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

Hypertension is a complex disorder with high prevalence rates all over the world. We conducted the first genome-wide gene-based association scan for hypertension in a Han Chinese population. By analyzing genome-wide single-nucleotide-polymorphism data of 400 matched pairs of young-onset hypertensive patients and normotensive controls genotyped with the Illumina HumanHap550-Duo BeadChip, 100 susceptibility genes for hypertension were identified and also validated with permutation tests. Seventeen of the 100 genes exhibited differential allelic and expression distributions between patient and control groups. These genes provided a good molecular signature for classifying hypertensive patients and normotensive controls. Among the 17 genes, IGF1, SLC4A4, WWOX, and SFMBT1 were not only identified by our gene-based association scan and gene expression analysis but were also replicated by a gene-based association analysis of the Hong Kong Hypertension Study. Moreover, cis-acting expression quantitative trait loci associated with the differentially expressed genes were found and linked to hypertension. IGF1, which encodes insulin-like growth factor 1, is associated with cardiovascular disorders, metabolic syndrome, decreased body weight/size, and changes of insulin levels in mice. SLC4A4, which encodes the electrogenic sodium bicarbonate cotransporter 1, is associated with decreased body weight/size and abnormal ion homeostasis in mice. WWOX, which encodes the WW domain-containing protein, is related to hypoglycemia and hyperphosphatemia. SFMBT1, which encodes the scm-like with four MBT domains protein 1, is a novel hypertension gene. GRB14, TMEM56 and KIAA1797 exhibited highly significant differential allelic and expressed distributions between hypertensive patients and normotensive controls. GRB14 was also found relevant to blood pressure in a previous genetic association study in East Asian populations. TMEM56 and KIAA1797 may be specific to Taiwanese populations, because they were not validated by the two replication studies. Identification of these genes enriches the collection of hypertension susceptibility genes, thereby shedding light on the etiology of hypertension in Han Chinese populations

Replication analysis of the seventeen genes with differential allelic and transcriptional distributions in cases and controls.

a<p>Test results include p-values of GBAS of the HKHS (Method: sTDT, QFAM_SBP, QFAM_DBP, and QFAM_MBP) and GBAS of the WTCCCHS (Method: LC_N, LC_C, LC_N,Gender, and LC_C,Gender) of the 17 genes characterized by both differential allelic distributions and transcriptional distributions between patient and control groups.</p>b<p>Raw p-values of genes that reached pFDR<5×10⁻² in the GBAS of the HKHS and the WTCCCHS are marked in bold.</p

Seventeen genes with differential allelic and transcriptional distributions identified by the TWNHS.

a<p>Test results include p-values of the gene-based association analysis (CLR_N, CLR_C, CLR_N,BMI, and CLR_C,BMI) and −log₁₀(p) of gene expression [GE] analysis.</p>b<p>Raw p-values of genes that reached pFDR<0.05 in GBAS of the TWNHS and p-values of genes that reached p<0.05 in gene expression studies are marked in bold.</p>c<p>NA denotes that expression data of a gene were not available in the mouse gene expression analysis.</p

A summary table of blood pressure and hypertension susceptibility genes identified by using GWAS.

a<p>Genes (marked in bold) which were also identified to show differential allelic distributions between patient and control groups by our GBAS.</p

Evaluation of the 17 differentially expressed genes in hypertension.

<p>(A) Cluster analysis of transcriptional data from 12 pairs of patients with hypertension (HT) and normotensive controls (NC). (B) Principal component analysis (PCA) of transcriptional data from 12 pairs of patients with hypertension and normotensive controls), where the variation explained by the first two principal components (PC #1 and PC #2) is 39% and 13.1%.</p

An analysis flowchart of this study.

<p>An analysis flowchart of this study.</p