Skip to main content
  • American Heart Association
  • Science Volunteer
  • Warning Signs
  • Advanced Search
  • Donate

  • Home
  • About this Journal
    • General Statistics
    • Editorial Board
    • Editors
    • Information for Advertisers
    • Author Reprints
    • Commercial Reprints
    • Customer Service and Ordering Information
  • All Issues
  • Subjects
    • All Subjects
    • Arrhythmia and Electrophysiology
    • Basic, Translational, and Clinical Research
    • Critical Care and Resuscitation
    • Epidemiology, Lifestyle, and Prevention
    • Genetics
    • Heart Failure and Cardiac Disease
    • Hypertension
    • Imaging and Diagnostic Testing
    • Intervention, Surgery, Transplantation
    • Quality and Outcomes
    • Stroke
    • Vascular Disease
  • Browse Features
    • AHA Guidelines and Statements
    • Acknowledgment of Reviewers
    • Clinical Implications
    • Clinical-Pathological Conferences
    • Controversies in Hypertension
    • Editors' Picks
    • Guidelines Debate
    • Meeting Abstracts
    • Recent Advances in Hypertension
    • SPRINT Trial: the Conversation Continues
  • Resources
    • Instructions to Reviewers
    • Instructions for Authors
    • →Article Types
    • → Submission Guidelines
      • Research Guidelines
        • Minimum Information About Microarray Data Experiments (MIAME)
      • Abstract
      • Acknowledgments
      • Clinical Implications (Only by invitation)
      • Conflict(s) of Interest/Disclosure(s) Statement
      • Figure Legends
      • Figures
      • Novelty and Significance: 1) What Is New, 2) What Is Relevant?
      • References
      • Sources of Funding
      • Tables
      • Text
      • Title Page
      • Online/Data Supplement
    • →Tips for Easier Manuscript Submission
    • → General Instructions for Revised Manuscripts
      • Change of Authorship Form
    • → Costs to Authors
    • → Open Access, Repositories, & Author Rights Q&A
    • Permissions to Reprint Figures and Tables
    • Journal Policies
    • Scientific Councils
    • AHA Journals RSS Feeds
    • International Users
    • AHA Newsroom
  • AHA Journals
    • AHA Journals Home
    • Arteriosclerosis, Thrombosis, and Vascular Biology (ATVB)
    • Circulation
    • → Circ: Arrhythmia and Electrophysiology
    • → Circ: Genomic and Precision Medicine
    • → Circ: Cardiovascular Imaging
    • → Circ: Cardiovascular Interventions
    • → Circ: Cardiovascular Quality & Outcomes
    • → Circ: Heart Failure
    • Circulation Research
    • Hypertension
    • Stroke
    • Journal of the American Heart Association
  • Facebook
  • Twitter

  • My alerts
  • Sign In
  • Join

  • Advanced search

Header Publisher Menu

  • American Heart Association
  • Science Volunteer
  • Warning Signs
  • Advanced Search
  • Donate

Hypertension

  • My alerts
  • Sign In
  • Join

  • Facebook
  • Twitter
  • Home
  • About this Journal
    • General Statistics
    • Editorial Board
    • Editors
    • Information for Advertisers
    • Author Reprints
    • Commercial Reprints
    • Customer Service and Ordering Information
  • All Issues
  • Subjects
    • All Subjects
    • Arrhythmia and Electrophysiology
    • Basic, Translational, and Clinical Research
    • Critical Care and Resuscitation
    • Epidemiology, Lifestyle, and Prevention
    • Genetics
    • Heart Failure and Cardiac Disease
    • Hypertension
    • Imaging and Diagnostic Testing
    • Intervention, Surgery, Transplantation
    • Quality and Outcomes
    • Stroke
    • Vascular Disease
  • Browse Features
    • AHA Guidelines and Statements
    • Acknowledgment of Reviewers
    • Clinical Implications
    • Clinical-Pathological Conferences
    • Controversies in Hypertension
    • Editors' Picks
    • Guidelines Debate
    • Meeting Abstracts
    • Recent Advances in Hypertension
    • SPRINT Trial: the Conversation Continues
  • Resources
    • Instructions to Reviewers
    • Instructions for Authors
    • →Article Types
    • → Submission Guidelines
    • →Tips for Easier Manuscript Submission
    • → General Instructions for Revised Manuscripts
    • → Costs to Authors
    • → Open Access, Repositories, & Author Rights Q&A
    • Permissions to Reprint Figures and Tables
    • Journal Policies
    • Scientific Councils
    • AHA Journals RSS Feeds
    • International Users
    • AHA Newsroom
  • AHA Journals
    • AHA Journals Home
    • Arteriosclerosis, Thrombosis, and Vascular Biology (ATVB)
    • Circulation
    • → Circ: Arrhythmia and Electrophysiology
    • → Circ: Genomic and Precision Medicine
    • → Circ: Cardiovascular Imaging
    • → Circ: Cardiovascular Interventions
    • → Circ: Cardiovascular Quality & Outcomes
    • → Circ: Heart Failure
    • Circulation Research
    • Hypertension
    • Stroke
    • Journal of the American Heart Association
Scientific Contributions

Editorial Commentary: The Sa Gene

What Does It Mean?

John Rapp
Download PDF
https://doi.org/10.1161/01.HYP.32.4.647
Hypertension. 1998;32:647-648
Originally published October 1, 1998
John Rapp
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Info & Metrics
  • eLetters

Jump to

  • Article
    • Footnotes
    • References
  • Info & Metrics
  • eLetters
Loading
  • Editorial
  • hypertension, genetic
  • genes
  • congenic strains
  • rats, inbred SHR

The Sa gene was first described in 1991 by Iwai and Inagami1 in a study to identify genes that were differentially expressed in the kidneys of spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). To find such genes they first prepared a cDNA library from 16-week-old SHR. The clones were grown on plates, and 4 replica filter lifts were prepared from each plate. Two filters were hybridized to 32P-labeled single-strand antisense cDNA fragments from kidneys of 16-week-old SHR, and 2 filters were hybridized with a similar probe prepared from WKY rat kidneys. Clones that gave a different intensity of autoradiographic signal with the SHR and WKY probes were selected for study; one of these was the Sa gene. The designation Sa is apparently arbitrary.

Iwai and Inagami1 confirmed that the Sa gene was differentially expressed in SHR and WKY kidneys by Northern blot analysis, with SHR expressing markedly more than WKY. They also showed that Dahl salt-sensitive (S) rats expressed the Sa gene more than Dahl salt-resistant (R) rats.1

Although the technique of differential hybridization is a standard one, its application to hypertensive rat models was innovative, and the Sa gene has generated a lot of interest. Important subsequent results were that (1) the Sa gene is expressed in the kidney proximal tubule,2 3 (2) the Sa gene is located on rat chromosome 1 and cosegregates with blood pressure (BP) in both the SHR/WKY4 5 6 7 and Dahl rat models,8 9 10 and (3) polymorphisms in the Sa gene and differential expression of the Sa gene cosegregate.7

The linkage of a candidate gene such as the Sa gene to BP certainly does not prove that the candidate is the causative factor. Such linkage is necessary but not sufficient. Linkage analysis for a quantitative trait such as BP in theory11 12 and in practice yields only a very broad segment of chromosome that is likely to include the causative gene (or genes). This region is typically 20 to 40 centimorgans and contains hundreds of genes. To be sure that in fact a BP quantitative trait locus (QTL) exists in the region of interest, the next logical step is the construction of congenic strains.13 14 The congenic strain also provides a vehicle for subsequent fine genetic mapping of the QTL.

In forming a congenic strain, a segment of chromosome is moved from one inbred rat strain (donor) to another strain (recipient) by a standard protocol involving a series of back-cross breeding to the recipient strain with selection for donor alleles at marker loci along the chromosomal segment to be moved.13 This results in a pair of strains (the congenic and the recipient strain) that are (essentially) genetically identical except that the congenic strain has a defined chromosomal segment from the donor. If the congenic region in fact contains a variant BP QTL allele compared with the recipient strain, then the 2 strains will have different BP, demonstrating the existence of a BP effect of the chromosomal region that was moved.

In this issue of Hypertension, Iwai et al15 and Frantz et al16 report the construction of congenic strains involving SHR and WKY chromosomal regions containing the Sa gene. In both cases, the congenic strains demonstrated the existence of a BP QTL in the general vicinity of the Sa gene. This work confirms and extends the results from a previous congenic strain on rat chromosome 1 using SHR and WKY17 ; an additional report on a chromosome 1 congenic strain also demonstrates a BP QTL using Dahl S and Lewis rats.10 Thus, there is an impressive consistency in these results.

Although the function of the Sa gene product is unknown, the Sa gene has passed several important tests as a hypertension candidate gene: (1) it has an interesting intermediate phenotype (differential expression between strains in the proximal tubule); (2) it cosegregates with BP; and (3) it is contained in a congenic region influencing BP. An important remaining step is to make congenic strains in which the alleles at the Sa locus are moved with reduced (preferably minimal) flanking DNA to reduce the chance that the real QTL is a locus linked to the Sa locus. This procedure has been applied to the loci for renin and the inducible form of nitric oxide synthase; in both cases, the candidate gene was eliminated as causative for the BP difference between the specific strains used.18 19 Thus, some caution is appropriate until fine genetic mapping of the QTL in the region of the Sa gene is accomplished by construction of congenic substrains.

Other data suggest that the Sa gene is not responsible for BP differences. The Milan hypertensive strain (MHS) carries the same Sa allele as the normotensive WKY, and the Milan normotensive strain (MNS) carries the same allele as SHR.20 This conclusion was based on the restriction fragment length patterns of 15 enzymes that yield a polymorphic pattern between the 2 alleles. Also, MNS express a high level of renal Sa mRNA compared with MHS, as would be expected based on the allele in each strain. This reversal of alleles compared with what might be anticipated based on the SHR/WKY and Dahl S/Dahl R comparison in itself has no bearing on interpretation of the linkage and congenic strain data. It is expected theoretically, and found experimentally, that some QTL alleles for increase of a quantitative trait will be carried by a low strain and visa versa; some examples are found in work by Garrett et al.10 A high or low strain is determined by the net effect over multiple loci, so alleles at any single locus do not determine the ultimate phenotype. Much more insightful is the observation20 in an F2 population derived from MHS and MNS that alleles at the Sa locus did not cosegregate with BP. This does imply that the Sa alleles that control the large difference in renal expression have nothing to do with BP and that the QTL on chromosome 1 does not have functionally variant alleles in the MHS versus MNS comparison. One could also argue (less convincingly in my view) that ancillary factors (epistatic interaction with the genetic background, environmental factors such as normal dietary NaCl) blunted the response of BP to the Sa alleles in the F2 (MHS×MNS) study.

Animal work with the Sa gene has stimulated work in humans; the Sa gene is located on human chromosome 16p13.11.21 22 In 1 study,23 there was a difference in allelic frequency of Sa alleles between hypertensive and control groups. In 3 other such association studies,24 25 26 no relationship was found; linkage analysis in humans was also negative.26 Thus, the studies on humans fail to provide convincing evidence for an effect of the Sa locus on BP.

In summary, the work of Iwai and Inagami1 and the subsequent work it generated is science at its best, regardless of the ultimate status of the Sa gene as one of “the” genes causing BP variation. At a very minimum, the Sa gene as a candidate led to the detection and confirmation of a BP QTL on rat chromosome 1. Fine genetic mapping in the animal models using derivatives of the new congenic strains will certainly determine the status of the Sa gene and provide a better QTL localization on rat chromosome 1 for guiding analyses on human chromosome 16.

Footnotes

  • The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.

References

  1. ↵
    Iwai N, Inagami T. Isolation of preferentially expressed genes in the kidneys of hypertensive rats. Hypertension. 1991;17:161–169.
    OpenUrlAbstract/FREE Full Text
  2. ↵
    Patel HR, Thiara AS, West KP, Lodwick D, Samani NJ. Increased expression of the SA gene in the kidney of the spontaneously hypertensive rat is localized to the proximal tubule. J Hypertens. 1994;12:1347–1352.
    OpenUrlPubMed
  3. ↵
    Yang T, Hassan SA, Singh I, Smart A, Brosius FC, Holzman LB, Schnermann JB, Briggs JP. SA gene expression in the proximal tubule of normotensive and hypertensive rats. Hypertension. 1996;27(pt 2):541–545.
  4. ↵
    Iwai N, Inagami T. Identification of a candidate gene responsible for the high blood pressure of spontaneously hypertensive rats. J Hypertens. 1992;10:1155–1157.
    OpenUrlCrossRefPubMed
  5. ↵
    Iwai N, Kurtz TW, Inagami T. Further evidence of the SA gene as a candidate gene contributing to the hypertension in spontaneously hypertensive rat. Biochem Biophys Res Commun. 1992;188:64–69.
    OpenUrlCrossRefPubMed
  6. ↵
    Lindpaintner K, Hilbert P, Ganten D, Nadal-Ginard B, Inagami T, Iwai N. Molecular genetics of the SA-gene: cosegregation with hypertension and mapping to rat chromosome 1. J Hypertens. 1993;11:19–23.
    OpenUrlCrossRefPubMed
  7. ↵
    Samani NJ, Lodwick D, Vincent M, Dubay C, Kaiser MA, Kelly MP, Lo M, Harris J, Sassard J, Lathrop M, Swales JD. A gene differentially expressed in the kidney of the spontaneously hypertensive rat cosegregates with increased blood pressure. J Clin Invest. 1993;92:1099–1103.
  8. ↵
    Harris EL, Dene H, Rapp JP. SA gene and blood pressure cosegregation using Dahl salt-sensitive rats. Am J Hypertens. 1993;6:330–334.
    OpenUrlAbstract/FREE Full Text
  9. ↵
    Gu L, Dene H, Deng AY, Hoebee B, Bihoreau M-T, James M, Rapp JP. Genetic mapping of two blood pressure quantitative trait loci on rat chromosome 1. J Clin Invest. 1996;97:777–788.
    OpenUrlPubMed
  10. ↵
    Garrett MR, Dene H, Walder R, Zhang Q-Y, Cicila GT, Assadnia S, Deng AY, Rapp JP. Genome scan and congenic strains for blood pressure QTL using Dahl salt-sensitive rats. Genome Res.. 1998;8:711–723.
    OpenUrlAbstract/FREE Full Text
  11. ↵
    van Ooijen JW. Accuracy of mapping quantitative trait loci in autogamous species. Theor Appl Genet. 1992;84:803–811.
    OpenUrlPubMed
  12. ↵
    Hyne V, Kearsey MJ, Pike DJ, Snape JW. QTL analysis: unreliability and bias in estimation procedures. Mol Breeding. 1995;1:273–282.
    OpenUrlCrossRef
  13. ↵
    Rapp JP, Deng AY. Detection and positional cloning of blood pressure quantitative trait loci: is it possible? Hypertension. 1995;25:1121–1128.
    OpenUrlAbstract/FREE Full Text
  14. ↵
    Lander ES, Schork NJ. Genetic dissection of complex traits. Science. 1994;265:2037–2048.
    OpenUrlAbstract/FREE Full Text
  15. ↵
    Iwai N, Tsujita Y, Kinoshita M. Isolation of a chromosome 1 region that contributes to high blood pressure and salt sensitivity. Hypertension. 1998;32:636–638.
    OpenUrlAbstract/FREE Full Text
  16. ↵
    Frantz SA, Kaiser M, Gardiner SM, Gauguier D, Vincent M, Thompson JR, Bennett T, Samani NJ. Successful isolation of a rat chromosome 1 blood pressure quantitative trait locus in reciprocal congenic strains. Hypertension. 1998;32:639–646.
    OpenUrlAbstract/FREE Full Text
  17. ↵
    St Lezin E, Liu W, Wang J-M, Wang N, Kren V, Krenova D, Musilova A, Zdobinska M, Zidek V, Lau D, Pravenec M. Genetic isolation of a chromosome 1 region affecting blood pressure in the spontaneously hypertensive rat. Hypertension. 1997;30:854–859.
    OpenUrlAbstract/FREE Full Text
  18. ↵
    Zhang QY, Dene H, Deng AY, Garrett MR, Jacob HJ, Rapp JP. Interval mapping and congenic strains for a blood pressure QTL on rat chromosome 13. Mamm Genome. 1997;8:636–641.
    OpenUrlCrossRefPubMed
  19. ↵
    Dukhanina OI, Dene H, Deng AY, Choi CR, Hoebee B, Rapp JP. Linkage map and congenic strains to localize blood pressure QTL on rat chromosome 10. Mamm Genome. 1997;8:229–235.
    OpenUrlCrossRefPubMed
  20. ↵
    Lodwick D, Zagato L, Kaiser MA, Torielli L, Casari G, Bianchi G, Samani NJ. Genetic analysis of the SA and Na+/K+-ATPase α1 genes in the Milan hypertensive rat. J Hypertens. 1998;16:139–144.
    OpenUrlCrossRefPubMed
  21. ↵
    Szpirer C, Riviere M, Szpirer J, Levan G, Guo DF, Iwai N, Inagami T. Chromosomal assignment of human and rat hypertension candidate genes: type 1 angiotensin II receptor genes and the SA gene. J Hypertens. 1993;11:919–925.
    OpenUrlCrossRefPubMed
  22. ↵
    Samani NJ, Whitmore SA, Kaiser MA, Harris J, See CG, Callen DF, Lodwick D. Chromosomal assignment of the human SA gene to 16p13.11 and demonstration of its expression in the kidney. Biochem Biophys Res Commun. 1994;199:862–868.
    OpenUrlCrossRefPubMed
  23. ↵
    Iwai N, Ohmichi N, Hanai K, Nakamura Y, Kinoshita M. Human SA gene locus as a candidate locus for essential hypertension. Hypertension. 1994;23:375–380.
    OpenUrlAbstract/FREE Full Text
  24. ↵
    Harrap SB, Samani NJ, Lodwick D, Connor JM, Fraser R, Davies DL, Lever AF, Foy CJW, Watt GCM. The SA gene: predisposition to hypertension and renal function in man. Clin Sci. 1995;88:665–670.
    OpenUrlPubMed
  25. ↵
    Zee RY, Stephen AL, Iwai N, Morris BJ. Association analyses of S(A) gene variant in essential hypertensives. Am J Hypertens. 1997;10:235–242.
    OpenUrlAbstract/FREE Full Text
  26. ↵
    Nabika T, Bonnardeaux A, James M, Julier C, Jeunemaitre X, Corvol P, Lathrop M, Soubrier F. Evaluation of the SA locus in human hypertension. Hypertension. 1995;25:6–13.
    OpenUrlAbstract/FREE Full Text
View Abstract
Back to top
Previous ArticleNext Article

This Issue

Hypertension
October 1998, Volume 32, Issue 4
  • Table of Contents
Previous ArticleNext Article

Jump to

  • Article
    • Footnotes
    • References
  • Info & Metrics
  • eLetters

Article Tools

  • Print
  • Citation Tools
    Editorial Commentary: The Sa Gene
    John Rapp
    Hypertension. 1998;32:647-648, originally published October 1, 1998
    https://doi.org/10.1161/01.HYP.32.4.647

    Citation Manager Formats

    • BibTeX
    • Bookends
    • EasyBib
    • EndNote (tagged)
    • EndNote 8 (xml)
    • Medlars
    • Mendeley
    • Papers
    • RefWorks Tagged
    • Ref Manager
    • RIS
    • Zotero
  • Article Alerts
    Log in to Email Alerts with your email address.
  • Save to my folders

Share this Article

  • Email

    Thank you for your interest in spreading the word on Hypertension.

    NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

    Enter multiple addresses on separate lines or separate them with commas.
    Editorial Commentary: The Sa Gene
    (Your Name) has sent you a message from Hypertension
    (Your Name) thought you would like to see the Hypertension web site.
  • Share on Social Media
    Editorial Commentary: The Sa Gene
    John Rapp
    Hypertension. 1998;32:647-648, originally published October 1, 1998
    https://doi.org/10.1161/01.HYP.32.4.647
    del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo

Related Articles

Cited By...

Hypertension

  • About Hypertension
  • Instructions for Authors
  • AHA CME
  • Guidelines and Statements
  • Permissions
  • Journal Policies
  • Email Alerts
  • Open Access Information
  • AHA Journals RSS
  • AHA Newsroom

Editorial Office Address:
7272 Greenville Ave.
Dallas, TX 75231
email: hypertension@heart.org

Information for:
  • Advertisers
  • Subscribers
  • Subscriber Help
  • Institutions / Librarians
  • Institutional Subscriptions FAQ
  • International Users
American Heart Association Learn and Live
National Center
7272 Greenville Ave.
Dallas, TX 75231

Customer Service

  • 1-800-AHA-USA-1
  • 1-800-242-8721
  • Local Info
  • Contact Us

About Us

Our mission is to build healthier lives, free of cardiovascular diseases and stroke. That single purpose drives all we do. The need for our work is beyond question. Find Out More about the American Heart Association

  • Careers
  • SHOP
  • Latest Heart and Stroke News
  • AHA/ASA Media Newsroom

Our Sites

  • American Heart Association
  • American Stroke Association
  • For Professionals
  • More Sites

Take Action

  • Advocate
  • Donate
  • Planned Giving
  • Volunteer

Online Communities

  • AFib Support
  • Garden Community
  • Patient Support Network
  • Professional Online Network

Follow Us:

  • Follow Circulation on Twitter
  • Visit Circulation on Facebook
  • Follow Circulation on Google Plus
  • Follow Circulation on Instagram
  • Follow Circulation on Pinterest
  • Follow Circulation on YouTube
  • Rss Feeds
  • Privacy Policy
  • Copyright
  • Ethics Policy
  • Conflict of Interest Policy
  • Linking Policy
  • Diversity
  • Careers

©2018 American Heart Association, Inc. All rights reserved. Unauthorized use prohibited. The American Heart Association is a qualified 501(c)(3) tax-exempt organization.
*Red Dress™ DHHS, Go Red™ AHA; National Wear Red Day ® is a registered trademark.

  • PUTTING PATIENTS FIRST National Health Council Standards of Excellence Certification Program
  • BBB Accredited Charity
  • Comodo Secured