Genome-wide linkage in three Dutch families maps a locus for abdominal aortic aneurysms to chromosome 19q13.3.

OBJECTIVES: Elucidation of the genetic background of familial abdominal aortic aneurysm (AAA) suggests a genetic etiology. METHODS AND RESULTS: We carried out a genome-wide scan in three Dutch families with four or five affected siblings. Suggestive loci were further studied by subsequent fine mapping of the locus performed in 101 affected sib-pairs. The genome-wide scan was performed with 400 DNA markers and results were given as non-parametric, multipoint linkage scores (NPL). We observed a suggestive linkage for AAA (NPL score 3.25 at D19S902, 72.72 cM) on chromosome 19q in the three families. After fine mapping on chromosome 19, the NPL score became nominal in the 101 affected sib-pairs. A separate analysis of the three families with fine mapping revealed a peak with significant evidence for linkage (NPL score 3.95 at D19S904, 78.08 cM) on chromosome 19q. This peak was situated to the right compared to the region found in a previously published article for familial AAA on chromosome 19q. CONCLUSIONS: Our results identified a candidate locus in three Dutch families with AAA at chromosome 19q13.3. Separate analysis of these three families provides evidence for genetic heterogeneity.     

Linkage/association study of a locus modulating total serum IgE on chromosome 14q13-24 in families with asthma

BACKGROUND: A study was undertaken to validate a locus modulating total serum IgE levels on 14q13-24. METHODS: A linkage and association study was performed between total serum IgE and a panel of seven microsatellites which map to the 14q13-24 region in 69 families with asthma recruited from Leeds, UK. RESULTS: Non-parametric, multipoint, sib pair analysis showed no evidence of genetic linkage between the quantitative trait "log IgE" and any of the tested markers. However, a significant association was observed between locus D14S63 (14q23) and total serum IgE (p = 0.017). Allelic analysis showed an association between low total IgE and allele 157 of D14S63 (p = 0.01, OR = 0.63, 95% CI 0.44 to 0.90). Modelling of allele 157 genotypes as a continuous covariate indicated evidence of a significant inverse linear trend across the three genotypes where 157 homozygotes had the lowest mean log IgE (p = 0.045). Association of D14S63 with log IgE was confirmed in the analysis of a combined dataset of 53 families from Southampton, UK and the 69 families from Leeds (total 122 families). An association was observed at the locus level (p = 0.022) and the allelic level where allele 165 showed an association with high total IgE (p = 0.001, OR = 3.79, 95% CI 1.54 to 9.7) and allele 157 showed an association with low total IgE (p = 0.041, OR = 0.77, 95% CI 0.6 to 0.99). The transmission disequilibrium test was positive for allele 165 (p<0.05) and negative for allele 157 (p>0.05). CONCLUSIONS: Despite the lack of linkage, the findings of this study support the previous observation of a gene(s) at 14q23 that modulates total serum IgE.     

Connective tissue growth factor expression is decreased in acute ascending aortic dissections and increased in degenerative ascending aortic aneurysms

Purpose. Both aortic aneurysms and aortic dissections exhibit abnormal extracellular matrix properties. Connective tissue growth factor (CTGF) can induce connective tissue cell proliferation and extracellular matrix synthesis. The role of CTGF in thoracic aortic disease has never been investigated. We sought to compare the expression of CTGF in degenerative ascending aortic aneurysms and ascending aortic dissection. Methods. Intraoperative samples of ascending aorta were obtained from 47 patients: 16 patients had ascending aortic aneurysms with medial degeneration, 10 had acute aortic dissection, 9 had aneurysms due to chronic dissection. Control ascending aorta was obtained from organ donors and heart transplant recipients (n = 10). Patients with Marfan syndrome were excluded from this study. CTGF mRNA expression within aortic wall was semiquantitatively determined by real-time RT-PCR using GAPDH as the internal standard. Results. There was a significant increase in CTGF mRNA in degenerative aneurysms compared to control tissue (P = 0.04). Conversely, patients with acute dissection had decreased CTGF mRNA expression compared with nondissection aneurysms (P = 0.019) and controls (P = 0.06). The increase in CTGF expression in chronic dissections compared to acute dissections approached statistical significance (P = 0.075). Conclusions. The altered tissue levels of CTGF in aneurysms and dissections suggest possibly different molecular pathology in these aortic disorders. Further investigation regarding the role of CTGF in thoracic aortic disease is warranted.     

Genome-wide scan for type 1 diabetic nephropathy in the Finnish population reveals suggestive linkage to a single locus on chromosome 3q

Diabetic nephropathy (DN) is the primary cause of morbidity and mortality in patients with type 1 as well as type 2 diabetes, and accounts for 40% of end-stage renal disease in the Western world. Familial clustering of DN suggests importance of genetic factors in the development of the disease. In the present study, we performed a two-stage genome-wide scan to search for chromosomal loci containing susceptibility genes for nephropathy in patients with type 1 diabetes. In total, 83 discordant sib pairs (DSPs), sibs concordant for type 1 diabetes but discordant for nephropathy, were collected from Finland, a homogeneous population with one of the highest incidences of type 1 diabetes. To map loci for DN, we applied DSP analysis to detect linkage. In the initial scan, 73 DSPs were typed using 900 markers with an average intermarker distance of approximately 4 cM. Multipoint DSP analysis identified five chromosome regions (3q, 4p, 9q, 16q, and 22p) with maximum logarithm of odds (LOD) score (MLS) >or=1.0 (corresponding to a nominal P-value 相似文献   

A sib-pair analysis study of 15 candidate genes in French families with morbid obesity: indication for linkage with islet 1 locus on chromosome 5q.

As part of an ongoing search for susceptibility genes in obese families, we performed linkage analyses in 101 French families between qualitative and quantitative traits related to morbid obesity and polymorphisms located in or near 15 candidate genes whose products are involved in body weight regulation. These included cholecystokinin A and B receptors (CCK-AR and CCK-BR), glucagon-like peptide 1 receptor (GLP-1R), the LIM/homeodomain islet-1 gene (Isl-1), the caudal-type homeodomain 3 (CDX-3), the uncoupling protein 1 (UCP-1), the beta3-adrenoceptor (beta3-AR), the fatty acid-binding protein 2 (FABP-2), the hormone-sensitive lipase (HSL), the lipoprotein lipase (LPL), the apoprotein-C2 (apo-C2), the insulin receptor substrate-1 (IRS-1), the peroxisome proliferator-activated receptor-gamma (PPAR-gamma), tumor necrosis factor-alpha (TNF-alpha), and the liver carnitine palmitoyltransferase-1 (CPT-1). Phenotypes related to obesity such as BMI, adult life body weight gain, fasting leptin, insulin, fasting glycerol, and free fatty acids were used for nonparametric sib-pair analyses. A weak indication for linkage was obtained between the Isl-1 locus and obesity status defined by a z score over one SD of BMI (n = 226 sib pairs, pi = 0.54 +/- 0.02, P = 0.03). Moreover, a suggestive indication for linkage was found between the Isl-1 locus and BMI and leptin values (P = 0.001 and 0.0003, respectively) and leptin adjusted for BMI (P = 0.0001). Multipoint analyses for leptin trait with Isl-1 and two flanking markers (D5S418 and D5S407) showed that the logarithm of odds (LOD) score is 1.73, coinciding with the Isl-1 locus. Although marginally positive indications for linkage in subgroups of families were found with IRS-1, CPT-1, and HSL loci, our data suggested that these genes are not major contributors to obesity. Whether an obesity susceptibility gene (Isl-1 itself or another nearby gene) lies on chromosome 5q should be determined by further analyses.     

Genetic linkage of candidate genes in families with abdominal aortic aneurysms?

OBJECTIVES: to examine possible involvement of several candidate genes in the aetiology of familial abdominal aortic aneurysm (AAA). DESIGN: after reviewing the literature on the genetics of familial AAA, betaine homocysteine methyltransferase (BHMT), collagen type Ialpha2 (COL1A2) and cathepsin H (CTSH), were selected as potential candidate genes, which influence structure, strength, elasticity and mechanical resistance of the aortic wall. MATERIALS: forty-eight families with 110 family members and AAA were included in the affected sib-pair analysis. One large family of three generations was analysed separately because in this family also other clinical symptoms were involved. METHODS: genetic linkage analysis was performed with DNA markers in the region of BHMT, COL1A2 and CTSH. RESULTS: In the overall sib-pair analysis, the LOD scores for BHMT, COL1A2 and CTSH were 0.7, 0.2 and -0.7, whereas in the large family these numbers were -0.6, -2.2 and -2.7, respectively. CONCLUSIONS: none of the candidate genes selected showed a suggestive linkage with AAA. Exclusion of the COL1A2 and CTSH genes was possible in the large family that was analysed separately.     

Familial nephrotic syndrome: clinical spectrum and linkage to chromosome 19q13

BACKGROUND: Familial nephrotic syndrome (NS) has both autosomal dominant and recessive forms of inheritance. Recent studies in families with an autosomal dominant form of focal segmental glomerulosclerosis (FSGS) have been at odds concerning linkage to chromosome 19q13 (Mathis et al, Kidney Int 53:282-286, 1998; Winn et al, Kidney Int 55:1241-1246, 1999), suggesting genetic heterogeneity. This study examines the clinical features and confirms linkage to chromosome 19q13 in a family with autosomal dominant NS. METHODS: DNA samples were obtained from 16 of 17 family members. Genomic DNA was isolated, and polymerase chain reaction was performed for five markers spanning the area of interest on chromosome 19q13. Data were evaluated using two- and six-point linkage analysis. RESULTS: Clinical features included presentation of NS in childhood, steroid unresponsiveness, and slow progression to renal failure. Renal biopsy in affected family members showed lesions ranging from minimal change to mesangial proliferative glomerulonephritis to FSGS. Linkage was confirmed between the disease state and chromosome 19q13, with a maximum logarithm of odds (LOD) score of 2.41. Linkage was observed for a 7 cM region on chromosome 19q13, defined by markers D19S425 and D19S220. CONCLUSIONS: This study confirms the Mathis et al report of linkage to chromosome 19q13 in a family with autosomal dominant NS. However, there were notable differences in the presenting clinical and histopathologic features of our affected family members compared with those of Mathis et al. This suggests that the gene on chromosome 19q13 may be responsible for considerable phenotypic heterogeneity and variable expression in both clinical presentation and renal histopathology.     

A long-term experience with the Cabrol root replacement technique for the management of ascending aortic aneurysms and dissections

BACKGROUND: Little information exists regarding the long-term results of the Cabrol technique. This study aimed at exploring, over a 16-year period, the results of aortic root replacements employing this procedure. METHODS: Between 1986 and 2002 forty-five patients (mean age 58.7 +/- 13.8 years old, 84.4% male) underwent a Cabrol procedure. Aortic dissection was the most frequent cause of aortic disease in this series (n = 17), followed by annuloaortic ectasia (n = 10), atherosclerotic aneurysm (n = 5) and poststenotic dilatation (n = 5). Six patients (13.4%) had undergone a previous aortic operation, 8 (17.7%) had a Marfan syndrome and five (11.1%) underwent concomitant arch replacement. Mean clinical follow-up was 87.3 +/- 24.3 months. Twenty-eight patients (93.3% of survivors) had a transesophageal echocardiography (TEE) performed at a mean of 64 +/- 32 months postoperatively. RESULTS: Early mortality was 20%. It was 9.1% for patients with an ascending aortic aneurysm and 41.2% for dissections (p = 0.026). Independent multivariate predictors of early mortality were: aortic dissection (p = 0.009), emergency operation (p < 0.001), operative year (p = 0.02), cross-clamp time (p = 0.001), and CPB duration (p < 0.001). Actuarial survival was 0.77 +/- 0.06, 0.72 +/- 0.06, 0.59 +/- 0.04 and 0.59 +/- 0.04 at 1, 5, 10, and 16 years, respectively. Multivariate analysis revealed age (p = 0.007), cross-clamp time (p = 0.0006) and CPB duration (p = 0.009) as strong predictors of poor late survival. A periprosthetic jet with significant valve regurgitation was detected by TEE in 3 patients. In one of them, an infected periprosthetic space-right ventricular fistula was demonstrated requiring reoperation. Altogether, freedom from reoperation and endocarditis at 16 years was 0.97 +/- 0.02 and 0.94 +/- 0.03, respectively. CONCLUSIONS: The Cabrol technique demonstrated a nonnegligible incidence of early and long-term complications. It should be rarely used and only when a "button" technique is not feasible.     

Quantitative trait linkage analysis of lipid-related traits in familial type 2 diabetes: evidence for linkage of triglyceride levels to chromosome 19q.

Macrovascular disease is a major complication of type 2 diabetes. Epidemiological data suggest that the risk of macrovascular complications may predate the onset of hyperglycemia. Hypertriglyceridemia, low levels of HDL cholesterol, and an atherogenic profile characterize the insulin resistance/metabolic syndrome that is also prevalent among nondiabetic members of familial type 2 diabetic kindreds. To identify the genes for lipid-related traits, we first performed a 10-cM genome scan using 440 markers in 379 members of 19 multiplex families ascertained for two diabetic siblings (screening study). We then extended findings for three regions with initial logarithm of odds (LOD) scores >1.5 to an additional 23 families, for a total of 576 genotyped individuals (extended study). We found heritabilities for all lipid measures in the range of 0.31 to 0.52, similar to those reported by others in unselected families. However, we found the strongest evidence for linkage of triglyceride levels to chromosome 19q13.2, very close to the ApoC2/ApoE/ApoC1/ApoC4 gene cluster (LOD 2.56) in the screening study; the LOD increased to 3.16 in the extended study. Triglyceride-to-HDL cholesterol ratios showed slightly lower LOD scores (2.73, extended family) in this same location. Other regions with LOD scores >2.0 included HDL linkage to chromosome 1q21-q23, where susceptibility loci for both familial type 2 diabetes and familial combined hyperlipidemia have been mapped, and to chromosome 2q in the region of the NIDDM1 locus. Neither region showed stronger evidence for linkage in the extended studies, however. Our results suggest that genes in or near the ApoE/ApoC2/ApoC1/ApoC4 cluster on 19q13.2 may contribute to the commonly observed hypertriglyceridemia and low HDL seen in diabetic family members and their offspring, and thus may be a candidate locus for the insulin resistance syndrome.     

Genome-wide linkage analysis for severe obesity in french caucasians finds significant susceptibility locus on chromosome 19q

To ascertain whether distinct chromosomal loci existed that were linked to severe obesity, as well as to utilize the increased heritability of this excessive phenotype, we performed a genome-wide scan in severely obese French Caucasians. The 109 selected pedigrees, totaling 447 individuals, required both the proband and a sibling to be severely obese (BMI >or=35 kg/m(2)), and 84.8% of the nuclear families possessed >or=1 morbidly obese sibling (BMI >or=40). Severe and morbid obesity are still relatively rare in France, with rates of 2.5 and 0.6%, respectively. The initial genome scan consisted of 395 evenly spaced microsatellite markers. Six regions were found to have suggestive linkage on 4q, 6cen-q, 17q, and 19q for a BMI >or=35 phenotypic subset, and 5q and 10q for an inclusive BMI >or=27 group. The highest peak on chromosome 19q (logarithm of odds [LOD] = 3.59) was significant by genome scan simulation testing (P = 0.042). These regions then underwent second-stage mapping with an additional set of 42 markers. BMI >or=35 analysis defined regions on 17q23.3-25.1 and 19q13.33-13.43 with an maximum likelihood score LOD of 3.16 and 3.21, respectively. Subsequent pooled data analysis with an additional previous population of 66 BMI >or=35 sib-pairs led to a significant LOD score of 3.8 at the 19q locus (empirical P = 0.023). For more moderate obesity and overweight susceptibility loci, BMI >or=27 analysis confirmed suggestive linkage to chromosome regions 5q14.3-q21.3 (LOD = 2.68) and 10q24.32-26.2 (LOD = 2.47). Plausible positional candidate genes include NR1H2 and TULP2.     

A locus for adolescent and adult onset familial focal segmental glomerulosclerosis on chromosome 1q25-31

Focal segmental glomerulosclerosis is a nonspecific renal lesion observed both as a primary (idiopathic) entity and in a secondary form, typically in association with reduced functional renal mass. Familial forms have been observed and two loci for autosomal dominant FSGS have been mapped. This study shows that an adolescent/adult form of recessive FSGS maps to a locus on chromosome 1q25-31, which overlaps with a region previously identified as harboring a locus for an early childhood onset recessive form of nephrotic syndrome (SRN1). Evaluation of a large family demonstrated linkage with a maximum two-point lod score of 3.98 at D1S254 and D1S222. Lod score calculations support the conclusion of linkage in four of five additional families. Haplotype analysis suggests that this FSGS gene is located in a 19-cM region flanked by D1S416 and D1S413, of which 6 cM overlaps with SRN1, suggesting that these distinct clinical subsets of kidney disease may be allelic. These regions may also overlap with the syntenic region of the glomerulosclerosis susceptibility locus in the BUF/Mna rat. Because the presentation of FSGS may be subtle, inherited FSGS may be much more common than generally realized and grossly underestimated because of the absence of clear familial patterns. This result increases the suspicion that polymorphisms at this locus may contribute to sporadic FSGS.     

Hybrid-procedures for the treatment of thoracoabdominal aortic aneurysms and dissections.

AIM: The conventional open repair of thoracoabdominal aneurysms and dissections remains complex and demanding and is associated with significant morbidity and mortality. We present our experience of hybrid open and endovascular treatment of thoracoabdominal aneurysms and dissections. METHODS: Within an experience of 226 aortic stent-grafts between 1998 and April 2006, 6 of the patients (median age 60 years, range 35 to 68 years) with thoracoabdominal aneurysms (Crawford type I, II, III, and V) were treated with a combined endovascular and open surgical approach. Five men and one woman, with median aneurysm diameter of 75 mm (range 70-100 mm), received revascularization of the renal arteries, the superior mesenteric artery, and the coeliac trunk accomplished via transperitoneal bypass grafting. Aneurysmal exclusion was then performed by stent-graft deployment. RESULTS: The entire procedure was technically successful in all patients. The patients were discharged a median of 9 days after the operation, while the postoperative studies revealed the patency of the vessels and no evidence of type I endoleak or secondary rupture of the aneurysm. During follow up (1 to 22 months) spiral-CT scanning revealed distinct shrinkage of the aneurysm, no graft migration or endoleak and patency of all revascularised vessels, except one renal artery in two patients. No patient experienced any temporary or permanent neurological deficit, and no dialysis was necessary. CONCLUSION: The combined endovascular and open surgical approach is feasible, without cross clamping of the aorta and with minimized ischemia time for renal and visceral arteries, and seems to be an appropriate strategy for patients with a thoraco-abdominal aortic aneurysm or dissection.     

Hybrid procedures for the treatment of thoracoabdominal aortic aneurysms and dissections

The search for less invasive therapeutic approaches to thoracoabdominal aortic aneurysms (TAAAs) brought endovascular procedures to establish themselves as alternatives to open surgery in high-risk patients. Aim of this study is to illustrate the hybrid - open and endovascular - treatment of dissecting and non-dissecting TAAAs, and to analyze short and midterm results at our Center. We analyzed 41 high-risk patients who underwent hybrid TAAA repair (dissecting TAAA in 17% of cases) with a variety of visceral rerouting configuration and of commercially available thoracic endografts. Thirty-one simultaneous (76%) and 10 staged procedures (24%) were performed with a four-vessel revascularization in 13 cases (32%), a three-vessel in 9 (22%) and a two-vessel in 19 (46%). No intraoperative deaths were observed in our series, with a technical success in endovascular TAAA repair of 100%. Two patients died in the intersurgical time. A perioperative mortality of 13% and a perioperative morbidity of 32% were recorded, including one case (2.4%) of permanent paraplegia. At a median follow-up of 23.3 months, we observed a visceral graft occlusion rate of 6%, three type II endoleak and one endograft migration. Six patients died for unrelated events. Typical complications of conventional TAAA open surgery have been not eliminated by hybrid repair and still significant mortality and morbidity have been reported. Dissecting etiology did not negatively affect the outcome of hybrid repair in our experience. Fate of visceral bypasses and incidence of endoleak and other endograft-related complications need to be carefully assessed. Hybrid TAAA repair should nowadays be limited as alternative to simple observation in patients unfit for the conventional open repair.     

Hybrid procedures for thoracoabdominal aortic aneurysms and chronic aortic dissections - a single center experience in 28 patients

OBJECTIVE: We report our 6-year experience with the visceral hybrid procedure for high-risk patients with thoracoabdominal aortic aneurysms (TAAA) and chronic expanding aortic dissections (CEAD). METHODS: Hybrid procedure includes debranching of the visceral and renal arteries followed by endovascular exclusion of the aneurysm. A series of 28 patients (20 male, mean age 66 years) were treated between January 2001 and July 2007. Sixteen patients had TAAAs type I-III, one type IV, four thoracoabdominal placque ruptures, and seven patients CEAD. Patients were treated for asymptomatic, symptomatic, and ruptured aortic pathologies in 20, and 4 patients, respectively. Two patients had Marfan's syndrome; 61% had previous infrarenal aortic surgery. The infrarenal aorta was the distal landing zone in 70%. In elective cases, simultaneous approach (n = 9, group I) and staged approach (n = 11, group II) were performed. Mean follow-up is 22 months (range 0.1-78). RESULTS: Primary technical success was achieved in 89%. All stent grafts were implanted in the entire thoracoabdominal aorta. Additionally, three patients had previous complete arch vessel revascularization. Left subclavian artery was intentionally covered in three patients (11%). Thirty-day mortality rate was 14.3% (4/28). One patient had a rupture before the staged endovascular procedure and died. Overall survival rate at 3 years was 70%, in group I 80%, and in group II 60% (P = .234). Type I endoleak rate was 8%. Permanent paraplegia rate was 11%. Three patients required long-term dialysis (11%). Peripheral graft occlusion rate was 11% at 30 days. Gut infarction with consecutive bowel resection occurred in two patients. There was no significant difference between group I and II regarding paraplegia and complications. CONCLUSIONS: Early results of visceral hybrid repair for high-risk patients with complex and extended TAAAs and CEADs are encouraging in a selected group of high risk patients in whom open repair is hazardous and branched endografts are not yet optional.     

Left subclavian artery management in endovascular repair of thoracic aortic aneurysms and aortic dissections

PURPOSE: The purpose is to report our experience and revise our previously published results in endovascular repair of short-necked thoracic aortic aneurysms or aortic type B dissections, in which the left subclavian artery (LSA) was occluded by the stent graft intentionally.METHODS: Seven patients with an aortic type B dissection and three patients who had a thoracic aortic aneurysm were treated endovascularly with stent grafts. In all patients the ostium of the LSA was occluded by the stent graft, only in two patients a primary, prophylactic revascularization of the LSA was performed by transposition to the left common carotid artery (LCA). Two types of stent grafts were used: the Talent (Medtronic) and the Excluder (Gore) stent graft. RESULTS: In all patients the sealing of the entry tear in aortic dissections and the exclusion of existing thoracic aortic aneurysms were achieved. No immediate neurological deficit or left arm ischemia occurred. Nevertheless, during a mean follow-up of 18 months (2 to 31 months) in three patients a second surgical intervention had to be performed due to subclavian steal syndrome, left arm ischemia, or continuing perfusion of the dissected false aortic channel. CONCLUSION: Intentional occlusion of the LSA in stent-graft repair of thoracic aortic diseases seems to be a safe procedure. Close follow-up is needed due to arising subclavian steal syndrome, arm ischemia, or persistent perfusion of the false channel via LSA in aortic dissections after patients' discharge, requiring surgical intervention.