Associations of Genes for Killer Cell Immunoglobulin-like Receptors and Their Human Leukocyte Antigen-A/B/C Ligands with Abdominal Aortic Aneurysm.

Joanna Dubis,Maciej Sobczyński,Norbert Zapotoczny,Piotr Kuśnierczyk,Wojciech Witkiewicz,Natalia Jędruchniewicz,Wanda Niepiekło-Miniewska

doi:10.3390/cells10123357

Abstract

Abdominal aortic aneurysm (AAA) is an immune-mediated disease with a genetic component. The multifactorial pathophysiology is not clear and there is still no pharmacotherapy to slow the growth of aneurysms. The signal integration of cell-surface KIRs (killer cell immunoglobulin-like receptors) with HLA (ligands, human leukocyte class I antigen molecules) modulates the activity of natural killer immune cells. The genetic diversity of the KIR/HLA system is associated with the risk of immune disorders. This study was a multivariate analysis of the association between genetic variants of KIRs, HLA ligands, clinical data and AAA formation. Genotyping was performed by single polymerase chain reaction with sequence-specific primers using commercial assays. Patients with HLA-A-Bw4 have a larger aneurysm by an average of 4 mm (p = 0.008). We observed a relationship between aneurysm diameter and BMI in patients with AAA and co-existing CAD; its shape was determined by the presence of HLA-A-Bw4. There was also a nearly 10% difference in KIR3DL1 allele frequency between the study and control groups. High expression of the cell surface receptor KIR3DL1 may protect, to some extent, against AAA. The presence of HLA-A-Bw4 may affect the rate of aneurysm growth and represents a potential regional pathogenetic risk of autoimmune injury to the aneurysmal aorta.

Highlights

An abdominal aortic aneurysm (AAA) is defined as a local permanent dilatation of the aorta with a diameter of >30 mm that occurs mostly in the infra-renal region [1]
Multivariate statistical analysis of our results indicates that the incidence of AAA does not depend on the frequency of polymorphic killer cell immunoglobulin-like receptors (KIRs) genes and their major ligands human leukocyte antigen (HLA)-A, B, C except for the KIR3DL1 gene’s high- and low-expressed variants
We could not detect any role of the Bw4 epitope, on HLA-A or on HLA-B, in the initiation of AAA, for three reasons: (a) the signal for education of natural killer (NK) cells is focused on position −21 of HLA-B, not on Bw4. (b) AAA might be initiated by KIR3DL1Low rather than KIR3DL1High because the too-weak inhibition by this KIR favours the activation of NK cells (Figure 3B). (c) Our test system did not differentiate between

Summary

Introduction

An abdominal aortic aneurysm (AAA) is defined as a local permanent dilatation of the aorta with a diameter of >30 mm that occurs mostly in the infra-renal region [1]. The main risk factors are male sex and older age of patients [1,2]. The prevalence of AAA in men aged 65–74 years is approximately 2.7%; it increases with age and it is an important public health problem [2,3,4]. As Eastern European populations age, the AAA prevalence is expected to increase significantly [1,3]. AAA usually remains asymptomatic until it ruptures; this occurrence represents a mortality risk for about 80% of patients [5]. Screening for aneurysms and early detection of local lesions remain fundamental to the management of this disease [1,2,3,4]

Objectives

Methods

Results

Discussion

Conclusion