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Previous studies have suggested that angiotensinogen (AGT) gene variants are associated with increased plasma AGT levels, and may also contribute towards the inherited component of predisposition to essential hypertension in humans. To explore the potential functionality of several AGT polymorphisms and estimate their effects, together with other sources of familial correlations, on plasma AGT, we undertook a large study involving 545 healthy French volunteers in 130 nuclear families that include 285 offspring. Plasma AGT levels were measured in all participants, and bi-allelic AGT variants were analysed as candidate functional variants at three sites in the 5'-flanking region (C-532T, A-20C, G-6A), two sites in exon 2 (M235T, T174M) and two newly identified variant sites in the untranslated sequence of exon 5 and the 3'-flanking region (C+2054A, C+2127T) of the gene. Analysis with the class D regressive model showed significant effects influencing plasma AGT levels of all AGT polymorphisms tested, with the exception of T174M. The most significant result was found at C-532T (P=0.000001), which accounts for 4.3% of total plasma AGT variability in parents and 5.5% in offspring, with substantial residual familial correlations. Maximum likelihood estimates of haplotype frequencies and tests of linkage disequilibrium between each AGT polymorphism and a putative QTL are in agreement with a complete confounding of C-532T with the QTL, when taking into account sex and generation specific effects of the QTL. However, further combined segregation-linkage analyses showed significant evidence for additional effects of G-6A, M235T and C+2054A polymorphisms after accounting for C-532T, which supports a complex model with at least two functional variants within the AGT gene controlling AGT levels.

Foods associated with precancerous colorectal adenoma, especially those associated with large adenomas, are poorly understood. We compared food intake in polyp-free controls (n = 427) with small adenoma (n = 154) or large adenoma (n = 208) cases in Burgundy (France). Logistic regression models controlled for age, gender, and energy. Consumption of lean meat was associated with a reduced risk of small adenomas [odds ratio (OR) for 4th vs. 1st quartile = 0.3, 95% confidence interval (CI) = 0.2-0.6] and large adenomas (OR = 0.4, 95% CI = 0.3-0.7) compared with controls. There was an increased risk with p t s and meat spread [OR = 2.1, 95% CI = 1.1-3.7 (small adenomas) and OR = 2.6, 95% CI = 1.5-4.4 (large adenomas)], bread [OR = 2.0, 95% CI = 1.1-3.6 (small adenomas) and OR = 2.2, 95% CI = 1.3-3.7 (large adenomas)], and pasta (OR = 1.7, 95% CI = 0.9-3.0 in small adenomas only). Animal fats were associated with an increased risk of large adenomas compared with small adenomas (OR = 2.4, 95% CI = 1.1-5.0), whereas yogurt intake was associated with a lower risk (OR for high vs. no intake = 0.5, 95% CI = 0.3-0.9). These findings suggest that some risk factors that have been found to be associated with cancer, such as refined cereal products and high-fat animal products, also influence early stages of colorectal carcinogenesis.

M. Thibonnier, M. K. Graves, M. S. Wagner, N. Chatelain, F. Soubrier, P. Corvol, H. F. Willard and X. Jeunemaitre. Study of V 1 -vascular Vasopressin Receptor Gene Microsatellite Polymorphisms in Human Essential Hypertension. Journal of Molecular and Cellular Cardiology (2000) 32 , 557–564. Vasopressin (AVP) actions on vascular tone and blood pressure are mainly mediated by the V 1 -vascular receptor (V 1 R). We recently reported the structure and functional expression of the human V 1 R cDNA and described the genomic characteristics, tissue expression, chromosomal localization, and regional mapping of the human V 1 R gene, AVPR1A . To test whether the V 1 R is a marker for human essential hypertension, we sequenced the human AVPR1A gene and its 5 upstream region and found several DNA microsatellite motifs. One (GT) 14 -(GA) 13 -(A) 8 microsatellite is located 2983 bp downstream of the transcription start site, within a 2.2 kbp intron interrupting the coding sequence of the receptor. Three other microsatellites are present in the 5 flanking DNA of the AVPR1A gene: a (GT) 25 dinucleotide repeat, a complex (CT) 4 -TT-(CT) 8 -(GT) 24 motif and a (GATA) 14 tetranucleotide repeat located respectively 3956 bp, 3625 bp and 553 bp upstream of the transcription start site. Analysis of these polymorphisms in 79 hypertensive and 86 normotensive subjects for the (GT) 14 -(GA) 13 -(A) 8 and the (GT) 25 motifs revealed a high percentage of heterozygosity but no difference in alleles frequencies between the two groups. A linkage study using the affected sib pair method and the (GT) 25 repeat in 446 hypertensive sib pairs from 282 French Caucasian pedigrees showed no excess of alleles sharing at the AVPR1A locus. No linkage was found in the subgroups of patients with early onset hypertension (diagnosis before age 40) or severe hypertension (diastolic blood pressure ≥100 mmHg or requirement for ≥two medications). These findings suggest that molecular variants of the V 1 R gene are not involved in unselected forms of essential hypertension.

AIM: Mutations of the 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) gene cause the syndrome of apparent mineralocorticoid excess, a rare autosomal recessive form of hypertension. We therefore investigated the question of whether variants of the 11beta-HSD2 gene can contribute to genetic susceptibility to essential hypertension. SUBJECTS AND METHODS: We performed a linkage study in 162 French hypertensive sibships using the affected sib-pair method on 347 sibling pairs and a polymorphic microsatellite marker that we identified in a 30 kb cosmid clone containing the 11beta-HSD2 gene. The coding sequence, introns 2-4 and 350 bp of the 5'-flanking region of the 11beta-HSD2 gene were screened for polymorphisms by polymerase chain reaction/single-strand conformation polymorphism, and a single polymorphism, Glu178/Glu (G534A), was identified in exon 3, which did not change the encoded amino acid sequence. A case-control study was conducted on 370 hypertensive subjects with a positive family history of hypertension and 783 French subjects with hypertension with or without a family history of hypertension, compared with 313 normotensive control subjects, all of whom were analyzed for the newly identified bi-allelic polymorphism. RESULTS: Statistical analyses using the affected sib-pair method did not show significant linkage between the 11beta-HSD2 microsatellite marker and hypertension. Furthermore, no positive association with hypertension was found with the Glu178/Glu (G534A) polymorphism. CONCLUSION: Our data do not suggest that variants of the 11beta-HSD2 gene contribute substantially to essential hypertension in Caucasians.

Resume :Les artistes fin-de-siècle nourrissent un pessimisme exacerbé qu’ils mettent en scène et revendiquent dans leurs œuvres. Un exemple des plus intéressants est celui des contes de fées écrits en nombre durant cette période, qui racontent de mille manières le déclin des fées et des génies. Les titres des contes et recueils d’alors sont sans équivoque, ils annoncent ou constatent la mort du merveilleux et plus particulièrement du merveilleux fin-de-siècle.

Abstract —Different family and case-control studies support genetic linkage and association at the human angiotensinogen ( AGT ) locus with essential hypertension. To extend these previous observations, a European collaborative study of nine centers was set up to create a large resource of affected sibling pairs. The AGT locus was studied using a highly polymorphic dinucleotide repeat in the 3′-flanking region of the gene in 350 European families, comprising 630 affected sibling pairs. Statistical analyses using two different methods did not show any evidence for linkage either in the whole panel or in family subsets selected for severity or early onset of disease. Although several arguments from association studies suggest a role of the AGT gene in essential hypertension, this large family study did not replicate the initial linkage reported in smaller studies. Our results highlight the difficulty of identifying susceptibility genes by linkage analysis in complex diseases.

Abstract —Anomalies in either of the tightly linked genes encoding the enzymes CYP11B1 (11β-hydroxylase) or CYP11B2 (aldosterone synthase) can lead to important changes in arterial pressure and are responsible for several monogenically inherited forms of hypertension. Mutations in these genes or their regulatory regions could thus contribute to genetic variation in susceptibility to essential hypertension. To test this hypothesis, we performed 2 complementary studies of the CYP11B1 / CYP11B2 locus in essential hypertension. After characterizing a DNA contig containing the CYP11B1 gene and mapping the gene in the Centre d’Etudes du Polymorphisme Humain reference panel of families, we performed a linkage study with 292 hypertensive sibling pairs and a highly informative microsatellite marker near CYP11B1 . We also analyzed the association of 2 frequent biallelic polymorphisms of the CYP11B2 gene, 1 in the promoter at position −344 (−344C/T) and the other, a common gene conversion in intron 2, with hypertension in 380 hypertensive patients and 293 normotensive individuals. Statistical analyses did not show significant linkage of the CYP11B1 microsatellite marker to hypertension. No positive association with hypertension was found with the gene conversion in intron 2, but a positive association with hypertension was found with the −344T allele. The hypertensive and normotensive samples differed significantly in both genotype ( P =0.023) and allele frequencies ( P =0.010). Our data suggest a modest contribution of the CYP11B2 gene to essential hypertension.

Objective To determine whether angiotensinogen (AGT) and angiotensin II type 1 (AT1) receptor genes contribute to the development of arterial hypertension in members of French Caucasian families and in subjects with hypertension associated with non-insulin-dependent diabetes mellitus (NIDDM). Methods Sibpair linkage analyses were performed with microsatellites near the AGT and AT1 receptor genes in 179 hypertensive sibpairs from 69 NIDDM kindreds. In addition, population/association studies were performed with the M235T and T174M polymorphisms of the AGT gene, and the A1166C polymorphism of the AT1 receptor gene. Results No evidence for linkage between the AGT and AT1 receptor loci and hypertension was observed. In addition, the distributions of genotypes of AGT and AT1 receptor gene polymorphisms did not differ significantly among a group of unrelated individuals with both hypertension and NIDDM (n = 188) and three groups of unrelated control subjects with NIDDM (n = 117), hypertension (n = 75) or none of these conditions (n = 125). Conclusions These results suggest that the AGT and AT1 receptor genes are not major genetic determinants of hypertension associated with NIDDM in this population, although we can not exclude the possibility that these loci make a minor contribution in a polygenic context.