Identification of igf1, slc4a4, wwox, and sfmbt1 as hypertension susceptibility genes in han chinese with a genome-wide gene-based association study

Hsin Chou Yang, Yu Jen Liang, Jaw Wen Chen, Kuang Mao Chiang, Chia Min Chung, Hung Yun Ho, Chih Tai Ting, Tsung Hsien Lin, Sheng Hsiung Sheu, Wei Chuan Tsai, Jyh Hong Chen, Hsin Bang Leu, Wei Hsian Yin, Ting Yu Chiu, Ching Iuan Chern, Shing Jong Lin, Brian Tomlinson, Youling Guo, Pak C. Sham, Stacey S. ChernyTai Hing Lam, G. Neil Thomas, Wen Harn Pan

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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.

Original languageEnglish
Article numbere32907
JournalPloS one
Volume7
Issue number3
DOIs
Publication statusPublished - 2012 Mar 29

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Yang, H. C., Liang, Y. J., Chen, J. W., Chiang, K. M., Chung, C. M., Ho, H. Y., Ting, C. T., Lin, T. H., Sheu, S. H., Tsai, W. C., Chen, J. H., Leu, H. B., Yin, W. H., Chiu, T. Y., Chern, C. I., Lin, S. J., Tomlinson, B., Guo, Y., Sham, P. C., ... Pan, W. H. (2012). Identification of igf1, slc4a4, wwox, and sfmbt1 as hypertension susceptibility genes in han chinese with a genome-wide gene-based association study. PloS one, 7(3), [e32907]. https://doi.org/10.1371/journal.pone.0032907