Gene Expression Study in Positron Emission Tomography–Positive Abdominal Aortic Aneurysms Identifies CCL18 as a Potential Biomarker for Rupture Risk
Courtois, Audrey ; Nusgens-Richelle, Betty ; HUSTINX, Roland et al
in Molecular Medicine (2015)
Rupture of abdominal aortic aneurysm (AAA) is a cause of significant mortality and morbidity in ageing populations. Uptake of 18-fluorodeoxyglucose (FDG) detected by positron emission tomography (PET) is ... [more ▼]
Rupture of abdominal aortic aneurysm (AAA) is a cause of significant mortality and morbidity in ageing populations. Uptake of 18-fluorodeoxyglucose (FDG) detected by positron emission tomography (PET) is observed in the wall of 12% of AAA (A+), most of them being symptomatic. We previously showed that the metabolically active areas displayed adventitial inflammation, medial degeneration and molecular alterations prefacing wall rupture. The aim of this study was to identify new factors predictive of rupture.Transcriptomic analyses were performed in the media and adventitia layers from three types of samples: AAA without (A0) and with FDG uptake (A+), both at the positive spot (A+Pos) and at a paired distant negative site (A+Neg) of the same aneurysm. Follow-up studies included RT-PCR, immunohistochemical staining and ELISA. A large number of genes, including matrix metalloproteinases, collagens and cytokines as well as genes involved in osteochondral development, were differentially expressed in the A+Pos as compared to A+Neg. Moreover, a series of genes, notably CCL18, was differentially expressed both in the A+Neg and A+Pos as compared to the A0. A significant increase of CCL18 was also found at the protein level in the aortic wall and in peripheral blood of A+ patients as compared to A0.In conclusion, new factors, including CCL18, involved in the progression of AAA and, potentially, in their rupture were identified by a genome-wide analysis of PET-positive and negative human aortic tissue samples. Further work is needed to study their role in AAA destabilization and weakening. [less ▲]Detailed reference viewed: 46 (14 ULg)
Family Members of Patients with Abdominal Aortic Aneurysms are at Increased Risk for Aneurysms: Analysis of 618 Probands and their Families from the Liege AAA Family Study.
SakalihasanN, Natzi ; Defraigne, Jean-Olivier ; et al
in Annals of vascular surgery (2014), 28
BACKGROUND: The objectives were to answer the following questions using a well-characterized population in Liege, Belgium: 1) what percentage of abdominal aortic aneurysm (AAA) patients have a positive ... [more ▼]
BACKGROUND: The objectives were to answer the following questions using a well-characterized population in Liege, Belgium: 1) what percentage of abdominal aortic aneurysm (AAA) patients have a positive family history for AAA, 2) what is the prevalence of AAAs among relatives of AAA patients; and 3) do familial and sporadic AAA cases differ in clinical characteristics. METHODS AND RESULTS: Unrelated AAA patients diagnosed at the Cardiovascular Surgery Department, University Hospital of Liege, Belgium, between 1999 and 2012 were invited to the study. A detailed family history was obtained in interviews and recorded using Progeny software. In the initial interview 62 (10%) of the 618 AAA patients reported a positive family history for AAA. We divided the 618 patients into two study groups: Group I: 296 AAA patients (268; 91% males) were followed up with computerized tomography combined with positron emission tomography, and Group II: 322 AAA patients (295; 92% males) whose families were invited to ultrasonography screening. Ultrasonography screening identified 24 new AAAs among 186 relatives (>/= 50 years) of 144 families yielding a prevalence of 13%. The highest prevalence (25%) was found among brothers. By combining the number of AAAs found by ultrasonography screening with those diagnosed previously the observed lifetime prevalence of AAA was estimated to be 32% in brothers. The familial AAA cases were more likely to have a ruptured AAA than the sporadic cases (8% vs. 2.4%; P<0.0001). CONCLUSIONS: The findings confirm previously found high prevalence of AAA among brothers, support genetic contribution to AAA pathogenesis and provide rationale for targeted screening of relatives of AAA patients. [less ▲]Detailed reference viewed: 41 (13 ULg)
Sex Differences in Abdominal Aortic Aneurysm: the Role of Sex Hormones.
Makrygiannis, Georgios ; Courtois, Audrey ; Drion, Pierre et al
in Annals of vascular surgery (2014), 28(8), 1946-1958
Abdominal aortic aneurysm (AAA) is a complex multifactorial disease with genetic and environmental components. AAA is more common in males, whereas women have a greater risk of rupture and more frequently ... [more ▼]
Abdominal aortic aneurysm (AAA) is a complex multifactorial disease with genetic and environmental components. AAA is more common in males, whereas women have a greater risk of rupture and more frequently have concomitant thoracic aortic aneurysms. Moreover, women are diagnosed with AAA about 10 years later and seem to be protected by female sex hormones. In this MEDLINE-based review of literature we examined human and animal, in vivo and in vitro studies, to further deepen our understanding of the sexual dimorphism of AAA. We focus on the role of sex hormones during the formation and growth of AAA. Endogenous estrogens and exogenous 17beta-estradiol were found to exert favorable actions protecting from AAA in animal models, whereas exogenous hormone replacement therapy in humans had inconclusive results. Androgens, known to have detrimental effects in the vasculature, in sufficient levels maintain the integrity of the aortic wall through their anabolic actions and act differentially in males and females, whereas lower levels of testosterone have been associated with AAA in humans. In conclusion, sex differences remain an important area of AAA research, but further studies especially in humans are needed. Furthermore, differential molecular mechanisms of sex hormones constitute a potential therapeutic target for AAA. [less ▲]Detailed reference viewed: 96 (44 ULg)
New Insights Into Aortic Diseases A Report From the Third International Meeting on Aortic Diseases (IMAD3)
; SakalihasanN, Natzi ; et al
in AORTA (2013), 1Detailed reference viewed: 42 (5 ULg)
Apolipoprotein(a) genetic sequence variants associated with systemic atherosclerosis and coronary atherosclerotic burden but not with venous thromboembolism.
; ; et al
in Journal of the American College of Cardiology (2012), 60(8), 722-9
OBJECTIVES: The purpose of this study is investigate the effects of variants in the apolipoprotein(a) gene (LPA) on vascular diseases with different atherosclerotic and thrombotic components. BACKGROUND ... [more ▼]
OBJECTIVES: The purpose of this study is investigate the effects of variants in the apolipoprotein(a) gene (LPA) on vascular diseases with different atherosclerotic and thrombotic components. BACKGROUND: It is unclear whether the LPA variants rs10455872 and rs3798220, which correlate with lipoprotein(a) levels and coronary artery disease (CAD), confer susceptibility predominantly via atherosclerosis or thrombosis. METHODS: The 2 LPA variants were combined and examined as LPA scores for the association with ischemic stroke (and TOAST [Trial of Org 10172 in Acute Stroke Treatment] subtypes) (effective sample size [n(e)] = 9,396); peripheral arterial disease (n(e) = 5,215); abdominal aortic aneurysm (n(e) = 4,572); venous thromboembolism (n(e) = 4,607); intracranial aneurysm (n(e) = 1,328); CAD (n(e) = 12,716), carotid intima-media thickness (n = 3,714), and angiographic CAD severity (n = 5,588). RESULTS: LPA score was associated with ischemic stroke subtype large artery atherosclerosis (odds ratio [OR]: 1.27; p = 6.7 x 10(-4)), peripheral artery disease (OR: 1.47; p = 2.9 x 10(-14)), and abdominal aortic aneurysm (OR: 1.23; p = 6.0 x 10(-5)), but not with the ischemic stroke subtypes cardioembolism (OR: 1.03; p = 0.69) or small vessel disease (OR: 1.06; p = 0.52). Although the LPA variants were not associated with carotid intima-media thickness, they were associated with the number of obstructed coronary vessels (p = 4.8 x 10(-12)). Furthermore, CAD cases carrying LPA risk variants had increased susceptibility to atherosclerotic manifestations outside of the coronary tree (OR: 1.26; p = 0.0010) and had earlier onset of CAD (-1.58 years/allele; p = 8.2 x 10(-8)) than CAD cases not carrying the risk variants. There was no association of LPA score with venous thromboembolism (OR: 0.97; p = 0.63) or intracranial aneurysm (OR: 0.85; p = 0.15). CONCLUSIONS: LPA sequence variants were associated with atherosclerotic burden, but not with primarily thrombotic phenotypes. [less ▲]Detailed reference viewed: 17 (4 ULg)
The same sequent variant on 9p21 associates with myocardial infarction, abdominal aortic aneurysm and intracranial aneurysm.
; ; et al
in Nature Genetics (2008), 40Detailed reference viewed: 9 (3 ULg)
Evidence for association between the HLA-DQA locus and abdominal aortic aneurysms in the Belgian population: a case control study.
; ; et al
in BMC Medical Genetics (2006), 7
BACKGROUND: Chronic inflammation and autoimmunity likely contribute to the pathogenesis of abdominal aortic aneurysms (AAAs). The aim of this study was to investigate the role of autoimmunity in the ... [more ▼]
BACKGROUND: Chronic inflammation and autoimmunity likely contribute to the pathogenesis of abdominal aortic aneurysms (AAAs). The aim of this study was to investigate the role of autoimmunity in the etiology of AAAs using a genetic association study approach with HLA polymorphisms. METHODS: HLA-DQA1, -DQB1, -DRB1 and -DRB3-5 alleles were determined in 387 AAA cases (180 Belgian and 207 Canadian) and 426 controls (269 Belgian and 157 Canadian) by a PCR and single-strand oligonucleotide probe hybridization assay. RESULTS: We observed a potential association with the HLA-DQA1 locus among Belgian males (empirical p = 0.027, asymptotic p = 0.071). Specifically, there was a significant difference in the HLA-DQA1*0102 allele frequencies between AAA cases (67/322 alleles, 20.8%) and controls (44/356 alleles, 12.4%) in Belgian males (empirical p = 0.019, asymptotic p = 0.003). In haplotype analyses, marginally significant association was found between AAA and haplotype HLA-DQA1-DRB1 (p = 0.049 with global score statistics and p = 0.002 with haplotype-specific score statistics). CONCLUSION: This study showed potential evidence that the HLA-DQA1 locus harbors a genetic risk factor for AAAs suggesting that autoimmunity plays a role in the pathogenesis of AAAs. [less ▲]Detailed reference viewed: 33 (8 ULg)
HLA-DQA is associated with abdominal aortic aneurysms in the Belgian population
; ; et al
in Annals of the New York Academy of Sciences (2006), 1085
Chronic inflammation and autoimmunity likely contribute to the pathogenesis of abdominal aortic aneurysms (AAAs). The aim of this study was to investigate the role of autoimmunity in the etiology of AAAs ... [more ▼]
Chronic inflammation and autoimmunity likely contribute to the pathogenesis of abdominal aortic aneurysms (AAAs). The aim of this study was to investigate the role of autoimmunity in the etiology of AAAs using a genetic association study approach with human leukocyte antigen (HLA) polymorphisms (HLA-DQA1, -DQB1, -DRB1 and -DRB3-5 alleles) in 387 AAA cases and 426 controls. We observed an association with the HLA-DQA1 locus among Belgian males, and found a significant difference in the HLA-DQA1 *0102 allele frequencies between AAA cases and controls. In conclusion, this study showed potential evidence that the HLA-DQA1 locus harbors a genetic risk factor for AAAs suggesting that autoimmunity plays a role in the pathogenesis of AAAs. [less ▲]Detailed reference viewed: 12 (1 ULg)
Genetic analysis of polymorphisms in biologically relevant candidate genes in patients with abdominal aortic aneurysms
; ; et al
in Journal of Vascular Surgery (2005), 41(6), 1036-1042
Background: Abdominal aortic aneurysms (AAAs) are characterized by histologic signs of chronic inflammation, destructive remodeling of extracellular matrix, and depletion of vascular smooth muscle cells ... [more ▼]
Background: Abdominal aortic aneurysms (AAAs) are characterized by histologic signs of chronic inflammation, destructive remodeling of extracellular matrix, and depletion of vascular smooth muscle cells. We investigated the process of extracellular matrix remodeling by performing a genetic association study with polymorphisms in the genes for matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), and structural extracellular matrix molecules in AAA. Our hypothesis was that genetic variations in one or more of these genes contribute to greater or lesser activity of these gene products, and thereby contribute to susceptibility for developing AAAs. Methods: DNA samples from 812 unrelated white subject (AAA, n = 387; controls, n = 425) were genotyped for 14 polymorphisms in 13 different candidate genes: MMP1(nt-1607), MMP2(nt-955), MMP3(nt-1612), MMP9(nt-1562), MMP10(nt+180), MMP12(nt-82), MMP13(nt-77), TIMP1(nt+434), TIMP1(rs;2070584), TIMP2(rs2009196), TIMP3(nt-1296), TGFBI(nt-509), ELN(nt+422), and COL3A1(nt+581). Odds ratios and P values adjusted for gender and country of origin using logistic regression and stratified by family history of AAA were calculated to test for association between genotype and disease status. Haplotype analysis was carried out for the two TIMP1 polymorphisms; in male subjects. Results: Analyses with one polymorphism per test without interactions showed an association with the two TIMP1 gene polymorphisms (nt+434, P =.0047; rs2070584, P =.015) in male subjects without a family history of AAA. The association remained significant when analyzing TIMP1 haplotypes (x(2) p =.014 and empirical P =.009). In addition, we found a significant interaction between the polymorphism and gender for MMP10 (P=.037) in cases without a family history of AAA, as well as between the polymorphism and country of origin for ELN (P =.0169) and TIMP3 (P =.0023) in cases with a family history of AAA. Conclusions: These findings suggest that genetic variations in TIMP1, TIMP3, MMP10, and ELN genes may contribute to the pathogenesis of AAAs. Further work is needed to confirm the findings in an independent set of samples and to study the functional role of these variants in AAA. It is noteworthy that contrary to a previous study, we did not find an association between the MMP9 (nt-1562) polymorphism and AAA, suggesting genetic heterogeneity of the disease. Clinical Relevance: Abdominal aortic aneurysms (AAAs) are an important cardiovascular disease, but the genetic and environmental risk factors, which contribute to individual's risk to develop an aneurysm, are poorly understood. Histologically, AAAs are characterized by signs of chronic inflammation, destructive remodeling of the extracellular matrix, and depletion of vascular smooth muscle cells. We hypothesized that genes involved in these events could harbor changes that make individuals more susceptible to developing aneurysms. This study identified significant genetic associations between DNA sequence changes in tissue inhibitor of metalloproteinase I (TIMP1), TIMP3, matrix metalloproteinase 10 (MMP10) and elastin (ELN) genes, and AAA. The results will require confirmation using an independent set of samples. After replication it is possible that these sequence changes in combination with other risk factors could be used in the future to identify individuals who are at increased risk for developing an AAA. [less ▲]Detailed reference viewed: 14 (1 ULg)
Genome scan for familial abdominal aortic aneurysm using sex and family history as covariates suggests genetic heterogeneity and identifies linkage to chromosome 19q13.
; ; et al
in Circulation (2004), 109(17), 2103-8
BACKGROUND: Abdominal aortic aneurysm (AAA) is a relatively common disease, with 1% to 2% of the population harboring aneurysms. Genetic risk factors are likely to contribute to the development of AAAs ... [more ▼]
BACKGROUND: Abdominal aortic aneurysm (AAA) is a relatively common disease, with 1% to 2% of the population harboring aneurysms. Genetic risk factors are likely to contribute to the development of AAAs, although no such risk factors have been identified. METHODS AND RESULTS: We performed a whole-genome scan of AAA using affected-relative-pair (ARP) linkage analysis that includes covariates to allow for genetic heterogeneity. We found strong evidence of linkage (logarithm of odds [LOD] score=4.64) to a region near marker D19S433 at 51.88 centimorgans (cM) on chromosome 19 with 36 families (75 ARPs) when including sex and the number of affected first-degree relatives of the proband (N(aff)) as covariates. We then genotyped 83 additional families for the same markers and typed additional markers for all families and obtained a LOD score of 4.75 (P=0.00014) with sex, N(aff), and their interaction as covariates near marker D19S416 (58.69 cM). We also identified a region on chromosome 4 with a LOD score of 3.73 (P=0.0012) near marker D4S1644 using the same covariate model as for chromosome 19. CONCLUSIONS: Our results provide evidence for genetic heterogeneity and the presence of susceptibility loci for AAA on chromosomes 19q13 and 4q31. [less ▲]Detailed reference viewed: 8 (4 ULg)
Familial abdominal aortic aneurysms: collection of 233 multiplex families.
; ; et al
in Journal of Vascular Surgery (2003), 37(2), 340-5
OBJECTIVE: This study investigated a large number of families in which at least two individuals were diagnosed with abdominal aortic aneurysms to identify the relationship of the affected relatives to the ... [more ▼]
OBJECTIVE: This study investigated a large number of families in which at least two individuals were diagnosed with abdominal aortic aneurysms to identify the relationship of the affected relatives to the proband. Subjects and Methods: Families for the study were recruited through various vascular surgery centers in the United States, Finland, Belgium, Canada, the Netherlands, Sweden, and the United Kingdom and through our patient recruitment website (www.genetics.wayne.edu/ags). RESULTS: We identified 233 families with at least two individuals diagnosed with abdominal aortic aneurysms. The families originated from nine different nationalities, but all were white. There were 653 aneurysm patients in these families, with an average of 2.8 cases per family. Most of the families were small, with only two affected individuals. There were, however, six families with six, three with seven, and one with eight affected individuals. Most of the probands (82%) and the affected relatives (77%) were male, and the most common relationship to the proband was brother. Most of the families (72%) appeared to show autosomal recessive inheritance pattern, whereas in 58 families (25%), abdominal aortic aneurysms were inherited in autosomal dominant manner, and in eight families, the familial aggregation could be explained by autosomal dominant inheritance with incomplete penetrance. In the 66 families where abdominal aortic aneurysms were inherited in a dominant manner, 141 transmissions of the disease from one generation to another were identified, and the male-to-male, male-to-female, female-to-male, and female-to-female transmissions occurred in 46%, 11%, 32%, and 11%, respectively. CONCLUSION: Our study supports previous studies about familial aggregation of abdominal aortic aneurysms and suggests that first-degree family members, male relatives, in particular, are at increased risk. No single inheritance mode could explain the occurrence of abdominal aortic aneurysms in the 233 families studied here, suggesting that abdominal aortic aneursyms are a multifactorial disorder with multiple genetic and environmental risk factors. [less ▲]Detailed reference viewed: 44 (5 ULg)