| | The role of human leukocyte antigen genes in the formation of abdominal aortic aneurysmsReceived 21 July 2006; accepted 19 September 2006. BackgroundIncreasing evidence suggests an autoimmune component to abdominal aortic aneurysm (AAA) formation. This study was conducted to determine if a difference exists in human leukocyte antigen (HLA) allele distribution between patients with AAA and population controls, and between patients with small and large AAA. MethodsPatients with known AAA attending the vascular unit were consented for recruitment. HLA-A, HLA-B and HLA-DR was determined by polymerase chain reaction and sequence-specific oligonucleotide probes. The distribution of these alleles in the Northern Ireland general population was obtained from the histocompatability and immunogenetics database. The χ2 test was used for statistical analysis with Bonferroni correction. ResultsA total of 241 AAA patients were recruited, with a wide range of aneurysm size. In class I, the most frequent allele families were HLA-A*02 and *01 and HLA-B*07, *08, and *44. In class II, HLA-DRB1*03, *04, *07, and *15 were the most frequent. HLA-A*11 was lower in AAA cases (10.4% vs 15.0%; P = .08), whereas HLA-B*08 was lower in the controls (29.8% vs 36.5%; P = .05) and HLA-DRB1*11 was lower in cases (4.2% vs 8.1%; P = .05). After Bonferroni correction, however, the proportion of allele families was not significantly different in AAA patients compared with the proportion seen in controls. HLA-DRB1*11 and *14 had a lower prevalence in large AAAs (0.9% vs 6.7% [P = .05]; 0.0% vs 5.9% [P = .03]). HLA-A*68 was also lower in large AAA (1.9% vs 11.9%; P = .0075). After Bonferroni correction, however, no difference was demonstrated between small and large aneurysms. ConclusionThis study provides more definitive results on this important subject and has failed to demonstrate the risk association between AAA and these alleles as reported by others. Therefore, the role of these particular genes and the autoimmune component in AAA etiology does not appear to be as crucial as previously proposed. Clinical RelevanceThe high mortality of patients who sustain ruptured abdominal aortic aneurysms compared with elective repair justifies surgery in medically suitable patients with a large aneurysm. Control of the growth of smaller aneurysms may offer an alternative to surgery, however. This is dependent on better elucidation of underlying causal factors, including the role of genetic predisposition and autoimmunity. This study was designed to assess the contribution of human leukocyte antigen genes, which could thereby lay the foundation for future preventive therapy of this important disease. The etiology of aneurysm formation in the infrarenal aorta is probably multifactorial and includes environmental and hereditary factors. Historically, the main cause was considered to be atherosclerosis owing to common risk factors and atherosclerotic degeneration of the aneurysm wall.1, 2 Recent data, however, suggest that it is much more complex than previously indicated, and the degeneration may be associated with an imbalance in cytokine production by inflammatory cells present in aortic walls.3, 4, 5 Since the first report of familial tendency of the disease in 1977,6 it has become increasingly apparent that there is a significant genetic contribution to abdominal aortic aneurysm (AAA) development. Many candidate genes have been suggested, including those encoding for cytokines, connective tissue aortic wall components, and homocysteine.7, 8, 9, 10, 11, 12, 13, 14 The disease is likely to be polygenetic in etiology and progression, but evidence continues to emerge that there could be an autoimmune role. Both T and B lymphocytes demonstrate a remarkable polyclonal response, and activated memory cells can be found in AAA patients.15, 16 Histologically, the presence of Russell bodies, as typically also seen in Hashimoto thyroiditis with chronic inflammation in the aortic wall, support the autoimmune hypothesis.17, 18, 19 Haug et al20 have reported an increased prevalence of autoimmune diseases in patients with inflammatory aneurysms, and further evidence includes elevated concentrations of proteolytic cytokines and autoantibodies relative to healthy subjects and patients with aorto-occlusive disease patients.18, 21 Human leukocyte antigen (HLA) genes, located on the short arm of chromosome 6, are the genetic determinants of immune response and are highly polymorphic.22 Receptors on CD8 suppressor T cells recognize class I antigens (HLA-A and HLA-B), whereas the class II molecules (HLA-DR) are recognized by CD4 helper T cells. Some studies have demonstrated an association between HLA-DRB*15 and AAA development and an apparent protective role for HLA-DQ3.23, 24, 25 The aim of this study was therefore twofold: 1.To determine if a difference exists in HLA-A, HLA-B, and HLA-DR distribution, between AAA patients and controls. 2.To determine if a difference exists in the allele families between small and large AAA. Patients and methods  Recruitment The Northern Ireland Research Ethical Committee approved the study, with local sponsorship and clinical indemnity provided by the Belfast City Hospital Trust. From August 2004 to September 2005, patients attending the vascular surgery unit for either routine follow-up of a small AAA or surgical assessment of a large AAA were recruited after written informed consent. All patients were equally eligible, but those patients who were known to have an inflammatory AAA, any history of autoimmune disorders, or had an aneurysm caused by a known genetic aberration were excluded. All of the patients were white and of local origin. The Histocompatability and Immunogenetic Laboratory database of blood donors provided the distribution proportions of HLA allele families in the Northern Ireland population. The results of the population phenotype frequencies at the HLA-A, HLA-B and HLA-DR alleles have been previously reported and do not deviate from expected Hardy Weinberg proportions.26, 27, 28 The results reflect the Northern Ireland population as a whole, and the clinical details of risk factors and autoimmune disorders were assumed to be normal and reflect the overall population. Because the database is historical, these individuals were not specifically screened for AAA; and, therefore the exact prevalence of AAA in this group was not known, but was assumed to be normal for the general population. Genetic testing A sample of whole blood was obtained from each AAA patient. DNA was extracted and stored at −80°C until all samples were acquired. The genetic HLA locus of interest was then amplified by polymerase chain reaction (PCR), with verification on 1.5% agarose gel electrophoresis. After hybridization, typing methods using sequence-specific oligonucleotide probes were used to identify the different alleles. The probes were labeled with digoxigenin and detection was done by chemiluminescence. The details of these have been previously described.26, 27, 28 Statistical analysis A total of 226 AAA patients were required to demonstrate a 75% increase in risk in HLA-DR B1*15 carriers, compared with a similar number of controls, with an 80% power to detect significance at the 5% level. Allelic presence was compared between the two groups using the χ2 test, with Bonferroni correction for multiple comparisons. The AAA patients were also divided into two subgroups, depending on the recorded AAA diameter, with AAAs of 3.0 to 5.5 cm compared with those >5.5 cm, where 5.5 cm is the accepted threshold for surgical intervention.29 Statistical significance was initially assumed at P < .05, but after Bonferroni correction, it was accepted only with a value of P < .0033 for HLA-A, P < .0024 for HLA-B, and P < .0042 for HLA-DR, with results given for both significance levels. Data are presented as mean ± standard deviation. Results Study participants Almost all of the patients invited to participate in the study gave informed consent, and 250 AAA patients were recruited. Nine were excluded owing to technical difficulties, leaving 241 (220 men) in the study. The overall mean age was 71.9 ± 6.8 years (range, 50-92 years), with no gender difference. The overall mean aneurysm size was 5.1 ± 1.6 cm. The database, which constituted the control group, consisted of 1000 healthy subjects (513 men) derived from the general population in Northern Ireland. They were randomly selected from a complete database of 5000 individuals as previously described.26, 27, 28 The mean age of the control group was 44.2 ± 6.8 years (range, 30 to 57 years), with no difference between men and women. HLA-A The distribution of allele families relating to HLA-A is shown in Fig 1. The most frequently occurring allele family in both groups was HLA-A*02, with 50.2% in AAA patients vs 49.2% in controls (P = NS). HLA-A*01 was the next most frequently carried, with 41.1% in AAA patients vs 36.4% in controls (P = NS). HLA-A*11 approached significance, with 10.4% in AAA patients vs 15.0% in controls (P = .08), but with Bonferroni correction, no difference was detected in any HLA-A allele families between the groups. HLA-B The distribution of allele families encoding for HLA-B is shown in Fig 2. The most frequent allele families carried in both groups were HLA-B*07, *08, *35, *40, and *44. HLA-B*08 was more frequently found in AAA cases (36.5% vs 29.8%; P = .05), but with Bonferroni correction, no difference was noted in the distribution between the two groups. HLA-DR The distribution of allele families relating to HLA-DR is shown in Fig 3. The most common in both groups were HLA-DRB1*01, *03, *04, *07, *13, and *15. The proportion of HLA-DRB1*11 in AAA cases was about half of controls (4.2% vs 8.1%; P = .05). With Bonferroni correction, however, no difference could be demonstrated between the groups for any of the allele families. Comparison between small and large aneurysms A total of 135 patients had an AAA with a diameter <5.5 cm, and the remaining 106 were greater. HLA-DRB1*11 was much lower in patients with larger aneurysms (0.9% vs 6.7%; P = .05), and HLA-DRB1*14 was also greater in the small aneurysms (0% vs 5.9%; P = .03). After statistical correction, however, no difference was found for any of the allele families on HLA-A, HLA-B, or HLA-DR. Only one allele family, HLA-A*68 approached corrected significance (1.9% in large aneurysms vs 11.9% in small aneurysms; P = .0075, where P = .0033 was considered significant). Discussion The immune response of an individual is determined by polymorphic cell surface glycoproteins, which are regulated by the genes of the major histocompatability complex. These genes, which determine the HLAs, are composed of class I and class II antigens. The first is towards the telomere, whereas the latter is closer to the centromere of chromosome 6. The huge and complex genetic polymorphism underlying this results an individual’s immune response being a distinctive characteristic. Autoimmunity has been reported in connection with other vascular conditions. Takayasu arteritis has a high prevalence in young Asian and South American females.30, 31 The disease has a familial tendency, and appears to be closely associated with a haplotype HLA-A24-B52-DR2.31, 32 Patient with thromboangiitis obliterans (Buerger disease) have a different gender, age profile, and clinical presentation. This disease has been associated with a haplotype HLA-A24-BW54-DR2, which was later postulated as a resistance profile for Takayasu arteritis.33, 34 Other alleles have been suggested for Buerger disease, whereas temporal arteritis may be linked with variants of HLA-DRB1*4.35, 36, 37 These associations suggest that certain autoimmune mechanisms may accelerate intramural inflammation, which is also a feature of AAA. Haug et al20 demonstrated that patients with inflammatory AAA have an increased prevalence of other autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, and giant cell arthritis, compared with patients with noninflammatory AAA. Inflammatory AAAs appear to be the extreme end of an inflammatory spectrum, because chronic inflammatory cells are commonly seen in the aortic adventitia.17 The trigger for this process may be an infective agent, which, through molecular mimicry, results in the immune system attacking shared epitopes of the protein matrix and pathogen.38 An autoimmune protein has been revealed that seems to be limited to the aorta and can be found in the thoracic and abdominal aorta and iliac arteries.39, 40 Immunoreactivity is strongest in the abdominal aorta, and this distribution and relative strength closely reflect the clinical disease incidence.41 One of the first studies to explore the link between AAA and HLA looked at a group of patients with histologically proven inflammatory aneurysms.42 HLA-DRB1*15 and *0404 alleles were enriched relative to the controls. The amino acid position 70, in antigen-binding pocket 4, was noted to be important, positioned critically at the pocket entrance. The binding characteristics alter significantly with the resultant presence of either negatively charged aspartic acid or positively charged glutamine. Later, the same researchers demonstrated that inflammatory and degenerative AAAs were associated with similar genetic traits.43 HLA-DR B1*02 and *04 were enhanced in both groups compared with non-AAA controls, with allele families DRB1*01, *08, and *14 decreased in both groups. The degree of inflammation of the aortic wall, determined historically at the time of operation, was inversely correlated with HLA-DRB1*01, suggesting a disease-modulating role for this allele expression.44 These findings of Rasmussen et al44 were replicated in a recent Spanish study.45 HLA-DR B1*0401 had a significantly higher incidence in AAA patients, with DRB1*01 again appearing to have a disease-modulating role. DRB1*12, *13, *15, and *16 have previously been proposed as risk factors for AAA in a small study group of North American black patients.46 Similar work by the same researchers on a more homogenous Japanese population highlighted alternative alleles, although on this occasion by serologic typing. In that study, HLA-DRB1*15 was found to be significantly more frequent in AAA patients, compared with controls.24 Of interest was that they later reported that HLA-DQ3 was significantly decreased in AAA patients, reflecting a possible protective effect, as seen in other conditions.25, 47 Only one study has reported on class I HLA genotypes relative to AAA.48 HLA-A*2 and HLA-B*61 were associated with AAA, but HLA-DRB1*15 failed to correlate with AAA, despite the study participants being of similar racial extraction to those of Hirose et al.24 The concurrent existence of aortoiliac occlusive disease was noted to explain differences in HLA-DR*15 results between studies, a fact of noteworthy moment. It is therefore interesting that our study found no association between HLA genetic profile and aneurysmal disease. The population of Northern Ireland is relatively homogenous and stable, with little influence from immigration, and is therefore an ideal target population to assess potential familial diseases. Some bias was potentially introduced because the control group individuals were not screened for AAA and were not matched to the disease group for risk factors. The random nature of compiling the control group resulted in equal gender contribution to the group and, therefore, AAA disease prevalence could be assumed to be appropriately only 3%, with other risk factors assumed to reflect the general population. Although this may slightly influence the results, this is likely to be statistically well compensated by the fourfold increase in the number of individuals in the control group than originally required by prestudy power calculations. Another weakness in this study is the potential for type II errors owing to the large numbers of alleles examined relative to the number of cohort size, particularly for class I results. Future research, however, could be targeted towards allele families highlighted by our results. Significant differences are likely between our AAA cohort and Japanese or North American black patients, but the lack of collaboration with the evidence from Minnesota and Spain is remarkable. The results of previous studies are undermined by the much smaller numbers of both patients and controls, compared with our figures, thus potentially questioning the strength of the autoimmune process in AAA development. No consistent findings have identified a culprit allele, with only relatively soft evidence thus far, and this is particularly emphasized by the apparent contradiction of the Japanese studies with regard to HLA-DR. Our results are given at both 5% level of significance and also with correction for multiple comparisons. Comparison with other work is difficult owing to the lack of clarity in some reports with regard to this important issue. Previously suggested culprit alleles may thus be due to a type 1 statistic error, rather than revealing a new etiologic factor; however, future research should perhaps be targeted towards those allele families identified to be deviating from the normal distribution. All of the preceding studies have concentrated on the large AAAs, with no comparison with small AAAs. The results of this study demonstrate no difference in the HLA genetic constitution between patients with small AAAs and those with larger AAAs. It is possible that the trigger factor for later expansion and rupture may not be infective or autoimmune related, as previously thought. 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a Vascular and Endovascular Surgery Centre, Belfast City Hospital, Belfast, United Kingdom b Histocompatability and Immunogenetics Laboratory, Belfast City Hospital, Belfast, United Kingdom.  Reprint requests: Mr S. Badger, Vascular Research Fellow, Belfast City Hospital, Lisburn Rd, Belfast BT9 7AB, UK.
Competition of interest: none. PII: S0741-5214(07)00021-3 doi:10.1016/j.jvs.2006.09.067 © 2007 The Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved. | |
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