Summary
Although essential arterial hypertension is believed to have a strong genetic predisposition, the gene(s) responsible are unknown. The mechanisms underlying the regulation of blood pressure and experimental studies place the renin gene among the main candidate genes that need to be tested in humans. We tested the hypothesis of a linkage between the renin gene and essential hypertension using the affected sib pair method. Siblings (133 subjects, 52.1±10.9 years) from 57 families were selected for sustained hypertension (160.7 ± 22.9/99.5 ± 12.8 mmHg with 80% of patients under antihypertensive treatment), of early onset (40.7 ± 12.0 years), in the absence of obesity, diabetes mellitus, and secondary hypertension. Eight renin haplotypes were generated from three diallelic renin restriction fragment length polymorphisms (RFLPs) (TaqI, Hinfi, HindIII) located throughout the renin gene. The allelic concordance between the sib pairs was analyzed by identity by state relationships for 98 sib pairs (41 for 41 couples, 39 for 13 trios, 18 for 3 quartets). Allelic frequencies in the 57 hypertensive probands were similar to those observed among 102 hypertensive subjects studied previously. Six of eight possible haplotypes were observed, the informativity of the marker corresponded to 70% of heterozygosity. Allelic concordance for all sib pairs according to sibship size was not significantly different from that expected under the hypothesis of no linkage (t = 0.52, P = 0.15) reflecting only a small excess of renin alleles shared by the hypertensive sibs (1.44 ± 0.6 vs 1.36 ± 0.6). Likewise the linkage hypothesis was unsupported by weighted estimates to correct for possible bias due to large sibship size. Thus, the sib pair analysis suggests that the renin gene does not have a frequent role in the pathogenesis of essential hypertension; further more powerful linkage studies or other approaches will be needed to detect contributions at the renin locus to the heritability of essential hypertension.
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References
Bishop DT, Williamson JA (1990) The power of identity-by-state methods for linkage analysis. Am J Hum Genet 46:254–265
Blackwelder WC, Elston RC (1985) A comparison of sib-pair linkage tests for disease susceptibility loci. Genet Epidemiol 2:85–97
Dawson DV, Kaplan EB, Elston RC (1990) Extensions to sib-pair linkage tests applicable to disorders characterized by delayed onset. Genet Epidemiol 7:453–466
Feinberg AP, Vogelstein B (1983) A technique for radiolabelling DNA restriction endonuclease fragments to high specific activity. Anal Biochem 132:6–13
Frossard PM, Gonzalez PA, Dillan NA, Coleman RT, Atlas SM (1986a) Human renin (REN) gene locus: BglII, RsaI and TaqI RFLPs. Nucleic Acids Res 14:6778
Frossard PM, Gonzalez PA, Fritz LC, Ponte PA, Fiddes JC, Atlas SM (1986b) Two RFLPs at the human renin (ren) gene locus. Nucleic Acids Res 14:4380
Fukamizu A, Nishi K, Cho T, Saitoh M, Nakayama K, Ohkubo H, Nakanishi S, Murakami K (1988) Structure of the rat renin gene. J Mol Biol 201:443–450
Green JR, Woodrow JC (1977) Sibling method for detecting HLA linked genes in disease. Tissue Antigens 9:31–35
Hamilton M, Pickering GW, Roberts JAF, Sowry GSC (1954) The etiology of essential hypertension. IV. The role of inheritance. Clin Sci 13:273–304
Hata A, Robertson M, Emi M, Lalouel JM (1990) Direct detection and automated sequencing of individual alleles after electrophoretic strand separation: identification of a common non-sense mutation in exon 9 of the human lipoprotein lipase gene. Nucleic Acids Res 18:5407–5411
Hill WG (1975) Tests of association of gene frequencies at several loci in random mating diploid populations. Biometrics 31:881–888
Hodge SE (1984) The information contained in multiple sibling pairs. Genet Epidemiol 1:109–122
Kannel W, Dawber T, McGee D (1980) Perspectives on systolic hypertension; the Framingham study. Circulation 61:1179–1182
Kurtz TW, Simonet L, Kabra PM, Wolfe S, Chan L, Hjelle BL (1990) Cosegregation of the renin allele of the spontaneously hypertensive rat with an increase in blood pressure. J Clin Invest 85:1328–1332
Lange K (1986) A test statistic for the affected-sib-set method. Am J Hum Genet 50:283–290
Lifton RP, Hopkins PN, Williams RR, Hollenberg NK, Williams GH, Dluhy RG (1989) Evidence for heritability of non-modulating essential hypertension. Hypertension 13:884–889
Masharani U (1989) HinfI RFLP at the human renin gene locus. Nucleic Acids Res 17:467
Morris BJ, Griffiths LR (1988) Frequency in hypertensives of alleles for a RFLP associated with the renin gene. Biochem Biophys Res Commun 150:219–224
Motro U, Thomson G (1985) The affected sib method. I. Statistical features of the affected sib-pair method. Genetics 110:525–538
Mullins JJ, Peters J, Ganten P (1990) Fulminant hypertension in transgenic rats harbouring the mouse Ren-2 gene. Nature 34:541–544
Naftilan AJ, Williams R, Burt D, Paul M, Pratt RE, Hobart P, Chirgwin J, Dzau V (1989) A lack of genetic linkage of renin gene restriction length polymorphisms with human hypertension. Hypertension 14:614–618
Ohkubo H, Kawakami H, Kakehu Y, Takumi T, Arai H, Yokota Y, Iwai M, Tanabe Y, Masu M, Hata J, Iwao H, Okamoto H, Yokoyama M, Nomura T, Katsuki M, Nakanishi S (1990) Generation of transgenic mice with elevated blood pressure by introduction of the rat renin and angiotensinogen genes. Proc Natl Acad Sci USA 87:5153–5157
Rapp JH, Wang SM, Dene H (1989) A genetic polymorphism in the renin gene of Dahl rats cosegregate with blood pressure. Science 243:542–544
Rigat B, Hubert C, Alhenc-Gelas F, Cambien F, Corvol P, Soubrier F (1990) An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest 86:1343–1346
Risch N (1990) Linkage strategies for genetically complex traits. II. The effect of marker polymorphism on analysis of affected relative pairs. Am J Hum Genet 46:242–253
Soubrier F, Panthier JJ, Corvol P, Rougeon F (1983) Molecular cloning and nucleotide sequence of a human renin cDNA fragment. Nucleic Acids Res 11:7181–7190
Soubrier F, Panthier JJ, Houot AM, Rougeon F, Corvol P (1986) Segmental homology between the promoter region of the human renin gene and the mouse ren1 and ren2 promoter regions. Gene 41:85–92
Soubrier F, Jeunemaitre X, Rigat B, Houot AM, Cambien F, Corvol P (1990) Similar frequencies of renin gene RFLPs in hypertensive and normotensives. Hypertension 16:712–717
Suarez BK, Rice J, Reich T (1978) The generalized sib pair IBD distribution: its use in the detection of linkage. Ann Hum Genet 42:87–94
Suarez BK, Hodge S, Reich T (1979) Is juvenile diabetes determined by a single gene closely linked to HLA? Diabetes 28:527–532
Suarez BK, Crouse J, Eerdewegh (1983) HLA sharing in multiplex sibships. Ann Hum Genet 47:153–159
Ward R (1990) Familial aggregation and genetic epidemiology of blood pressure. In: Laragh JH, Brenner BM (eds) Hypertension: pathophysiology, diagnosis and management. Raven Press, New York, pp 81–100
Weeks DE, Lange K (1988) The affected-pedigree-member method of linkage analysis. Am J Hum Genet 42:315–326
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Jeunemaitre, X., Rigat, B., Charru, A. et al. Sib pair linkage analysis of renin gene haplotypes in human essential hypertension. Hum Genet 88, 301–306 (1992). https://doi.org/10.1007/BF00197264
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DOI: https://doi.org/10.1007/BF00197264