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• W2059697466 abstract "To the Editor: Preeclampsia is an important inheritable pregnancy-related hypertension syndrome. Since it develops as a result of widespread endothelial dysfunction, the NOS3 gene responsible for endothelium-derived nitric oxide (NO) production via its gene product, eNOS, has been suggested as an obvious candidate gene for preeclampsia (Morris et al. Morris et al., 1996Morris N Eaton BM Dekker G Nitric oxide, the endothelium, pregnancy and pre-eclampsia.Br J Obstet Gynaecol. 1996; 103: 4-15Crossref PubMed Scopus (152) Google Scholar). We were intrigued, therefore, by the report, by Arngrímsson et al. (Arngrímsson et al., 1997Arngrímsson R Hayward C Nadaud S Baldursdóttir A Walker JJ Liston WA Bjarnadóttir RI et al.Evidence for a familial pregnancy-induced hypertension locus in the eNOS-gene region.Am J Hum Genet. 1997; 61: 354-362Abstract Full Text PDF PubMed Scopus (117) Google Scholar), of linkage in the region of the NOS3 gene and have attempted to repeat their findings in our own collection of preeclampsia families. Evidence for linkage was sought by use of two, separately ascertained, affected sister-pairs (ASPs) collections, from Amsterdam and Cambridge (United Kingdom), that contained 104 sibships. In the Cambridge Centre, a total of 21 extended pedigrees were also identified, some on the basis of the ASPs suitable for conventional parametric linkage studies. All affected individuals were Caucasian and met the Redman and Jefferies criteria of preeclampsia: they were proteinuric (>300 mg/24 h) and hypertensive, with a blood pressure of >140/90 occurring after 20-wk gestation and with a ⩾25-mmHg rise in diastolic blood pressure (Redman and Jefferies Redman and Jefferies, 1988Redman CW Jefferies M Revised definition of pre-eclampsia.Lancet. 1988; 1: 809-812Abstract PubMed Scopus (136) Google Scholar). These features all resolved by 3 mo postpartum, and none of the subjects had concurrent diabetes, renal disease, or essential hypertension. Some sibships (<5%) contained subjects showing features of pregnancy-induced hypertension (PIH) alone (i.e., they were not proteinuric). These members were not included in subsequent sib-pair analysis, and none of the larger pedigrees used contained subjects with PIH. For the purposes of linkage analysis, all males were assigned to the affection status of “unknown.” Subjects were genotyped for the CA-repeat marker within intron 13 of the NOS3 gene (referred to here as “NOS3i13”). The Cambridge samples were also genotyped for the two flanking markers D7S483 and D7S505. Genotyping was performed by use of PCR amplification of the microsatellite markers by means of primer pairs, in which the forward primer had been 5′ end–labeled with a fluorescent amidite. CEPH primer sequences were used for the flanking markers, and primer sequences published elsewhere were used for NOS3i13 (Nedaud et al. Nadaud et al., 1994Nadaud S Bonnardeaux A Lathrop M Soubrier F Gene structure, polymorphism and mapping of the human endothelial nitric oxide synthase gene.Biochem Biophys Res Commun. 1994; 198: 1027-1033Crossref PubMed Scopus (193) Google Scholar). The PCR products were multiplexed and were run on an ABI 377, and allele sizes were determined by use of version 2 of GENOTYPER (Applied Biosystems). The number of alleles shared identical by descent (IBD) was calculated for the ASPs by use of the maximum-likelihood method, as implemented in SPLINK (Holmans Holmans, 1993Holmans P Asymptotic properties of affected-sib-pair linkage analysis.Am J Hum Genet. 1993; 52: 362-374PubMed Google Scholar; Holmans and Clayton Holmans and Clayton, 1995Holmans P Clayton D Efficiency of typing unaffected relatives in an affected-sib-pair linkage study with single-locus and multiple tightly linked markers.Am J Hum Genet. 1995; 57: 1221-1232PubMed Google Scholar). Parental genotype data were used where available but were incomplete for the Cambridge ASPs and were not available for the Amsterdam ones. Comparison of allele frequencies and marker heterozygosity from the SPLINK output for the two groups showed no significant differences between the two collections. The allele sharing for the NOS3i13 marker is shown in table 1, for both the Amsterdam and Cambridge ASPs. There is no evidence of excess allele sharing in either group. In fact, the Cambridge group shows a deficit of allele sharing, attributable to chance alone. To confirm this, allele sharing for the two flanking markers for NOS3, D7S483 and D7S505, was investigated. These two flanking markers are approximately equidistant from NOSi13 and span a 4-cM region over 7q36. Again, there was no evidence of a significant positive deviation from a 1:2:1 distribution in the Cambridge group, either for D7S483 or for D7S505.Table 1Allele Sharing for NOS3i13 and Flanking MarkersNo. of Alleles Shared IBDASP Collection and Marker012PAmsterdam (n=46): NOS3i1311.120.214.6.250Cambridge (n=58): D7S48311.332.014.7.388 NOS3i1318.028.012.0.584 D7S50515.130.013.8.584Combined (n=104): NOS3i1328.947.826.3.547 Open table in a new tab Parametric analysis of the preeclampsia pedigrees was performed by use of four of the models, employed elsewhere (Arngrímsson et al. Arngrímsson et al., 1997Arngrímsson R Hayward C Nadaud S Baldursdóttir A Walker JJ Liston WA Bjarnadóttir RI et al.Evidence for a familial pregnancy-induced hypertension locus in the eNOS-gene region.Am J Hum Genet. 1997; 61: 354-362Abstract Full Text PDF PubMed Scopus (117) Google Scholar), as follows (q is the frequency of disease gene, and f is the penetrance): an autosomal model (AD) of high arbitrary penetrance (q=.02, f=0.9), a partial-dominance model (AD/LP; q=.10, fAa=0.21, fAA=1.0), a fully recessive model (AR; q=.2), and an affecteds-only model (AO; q=.02, fAa=fAA=0.001). The power of the preeclampsia pedigree collection to detect linkage was estimated by means of simulation of each model, by use of SLINK (Weeks et al. Weeks et al., 1991Weeks DE Ott J Lathrop GM SLINK: a general simulation program for linkage analysis.Am J Hum Genet Suppl. 1991; 47: A204Google Scholar; Ott Ott, 1989Ott J Computer-simulation methods in human linkage analysis.Proc Natl Acad Sci USA. 1989; 86: 4175-4178Crossref PubMed Scopus (411) Google Scholar). The results of 500 replications of each model generated by SLINK, if a hypothetical marker with eight equally frequent alleles (PIC=.86) is assumed, are summarized in tables 2 and 3. These results show that such a marker linked tightly to preeclampsia provides an average LOD score sufficient to establish linkage in three of the four models. The power of the simulated marker to detect linkage in the AD/LP model is substantially less than that of the other three models, as has been noted elsewhere (Harrison et al. Harrison et al., 1997Harrison GA Humphrey KE Jones N Badenhop R Guo G Elakis G Kaye JA et al.A genomewide linkage study of preeclampsia/eclampsia reveals evidence for a candidate region on 4q.Am J Hum Genet. 1997; 60: 1158-1167PubMed Google Scholar).Table 2Results of Computer Simulations with SLINK, for 500 ReplicatesAverage LOD Score at θ =Model.0.1.2.3.4AD6.054.893.371.92.75AD/LP1.701.49.99.53.18AR4.893.812.481.26.39AO3.883.122.051.08.37 Open table in a new tab Table 3Results of Two-Point Linkage Analysis% of Replicates with LOD-Score Threshold >Model123AD100.099.497.6AD/LP78.441.410.8AR100.098.489.2AO98.889.672.4 Open table in a new tab The models were tested by use of all three markers for the 4-cM interval, on 7q, encompassing the NOS3 locus. Table 4 shows the results of two-point linkage analysis, using allele frequencies provided by SPLINK; the findings were not altered significantly by the assignment of equal allele frequencies throughout. For all the models, linkage to NOS3i13 could be excluded with LOD<-2. As expected from the SLINK modeling, the low-penetrance AD/LP model provided smaller LOD scores than did the other three models, and linkage to the flanking markers could not be excluded in our preeclampsia pedigrees. However, for neither of the markers under the AD/LP model did the LOD scores approach the required threshold of 3+log(4) (Kidd and Ott Kidd and Ott, 1984Kidd KK Ott J Power and sample size in linkage studies.Hum Gene Mapping. 1984; 7: 510-511Google Scholar).Table 4Two-Point Linkage Results for the Four Models TestedLOD Score at θ =Model and Marker.00.01.05.10.20.30.40AD: D7S505−7.22−5.52−3.01−1.59−.34.08.14 NOS3i13−9.76−8.40−5.41−3.44−1.40−.46−.07 D7483−2.37−2.05−1.27−.80−.41−.26−.15AD/LP: D7S505−1.56−1.40−.90−.49−.07.07.07 NOS3i13−2.08−1.86−1.20−.67−.12.07.08 D7483.34.39.51.53.39.17.02AR: D7S505−∞−7.02−3.63−2.08−.74−.23−.04 NOS3i13−∞−7.69−3.98−2.16−.58−.04.07 D7483−∞−3.80−1.46−.50.11.14.03AO: D7S505−3.20−2.51−1.03−.22.32.34.20 NOS3i13−6.03−5.05−2.92−1.63−.47−.06.04 D7483−1.91−1.59−.86−.43−.13−.09−.08 Open table in a new tab These results, therefore, have failed to confirm linkage of preeclampsia to a chromosome 7q 4-cM region containing the NOS3 gene, as reported by Arngrímsson et al. (Arngrímsson et al., 1997Arngrímsson R Hayward C Nadaud S Baldursdóttir A Walker JJ Liston WA Bjarnadóttir RI et al.Evidence for a familial pregnancy-induced hypertension locus in the eNOS-gene region.Am J Hum Genet. 1997; 61: 354-362Abstract Full Text PDF PubMed Scopus (117) Google Scholar). This failure occured despite use of a similar combination of ASPs and conventional two-point linkage in pedigrees. Our study used two independently ascertained collections of ASPs, containing a total of 104 ASPs that appeared to be powered adequately. We have estimated the λs for preeclampsia at ∼10, assuming a local prevalence of preeclampsia (using our strict definition) of some 2%. Since our total ASP collection contains 70 fully informative pairs (estimated by SPLINK) for the NOSi13 marker, an expected maximized LOD score of 7.6 is given (Risch Risch, 1990Risch N Linkage strategies for genetically complex traits. II. The power of affected relative pairs.Am J Hum Genet. 1990; 46: 229-241PubMed Google Scholar). Even if λs has been overestimated, a figure of 5 would still result in a LOD score substantially >3 (actually 5.7). Our inability to replicate the earlier linkage report could reflect population differences, although both studies are based on white northern Europeans. It is possible that significant differences in our definition of the preeclampsia phenotype may be important, although the differences in our method of ASP analysis seem unlikely. We have focused in our study only on ASPs with a definite diagnosis of preeclampsia, excluding ones in which the diagnosis either is uncertain or is consistent only with isolated PIH. Nevertheless, Arngrímsson et al. (Arngrímsson et al., 1997Arngrímsson R Hayward C Nadaud S Baldursdóttir A Walker JJ Liston WA Bjarnadóttir RI et al.Evidence for a familial pregnancy-induced hypertension locus in the eNOS-gene region.Am J Hum Genet. 1997; 61: 354-362Abstract Full Text PDF PubMed Scopus (117) Google Scholar) report that the significance of the excess allele sharing was not substantially altered by removal of the milder phenotypes from the sib-pair analysis. Our method of sib-pair analysis relies on a maximum-likelihood method (SPLINK) to calculate allele sharing that is IBD. The SPLINK program is able to utilize parental genotype data, although this was not available for most of our ASPs. The previous linkage study on 7q also used a likelihood ratio–based method (SIBPAIR), as well as direct testing of increased identity by state (IBS) sharing (APM). A recent comparison of the various methods available to detect linkage in nuclear pedigrees, including sib pairs, showed the superiority of IBD-based programs versus IBS-based programs (Davis and Weeks Davis and Weeks, 1997Davis S Weeks DE Comparison of nonparametric statistics for detection of linkage in nuclear families, single-marker evaluation.Am J Hum Genet. 1997; 61: 1431-1444Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar). In this comparison, SPLINK actually showed comparable power to detect linkage with the SIBPAIR program, except when additional genotypes were available from unaffected members, which was not the case in this study. Our choice of SPLINK, therefore, is unlikely to have increased the possibility of a false-negative result. The previous positive sib-pair analysis reported by Arngrímsson's group was also supported by two-point linkage results from their pedigree collection (Arngrímsson et al. Arngrímsson et al., 1997Arngrímsson R Hayward C Nadaud S Baldursdóttir A Walker JJ Liston WA Bjarnadóttir RI et al.Evidence for a familial pregnancy-induced hypertension locus in the eNOS-gene region.Am J Hum Genet. 1997; 61: 354-362Abstract Full Text PDF PubMed Scopus (117) Google Scholar). They investigated a number of different models, reported elsewhere, from the literature. The LOD score, maximized over the five models, was 4.03, by use of the D7S505 flanking marker rather than the NOS3i13 marker. This suggests that the preeclampsia locus may be some distance away from the NOS3 gene itself, although the NOS3i13 marker and the preeclampsia locus must be in linkage disequilibrium, on the basis of their transmission/disequilibrium-test results. Adopting a similar parametric analysis in our own preeclampsia pedigrees, we have failed to demonstrate a LOD score high enough to confirm linkage in any of the models. In fact, the LOD scores generated actually have enabled us to exclude linkage in all of them, except the AD/LP model. Using the AD/LP model, we did find a small, nonsignificant LOD score, using a flanking marker, but it was by use of D7S483 and not D7S505—that is, at the opposite end of the 7q interval. A key role for endothelium-derived NO in pregnancy is well supported. An eNOS inhibitor, for example, infused chronically into pregnant animals, produces a preeclampsia-like state, with hypertension, proteinuria, thrombocytopenia, and growth retardation (Molnar and Hertelendy Molnar and Hertelendy, 1992Molnar M Hertelendy F N-nitro-L-arginine, an inhibitor of nitric oxide synthesis, increases blood pressure in rats and reverses the pregnancy-induced refractoriness to vaspressor agents.Am J Obstet Gynecol. 1992; 166: 1560-1567Abstract Full Text PDF PubMed Scopus (178) Google Scholar). More-recent findings also provide direct evidence for the role of NO production in the fall in peripheral vascular resistance (and blood pressure) seen in normal human pregnancy (Knock and Poston Knock and Poston, 1996Knock GA Poston L Bradykinin-mediated relaxation of isolated maternal resistance arteries in normal pregnancy and preeclampsia.Am J Obstet Gynecol. 1996; 175: 1668-1674Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar). It is possible that NO forms part of an adaptation pathway, to accommodate the cardiovascular changes of pregnancy and to prevent the development of maternal hypertension and the clinical syndrome of preeclampsia. However, although these data provide a tantalizing circumstantial argument for NOS3 being a candidate gene for preeclampsia, they do not prove that a primary abnormality in eNOS underlies the pathophysiology of preeclampsia. It is equally plausible that the observed changes in NO production during preeclampsia are secondary to free-radical damage of the vascular endothelium. In summary, then, we have been unable to replicate the previous report of linkage of preeclampsia to the region of the NOS3 gene. Although abnormalities in NO production have been observed in preeclampsia, we believe that the case for the NOS3 gene or its product, eNOS, having a primary role in the pathophysiology of preeclampsia remains unproved. Generous support for this work was provided by a project grant and Ph.D. studentship (to I.L.) from the British Heart Foundation." @default.
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• W2059697466 title "Failure to Detect Linkage of Preeclampsia to the Region of the NOS3 Locus on Chromosome 7q" @default.
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