Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Haplotype-based, case–control study of the receptor (calcitonin) activity-modifying protein (RAMP) 1 gene in essential hypertension

Journal of Human Hypertension volume 31, pages 361–365 (2017)Cite this article

Subjects

Abstract

The adrenomedullin receptor is a complex molecule that comprises the calcitonin-receptor-like receptor (CRLR) and the receptor-activity-modifying protein (RAMP). RAMP1 is a vasodilation factor, and RAMP1-deficient mice (RAMP1(−/−)) exhibit inflammatory responses with a significant transient increase in serum calcitonin-gene-related peptide levels and proinflammatory cytokines when compared with RAMP1(+/+) mice. The purpose of the present study was to investigate the relationships between essential hypertension (EH) and RAMP1 gene single-nucleotide polymorphisms (SNPs) or haplotypes in a Japanese population via a case–control study. Based on a database search of the National Center of Biotechnology Information website and the HapMap project, we chose six RAMP1 gene SNPs and performed an association study involving 263 patients with EH and 267 age-matched normotensive (NT) subjects. There was no significant difference between the EH and NT groups with regard to overall distribution of genotypes or SNP alleles. However, the haplotype-based case–control analysis revealed that there was a significant difference between the EH and NT groups with regard to overall distribution of the allele combinations at three SNPs—rs3754701–rs3769048–rs10199956—(P=0.002). The T-A-T haplotype was significantly more common in the EH group (10.3%) than in the NT control group (6.1%) (P=0.047). These results suggested that this T-A-T RAMP1 gene haplotype might have utility as a genetic marker for EH and that the RAMP1 gene or a neighbouring gene may be associated with increased susceptibility to EH.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Similar content being viewed by others

References

  1. Steiner S, Muff R, Gujer R, Fischer JA, Born W . The transmembrane domain of receptor-activity-modifying protein 1 is essential for the functional expression of a calcitonin gene-related peptide receptor. Biochemistry 2002; 41: 11398–11404.

    Article  CAS  Google Scholar 

  2. Watkins HA, Walker CS, Ly KN, Bailey RJ, Barwell J, Poyner DR et al. Receptor activity-modifying protein-dependent effects of mutations in the calcitonin receptor-like receptor: implications for adrenomedullin and calcitonin gene-related peptide pharmacology. Br J Pharmacol 2014; 171: 772–788.

    Article  CAS  Google Scholar 

  3. Hay DL, Walker CS, Gingell JJ, Ladds G, Reynolds CA, Poyner DR . Receptor activity-modifying proteins; multifunctional G protein-coupled receptor accessory proteins. Biochem Soc Trans 2016; 44: 568–573.

    Article  CAS  Google Scholar 

  4. Edvinsson L, Ahnstedt H, Larsen R, Sheykhzade M . Differential localization and characterization of functional calcitonin gene-related peptide receptors in human subcutaneous arteries. Acta Physiol (Oxf) 2014; 210: 811–822.

    Article  CAS  Google Scholar 

  5. Duboz P, Boëtsch G, Gueye L, Macia E . Hypertension prevalence, awareness, treatment and control in Dakar (Senegal). J Hum Hypertens 2014; 28: 489–493.

    Article  CAS  Google Scholar 

  6. Booth HP, Prevost AT, Gulliford MC . Severity of obesity and management of hypertension, hypercholesterolaemia and smoking in primary care: population-based cohort study. J Hum Hypertens 2016; 30: 40–45.

    Article  CAS  Google Scholar 

  7. Wang Z, Nakayama T, Sato N, Izumi Y, Kasamaki Y, Ohta M et al. The purinergic receptor P2Y, G-protein coupled, 2 (P2RY2) gene associated with essential hypertension in Japanese men. J Hum Hypertens 2010; 24: 327–335.

    Article  Google Scholar 

  8. Pan S, Nakayama T, Sato N, Izumi Y, Soma M, Aoi N et al. A haplotype of the GOSR2 gene is associated with myocardial infarction in Japanese men. Genet Test Mol Biomarkers 2013; 17: 481–488.

    Article  CAS  Google Scholar 

  9. Nakayama T, Soma M, Rahmutula D, Ozawa Y, Kanmatsuse K . Isolation of the 5'- flanking region of genes by thermal asymmetric interlaced polymerase chain reaction. Med Sci Monit 2001; 7: 345–349.

    CAS  Google Scholar 

  10. Sano M, Kuroi N, Nakayama T, Sato N, Izumi Y, Soma M et al. The association study of calcitonin-receptor-like receptor gene in essential hypertension. Am J Hypertens 2005; 18: 403–408.

    Article  CAS  Google Scholar 

  11. Maximum likelihood from incomplete data via the EM algorithm. J R Stat Soc; Series B (Methodological) 1977; 39: 1–38.

  12. Excoffier L, Slatkin M . Maximum-kikekihood estimation of molecular haplotype frequencies in a diploid population. Mol Biol Evol 1995; 12: 921–927.

    CAS  Google Scholar 

  13. Shimodaira M, Nakayama T, Sato I, Sato N, Izawa N, Mizutani Y et al. Glucocorticoid synthesis related-genes: HSD11B1 and HSD11B2 in hypertensive disorders in pregnancy. Gynecol Endocrinol 2013; 29: 657–661.

    Article  CAS  Google Scholar 

  14. Nakazato T, Nakayama T, Naganuma T, Sato N, Fu Z, Wang Z et al. Haplotype-based case-control study of receptor (calcitonin) activity modifying protein-1 gene in cerebral infarction. J Hum Hypertens 2010; 24: 351–358.

    Article  CAS  Google Scholar 

  15. Wan D, Hou L, Zhang X, Han X, Chen M, Tang W et al. DNA methylation of RAMP1 gene in migraine: an exploratory analysis. J Headache Pain 2015; 16: 90.

    Article  Google Scholar 

  16. Cargnin S, Pautasso C, Viana M, Sances G, Mittino D, Cantello R et al. Association of RAMP1 rs7590387 with the risk of migraine transformation into medication overuse headache. Headache 2015; 55: 658–668.

    Article  Google Scholar 

  17. Morris RW, Kaplan NL . On the advantage of haplotype analysis in the presence of multiple disease susceptibility alleles. Genet Epidemiol 2002; 23: 221–233.

    Article  Google Scholar 

  18. Sato N, Nakayama T, Mizutani Y, Yuzawa M . Novel mutations of ABCC6 gene in Japanese patients with angioid streaks. Biochem Biophy Res Commun 2009; 380: 548–553.

    Article  CAS  Google Scholar 

  19. Naganuma T, Nakayama T, Sato N, Fu Z, Soma M, Yamaguchi M et al. Haplotype-based case-control study on human apurinic/apyrimidinic endonuclease 1/redox effector factor-1 gene and essential hypertension. Am J Hypertens 2010; 23: 186–191.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Ms K Sugama for her technical assistance. This work was supported by grants from Toray Co, Ltd, and from the Ministry of Education, Culture, Sports, Science and Technology of Japan (16K089780002). This work was also supported by a grant from the Health Sciences Research Institute, Inc, Yokohama, Japan to the Division of Companion Diagnostics, Department of Pathology of Microbiology, Nihon University School of Medicine, Tokyo, Japan.

Author information

Authors and Affiliations

  1. Division of Laboratory Medicine, Department of Pathology and Microbiology, Nihon University School of Medicine, Tokyo, Japan

    T Nakayama, T Nakazato, H Naruse, T Hoshino & M Shimodaira

  2. Division of Companion Diagnostics, Department of Pathology of Microbiology, Nihon University School of Medicine, Tokyo, Japan

    T Nakayama

  3. Fujioka Surgeon Clinic, Gunma, Japan

    T Nakazato

  4. Health Sciences Research Institute, Yokohama, Japan

    H Naruse

  5. Division of Molecular Diagnostics, Department of Advanced Medical Science, Nihon University School of Medicine, Tokyo, Japan

    Z Fu, Z Wang & M Shimodaira

  6. Divisions of General Medicine, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan

    M Soma

  7. Division of Genomic Epidemiology and Clinical Trials, Department of Advanced Medical Science, Nihon University School of Medicine, Tokyo, Japan

    N Aoi

Authors
  1. T Nakayama
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. T Nakazato
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. H Naruse
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Z Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Z Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M Soma
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. T Hoshino
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. M Shimodaira
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. N Aoi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to T Nakayama.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nakayama, T., Nakazato, T., Naruse, H. et al. Haplotype-based, case–control study of the receptor (calcitonin) activity-modifying protein (RAMP) 1 gene in essential hypertension. J Hum Hypertens 31, 361–365 (2017). https://doi.org/10.1038/jhh.2016.96

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/jhh.2016.96

Search

Advanced search

Quick links