title: 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.
authors.affiliation: Institute of Statistical Science, Academia Sinica, Taipei, Taiwan.
authors.forename: Hsin-Chou
authors.initials: HC
authors.lastname: Yang
authors.forename: Yu-Jen
authors.initials: YJ
authors.lastname: Liang
authors.forename: Jaw-Wen
authors.initials: JW
authors.lastname: Chen
authors.forename: Kuang-Mao
authors.initials: KM
authors.lastname: Chiang
authors.forename: Chia-Min
authors.initials: CM
authors.lastname: Chung
authors.forename: Hung-Yun
authors.initials: HY
authors.lastname: Ho
authors.forename: Chih-Tai
authors.initials: CT
authors.lastname: Ting
authors.forename: Tsung-Hsien
authors.initials: TH
authors.lastname: Lin
authors.forename: Sheng-Hsiung
authors.initials: SH
authors.lastname: Sheu
authors.forename: Wei-Chuan
authors.initials: WC
authors.lastname: Tsai
authors.forename: Jyh-Hong
authors.initials: JH
authors.lastname: Chen
authors.forename: Hsin-Bang
authors.initials: HB
authors.lastname: Leu
authors.forename: Wei-Hsian
authors.initials: WH
authors.lastname: Yin
authors.forename: Ting-Yu
authors.initials: TY
authors.lastname: Chiu
authors.forename: Ching-luan
authors.initials: CL
authors.lastname: Chern
authors.forename: Shing-Jong
authors.initials: SJ
authors.lastname: Lin
authors.forename: Brian
authors.initials: B
authors.lastname: Tomlinson
authors.forename: Youling
authors.initials: Y
authors.lastname: Guo
authors.forename: Pak C
authors.initials: PC
authors.lastname: Sham
authors.forename: Stacey S
authors.initials: SS
authors.lastname: Cherny
authors.forename: Tai Hing
authors.initials: TH
authors.lastname: Lam
authors.forename: G Neil
authors.initials: GN
authors.lastname: Thomas
authors.forename: Wen-Harn
authors.initials: WH
authors.lastname: Pan
mesh_terms: D044466:Asian People / Q000235:genetics; D016022:Case-Control Studies; D002681:China; D020869:Gene Expression Profiling; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods; D005838:Genotype; D006801:Humans; D006973:Hypertension / Q000208:ethnology / Q000235:genetics*; D007334:Insulin-Like Growth Factor I / Q000235:genetics*; D016015:Logistic Models; D020411:Oligonucleotide Array Sequence Analysis; D010088:Oxidoreductases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012097:Repressor Proteins / Q000235:genetics*; D027982:Sodium-Bicarbonate Symporters / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D000074584:WW Domain-Containing Oxidoreductase
chemical_list: D012097:Repressor Proteins; C523369:SFMBT1 protein, human; C498898:SLC4A4 protein, human; D027982:Sodium-Bicarbonate Symporters; D025521:Tumor Suppressor Proteins; D007334:Insulin-Like Growth Factor I; D010088:Oxidoreductases; D000074584:WW Domain-Containing Oxidoreductase; C486071:WWOX protein, human