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Hereditary angioneurotic edema (HAE) is an autosomal dominant disorder characterized by episodic local subcutaneous and submucosal edema caused by the deficiency of activated C1 esterase inhibitor protein (C1-INH, type I (C1NH): reduced serum antigen level, type II: reduced activity and normal serum antigen level). The aim of the present study was to determine the disease-causing mutations in the C1INH gene (SERPING1) among Hungarian HAE-patients. The estimated number of affected HAE-families in Hungary is 40-50, out of which 26 families (type I:23, type II:3) managed in a single center were enrolled in the current study. To detect large deletions/insertions, we used Southern-blotting analysis followed by real time PCR based gene dosage analysis. In the absence of large structural changes, we employed direct sequencing covering the whole coding region and splicing sites of the C1INH gene. Large deletions were detected in 4/23 (17.4%) type I families. We found the g.16788C>T (p.Arg444Cys) mutation in each 3, type II HAE-families. In the remaining type

The RCCX region is a complex, multiallelic, tandem copy number variation (CNV). Two complete genes, complement component 4 (C4) and steroid 21-hydroxylase (CYP21A2, formerly CYP21B), reside in its variable region. RCCX is prone to nonallelic homologous recombination (NAHR) such as unequal crossover, generating duplications and deletions of RCCX modules, and gene conversion. A series of allele-specific long-range polymerase chain reaction coupled to the whole-gene sequencing of CYP21A2 was developed for molecular haplotyping. By means of the developed techniques, 35 different kinds of CYP21A2 haplotype variant were experimentally determined from 112 unrelated European subjects. The number of the resolved CYP21A2 haplotype variants was increased to 61 by bioinformatic haplotype reconstruction. The CYP21A2 haplotype variants could be assigned to the haplotypic RCCX CNV structures (the copy number of RCCX modules) in most cases. The genealogy network constructed from the CYP21A2 haplotype variants delineated the origin of RCCX structures. The different RCCX structures were located in tight groups. The minority of groups with identical RCCX structure occurred once in the network, implying monophyletic origin, but the majority of groups occurred several times and in different locations, indicating polyphyletic origin. The monophyletic groups were often created by single unequal crossover, whereas recurrent unequal crossover events generated some of the polyphyletic groups. As a result of recurrent NAHR events, more CYP21A2 haplotype variants with different allele patterns belonged to the same RCCX structure. The intraspecific evolution of RCCX CNV described here has provided a reasonable expectation for that of complex, multiallelic, tandem CNVs in humans.

H ypertension is one of the most important risk factors for cardiovascular diseases. Despite extensive research examining the causes of blood pressure variation, a significant proportion of blood pressure variation is yet to be explained. Studies of families and twins suggest that 20-40% of blood pressure variation can be attributed to genetic factors.1 Evidence shows that the genetic contribution is even greater for young onset hypertension. 2 We feel that genetic approaches focusing on young onset hypertension will provide new insight into the pathogenesis of hypertension.In our previous report, the affected sib pairs (25 independent, affected sib pairs) method showed positive signs of linkage for markers of the atrial natriuretic peptide gene (NPPA) (D1S1612, p=0.0162), angiotensinogen gene (AGT) (D1S547, p=0.0263), lipoprotein lipase gene (LPL) (D8S1145, p=0.0284), and angiotensin converting enzyme gene (DCP1) (D17S2193, p=0.0256), 3 indicating that multiple pathogenic pathways may be involved in the aetiology of young onset hypertension. Owing to this aetiological complexity, in the current study we focus on high resolution mapping of AGT (located on 1q42-43) and DCP1 (located on 17q23), genes of the renin angiotensin system (RAS). Renin catalyses the first step of the activation pathway of angiotensinogen to angiotensin I, which is then cleaved to angiotensin II by angiotensin I converting enzyme. This cascade can lead to aldosterone release, vasoconstriction, and increased blood pressure. Although the RAS has been extensively studied, it remains unclear how and to what extent RAS gene variants contribute to the blood pressure variations in various human populations. MATERIALS AND METHODSWe have recruited 59 nuclear families (a total of 214 subjects) from a hypertension clinic at Taipei Veterans General Hospital, Taiwan. Our study group included 81 young onset hypertensive patients (59 probands and 22 affected sibs, mean age 30.4 (SD 0.95)), 39 normotensive sibs (mean age 32.2 (SD 1.6)), and 94 parents. Our previous study included 25 affected sib pairs from 18 families for affected sib pair analysis. This transmission disequilibrium test (TDT) study used information from all 59 families with probands. Therefore, the former is a subset of the latter. The protocol of this study was approved by the Human Investigation Committee of the Institute of Biomedical Sciences, Academia Sinica.Polymorphic microsatellite markers located on 1q42-43 and 17q23 were selected based on GeneMap'99 and comprehensive human genetic maps from the Marshfield Medical Research Foundation, and obtained from Multi-Colored Fluorescent Human MapPairs Markers of Research Genetics (Huntsville, AL). Nine markers on 1q42-43 were selected: D1S2805 (245.05 cM), D1S3462 (247.23 cM), D1S459 (247.23 cM), D1S1540 (252.12 cM), D1S235 (254.64 cM), D1S517 (262.96 cM), D1S1149 (262.96 cM), D1S1594 (265.49 cM), and D1S547 (267.51 cM). The six markers on 17q23 were D17S1297 (83.40 cM), D17S1295 (83.40 cM), D17S942 (85.94 cM), ATA108a05 (88.76 cM), D17...

Our present findings indicate that removal of atherosclerotic plaques from the carotid arteries markedly decreases the production of two acute phase proteins due to the decrease of the inflammatory burden or the removal of the advanced plaques able to produce these proteins.