a genome-wide association study. Genome-wide genotype data (original study n¼7551, SNP¼352 228; replication study n¼3703, SNP¼20) were obtained from the Korea National Institute of Health, wherein 29 921 of 352 228 SNPs lay within 5 kbp upstream of genes. Linear regression analysis was performed for systolic and diastolic blood pressure (DBP) by controlling for cohort, age, sex and body mass index. For the 20 SNPs that were associated with both blood pressure values, a replication study was performed in an independent population. A total of 20 SNPs were significantly associated with both blood pressure values in the original study, 13 of which lay in a conserved transcription factor-binding site. One SNP (rs11638762), in the GATA-3 binding site upstream of the AKAP13 gene, was significantly replicated in another cohort (P-value of the meta-analysis ¼1.4Â10 À5 for systolic blood pressure and 6.3Â10 À4 for DBP). A functional GWAS was performed using upstream SNPs, and a novel genetic factor (AKAP13), which is essential for cardiac myocyte development in mice, was identified as a regulator of blood pressure.

The C-terminus of the long AKAP13 isoform (AKAP-Lbc) is critical for development of compensatory cardiac hypertrophy

“…Recent data from a Genome-Wide Association Study (GWAS) in a Korean population has linked high blood pressure with a single nucleotide polymorphism (SNP) in the GATA-3 transcription factor binding promoter region of the AKAP13 gene [40]. Therefore, we wondered if blood pressure was affected in the AKAP-Lbc-ΔPKD mice compared to WT control littermates and whether this might affect the development of cardiac hypertrophy and heart failure in the AKAP-Lbc-ΔPKD mice.…”

Identification of IGF1, SLC4A4, WWOX, and SFMBT1 as Hypertension Susceptibility Genes in Han Chinese with a Genome-Wide Gene-Based Association Study

“…There were also 70 cis-eQTL on 11 genes ( TMEM56 , KIAA1797 , LARS , GRB14 , IGF1 , WWOX , HLCS , CSF1 , CSNK1G3 , TTC12 and SYNE2 ) associated with YOH in our TWNHS study (p<5×10 −2 ), where the disease associated alleles of 40 cis-eQTL increased genetic risk of YOH as well as up-regulated gene expression ( Table S4 ). In addition to the 17 genes in Table 2 , we also examined cis-eQTL of the hypertension-associated genes identified by previous hypertension genomic studies [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34] in Table 1 where GRB14 and WWOX were excluded here because they were also identified by the present study and their cis-eQTL were already examined. Cis-eQTL of 54 genes were studied, although 6 of these genes ( CYP17A2 , HLA-B , KIAA0789 , LOC344371 , MYADML and ULK4 ) did not have cis-eQTL in Genevar database [37].…”

“…Methods to map the genes of complex diseases have evolved from linkage approaches for rare Mendelian traits to genome-wide association studies (GWAS). Several GWAS have been conducted for blood pressure or hypertension in recent years [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34]. Blood pressure and hypertension susceptibility genes identified using GWAS are summarized ( Table 1 ).…”

Genome-Wide Association Studies (Gwas) of Blood Pressure in Different Populations

“…Among other GWAS findings in Asian populations include AKAP13 gene association in a Korean population [40]; IGF1, SLC4A4, WWOX; SFMBT1 gene associations a Han-Chinese population [41]; and FSTL4 in another population of Chinese ancestry [42]. Among the GWAS in which no SNP reached GWS ( P < 5 × 10 −7) were studies on genetically isolated founder population of the Pacific island of Kosrae [43], Indian-Asian men [44], and Japanese subjects [45].…”