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

Abstract

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.

Epithelial Sodium Transport and Its Control by Aldosterone: The Story of Our Internal Environment Revisited

“…GWAS have identified loci in or near genes that generally were not expected to be associated with blood pressure or essential hypertension (84). A summary of the main loci identified as of 2012 can be found in Yang et al (348) who compared the first genome-wide gene-based association scan for hypertension in a Han Chinese population with that previously conducted in other populations worldwide (2, 50, 103, 175, 176, 192-194, 234, 244, 338) (see TABLE 1 of Ref. 348).…”

“…Common variant with small effect implicated in hypertension by GWAsAdrenal CYP17 Liver AGTFor an updated list see referenceYang et al 2012 …”

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].…”

Genetic and Functional Evidence Supports LPAR1 as a Susceptibility Gene for Hypertension

“…It was probably because the results of GWAS can be affected by several factors, such as population size, stratification, conservative statistic cutoff, and chip density. Unfortunately, the genotyped individuals in original GWAS of Chinese hypertensive populations 38,39 were relatively small, which may not be sufficient to discover the association of LPAR1 with hypertension when P value cutoff was set as GWAS significance (<10 -7 ). Although some meta-analysis 35,40,41 in East Asian increased sample size by combining various experiments, it can be strongly disturbed by the experimental similarity and validity.…”

“…[32][33][34][35][36][37][38][39][40][41] However, LPAR1 has not been reported by these GWAS. It was probably because the results of GWAS can be affected by several factors, such as population size, stratification, conservative statistic cutoff, and chip density.…”