Magdalena Skunca

Genome Scan for Familial Abdominal Aortic Aneurysm Using Sex and Family History as Covariates Suggests Genetic Heterogeneity and Identifies Linkage to Chromosome 19q13

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 (Naff) 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, Naff, 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.

Intracranial Aneurysms in Finnish Families: Confirmation of Linkage and Refinement of the Interval to Chromosome 19q13.3

We recently reported a two-stage genomewide screen of 48 sib pairs affected with intracranial aneurysms (IAs) that revealed suggestive linkage to chromosome 19q13, with a LOD score of 2.58. The region supporting linkage spanned approximately 22 cM. Here, we report a follow-up study of the locus at 19q13, with a sample size expanded to 139 affected sib pairs, along with 83 other affected relative pairs (222 affected relative pairs in total). Suggestive linkage was observed in both independent sample sets, and linkage was significant in the combined set at 70 cM (LOD score 3.50; P=.00006) and at 80 cM (LOD score 3.93; P=.00002). Linkage was highly significant at 70 cM (LOD score 5.70; P=.000001) and at 80 cM (LOD score 3.99; P=.00005) when a covariate measuring the number of affected individuals in the nuclear family was included. To evaluate further the contribution to the linkage signal from families with more than two affected relatives, we performed model-based linkage analysis with a recessive model and a range of penetrances, and we obtained maximum linkage at 70 cM (LOD score 3.16; P=.00007) with a penetrance of 0.3. We then estimated location by using GENEFINDER. The most likely location for a gene predisposing to IAs in the Finnish population is in a region with a 95% confidence interval of 11.6 cM (P=.00007) centered 2.0 cM proximal to D19S246.

Evidence for association between the HLA-DQA locus and abdominal aortic aneurysms in the Belgian population: a case control study

BackgroundChronic 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.MethodsHLA-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.ResultsWe 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).ConclusionThis 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.

Global expression profiles in human normal and aneurysmal abdominal aorta based on two distinct whole genome microarray platforms

Abstract:  Abdominal aortic aneurysms (AAA) are the thirteenth cause of death in the United States. The etiology of the disease is yet largely unknown, although several environmental risk factors (e.g., smoking) have been identified and the search for finding genetic risk factors has been initiated. The purpose of our study was to gain insight into the pathobiology of AAA by determining which genes are expressed in the abdominal aorta under either the diseased or normal states, thereby generating the whole‐genome‐wide expression profiles for these conditions.

HLA-DQA is associated with abdominal aortic aneurysms in the Belgian population

Abstract:  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.

Thymosin α1 does not promote growth or oncogenic transformation

Abstract Thymosin α1(Tα1) is an immune modulatory peptide which has been evaluated in a variety of clinical trials. Although no in vivo adverse effects, including enhancement of tumor growth, have been noted, in vitro studies suggesting a role for Tα1 in cell growth have been reported. The studies presented in this report evaluated both exogenously added Tα1 and endogenously expressed Tα1 as factors which could either promote growth of tumor cells or induce transformation. No effect of exogenous Tα1 on cell growth was found. NIH3T3 cells transfected with cDNA for the precursor ProThymosin α (ProTα) expressed elevated levels of authentic Tα1 but did not demonstrate either enhanced proliferation in liquid culture or transformation as defined by the loss of contact inhibition or anchorage independent growth in soft agar. Thus these studies argue against the hypothesis that Tα1 is either an intracellular or extracellular growth promoter.