The Correlation Study Between Human Leukocyte Antigens-A、 B、DRB1 High-resolution Alleles And Chronic Renal Failure Caused By Immunoglobulin-a Nephropathy

Research backgroundChronic renal failure(CRF),also called uremia, is caused by all kinds of primary or secondary kidney disease development to the late common result. Chronic renal failure is a systemic involvement as the main performance of each system clinical syndrome which is a set of progressive renal parenchyma damage, kidney obvious atrophy, unable to maintain its basic functions, clinically appear to metabolites retention, water, electrolyte and acid-base balance disorders. It is one of the common diseases threating human health, with natural populations incidence rate (500-200)/1 million people.In recent years, according to global relevant statistics show that the incidence and prevalence of chronic renal failure in the trend to rise. American adults (total 200 million) the prevalence of chronic renal failure has been as high as 7.6%, the prevalence of chronic renal failure in china is as high as 8%～10%.So far, about the pathogenesis of chronic renal failure is still not clear. Except for the interpretation of the chronic renal failure mainly on glomerular high pressure,high perfusion,high filtration,high pressure, high metabolism of renal tubular and renal compensatory hypertrophy, glomerular and renal interstitial changes:renal glomerual cells, tubular interstitial cells and kidney infiltrating cells produce a large number of immune inflammatory cytokines which was also involved in the process of renal function deterioration.The name of IgA nephropathy (IgAN) was described by the French scholar J.B erger and N.H inglais for the first time in 1968, also known as Berger’s disease (Berger’s disease). The glomerular mesangial area and capillary loops is deposited by the IgA immune globulin is the main pathological factures of immunoglobulin-a nephropathy. It is generally known that immunoglobulin-a nephropathy is the most common form of primary glomerulonephritis in the world which is one of the important causes of chronic renal failure. According to the statistics, immunoglobulin-a nephropathy in the Asia-pacific region (China, Japan, southeast Asia and Australia, etc.),Europe, North America are respectively accounted for 40% to 50%,20%,8% to 20% from the primary glomerulonephritis. But so far, the pathogenesis of immunoglobulin-a nephropathy has not been clear. Now, some people argue that the occurrence of immunoglobulin-a nephropathy is related to the mucosal infection, immune response, inflammation medium, genetic and environmental factors. Meanwhile, more and more research evidence indicate that immunoglobulin-a nephropathy has race or region hereditary and familial transmissibility. It is indicated that the genetic factor play a vital role in the pathogenesis of immunoglobulin-a-nephropathy. Accordingly, people suspect that immunoglobulin-a nephropathy may be a polygenic disease. In recent years, with the rapid development of molecular biology, molecular genetics and human genome project was basically completed, many studies have shown that immunoglobulin-a nephropathy is a polygenic and multi-factor complex disease.With the gradually understanding of the immune pathogenesis of kidney disease, the development process of various glomerular diseases which have many immune inflammatory factors to participate is found. The immune inflammatory factors include T cells, B cells, NK cells, mononuclear cells or macrophages, platelets and granulocyte, etc. Moreover, the study found that these immune active cells were all require Human Leukocyte antigen (HLA) as the immune response of ligands which combine with their cell membrane receptors. Then, these immune active cells can play immune inflammatory reaction. By puncturing biopsy pathology of renal parenchyma, Foreign scholars Franco C found that the glomerular mesangial area deposited by complement C4 which is the expression product of human leukocyte antigen gene complex class III gene. This shows that the Human Leukocyte Antigens play a vital role in the occurrence and development of kidney disease. Human Leukocyte antigen system is the human major histocompatibility complex (MHC), which encodes Human Leukocyte Antigens and is the most complex immune complex.It is a tight chain with multiple genes and polymorphism of gene group which located in human chromosome short arm of 6p21.31. Meanwhile, it is human important genetic marker which has highly polymorphic,racial and ethnic specificity. Human Leukocyte antigen gene region is divided into three categories. Human Leukocyte Antigens class I molecules has two polypeptide chain:alpha microglobulin and beta 2 microglobulin. The alpha chains have three functional areas:alpha 1,alpha 2 and alpha 3 functional areas. The alpha 1 and alpha 2 determine their antigen polymorphisms, however, alpha 3 is a constant region. The classical area of Human Leukocyte Antigens class I genes including the classic A, B, C sites, the atypical area of Human Leukocyte Antigens class I genes including the classic E, F, G sites, etc. The products of these Human Leukocyte Antigens class I genes express in the nucleated cell which are own with the function of identifying self and nonself in the immune system. This products play a vital role in the immune systems against viruses and tumors. Human Leukocyte Antigens classical II molecules is composed of alpha and beta chain glycoprotein, The classical area of Human Leukocyte Antigens class Ⅱ genes including the classic DR, DQ, DP sites, the atypical area of Human Leukocyte Antigens class II genes including the classic DN, DM, DO sites, etc, which are mainly distributed in B cells, macrophages and activation of T cells surface. The products encode by these Human Leukocyte Antigens class I genes which are in charge of handing, processing and providing antigens. Human Leukocyte Antigens classical III molecules is also known as complement which between class I and class II genes, including the genes encoding C2, Bf, C4A, C4B, sterols-21 hydroxylase complement components. With the deepening of the research, the significant role of Human Leukocyte Antigens in human physiological and pathological mechanism gradually been confirmed. The study found that Human Leukocyte Antigens is not only connected with transplantation rejection, genetic regulation of immune response, immune cells and restrictions on mutual recognition, but also associated with many diseases, especially the autoimmune disease.In recent years, some transplant centers have done a lot of research about Human Leukocyte Antigens play immune genetic role in the process of all kinds of kidney disease eventually lead to chronic renal failure, and put forward the possible genetic susceptibility genes and protection genes. PEREZ-LUQUE reported that 89 cases Mexico patients with type 2 diabetic nephropathy complicated with chronic renal failure were with significantly high antigen frequency of Human Leukocyte Antigens-DR15, suggesting that Human Leukocyte Antigens-DR15 may be a susceptibility gene for the type 2 diabetic nephropathy complicated with chronic renal failure in Mexico region patients. El-Gezawy reported that 207 cases Egypt chronic renal failure patients with different primary disease expressed with high antigen frequency of Human Leukocyte Antigens-A2、Human Leukocyte Antigens-B8、Human Leukocyte Antigens-DRB13、Human Leukocyte Antigens-DRB111,and he considered that the determination of susceptibility genes may be helpful for the patients with kidney disease to delay the progression of chronic renal failure. Moreover, it has a great significance to research which preventing the recurrence of the primary disease after transplantation. The Human Leukocyte Antigens gene polymorphism of 1620 European white immunoglobulin-a nephropathy patients with end-stage kidney failure were studied by Doxiadis,the results found that the antigen frequency of Human Leukocyte Antigens-B35 and Human Leukocyte Antigens-DR5 in patients were higher than the healthy controls, and the statistical difference was significant. Accordingly, he claimed that the Human Leukocyte Antigens-B35 and Human Leukocyte Antigens-DR5 may be a susceptibility gene for the IgA nephropathy complicated with chronic renal failure in European white patients, while the Human Leukocyte Antigens-B7、Human Leukocyte Antigens-B8、Human Leukocyte Antigens-DR2 and Human Leukocyte Antigens-DR3 may be a protection gene. Domestic scholar zhi-ming han used the PCR-SSP technology to study the Human Leukocyte Antigens-A, B, DRB1 gene polymorphism of 3911 cases han nationality patients who waiting kidney transplantation with chronic renal failure in the south China, the study found that the antigen frequency of Human Leukocyte Antigens-B75, Human Leukocyte Antigens-DR4 and Human Leukocyte Antigens-DR17 in chronic renal failure patients were higher than the healthy controls, and the antigen frequency of Human Leukocyte Antigens-DR8、Human Leukocyte Antigens-DR9 in chronic renal failure patients were lower than the healthy controls. He hold that the Human Leukocyte Antigens-B75,Human Leukocyte Antigens-DR4 and Human Leukocyte Antigens-DR17 gene may be a susceptibility gene for kidney disease complicated with chronic renal failure in southern China patients, while the Human Leukocyte Antigens-DR8 and Human Leukocyte Antigens-DR9 gene may be a protection gene. And it has a great guiding significance for clinical transplantation work after the determination of susceptibility genes. Yue huan Wu researched the Human Leukocyte Antigens-DRB1 between 89 cases of han nationality chronic renal failure patients of Fujian province and 344 cases of healthy controls, the study found that the antigen frequency of Human Leukocyte Antigens-DRB 1*0701 and Human Leukocyte Antigens-DRB 1*1201/1202 in chronic renal failure patients were higher than the healthy controls, and the statistical difference was significant. She argued that the Human Leukocyte Antigens-DRB 1*0701 and Human Leukocyte Antigens-DRB 1* 1201/1202 gene may be closely related to the patients with chronic renal failure and speculated that the patients with kidney disease who carried the Human Leukocyte Antigens-DRB 1*0701 and Human Leukocyte Antigens-DRB1*1201/1202 gene may be easy to develop into end-stage renal failure.Because of the Human Leukocyte Antigens class Ⅱ genes are closely related with immune response and most research focused on the Human Leukocyte Antigens Ⅱ genes polymorphism of immunoglobulin-a nephropathy patients or chronic renal failure patients. So, the report about the correlation study is rare between the expression of Human Leukocyte Antigens high resolution alleles and chronic renal failure caused by immunoglobulin-a nephropathy. Meanwhile, the traditional methods which include serological typing, polymerase chain reaction with restricted fragment length polymorphism(PCR-RFLP), polymerase chain reaction sequence-specific primers (PCR-SSP), polymerase chain reaction with sequence-specific oligonucleotide probe(PCR-SSOP),polymerase chain reaction with single strand conformation polymorphism, PCR-SSCP), etc, were used for Human Leukocyte Antigens sequencing typing. However, the most accurate genotyping method which is the polymerase chain reaction-sequence-based typing (PCR-SBT) is rarely used at present. Consequently, we choose the chronic renal failure patients and healthy people as the research subjects for this topic. We use the most accurate genotyping method PCR-SBT technology to classify the Human Leukocyte Antigens-A, B, DRB1 high resolution alleles for the chronic renal failure patients caused by immunoglobulin-a nephropathy and compare with healthy people. Analysis of the difference and allele frequency of Human Leukocyte Antigens-A, B, DRB1 and explore the susceptible correlation between Human Leukocyte Antigens-A、B、DRB1 high-resolution alleles and chronic renal failure caused by immunoglobulin-a nephropathy.Objective:To investigate the correlation study between Human Leukocyte Antigens-A、B、DRB1(HLA-A、B、DRB1)high-resolution alleles and chronic renal failure(CRF)caused by immunoglobulin-a nephropathy(IgAN).Methods:We used the polymerase chain reaction-sequence-based typing (PCR-SBT) method to investigate the genotypes of Human Leukocyte Antigens-A、 B and DRB1 high-resolution alleles in 191 chronic renal failure caused by immunoglobulin-a nephropathy patients and 503 healthy blood donors, who were selected from Nanfang Hospital and Zhujiang Hospital affiliated of Southern Medical University、the First Affiliated Hospital of Yat-sen University. We compared the alleles frequencies in two groups and analysed the association between chronic renal failure caused by immunoglobulin-a nephropathy and the polymorphism of HLA.Results:(1)There were 25 alleles at A locus,48 alleles at B locus and 32 alleles at DRB1 locus in chronic renal failure caused by immunoglobulin-a nephropathy patients.(2) The genetic frequency of HLA-A*2901(Pc=0.033, OR=10.738,95%CI (1.193,96.691)), HLA-DRB1*1106 (Pc=0.0001, OR=0.969,95%CI(0.944, 0.994)), HLA-DRB1*1202 (Pc=0.002,OR=1.859,95%CI (1.259,2.745)), HLA-DRB1*1401(Pc=0.021, OR=0.984,95%CI (0.967,0.998)), HLA-DRB1*1602 (Pc=0.015, OR=1.915,95%CI (1.157,3.17)) in chronic renal failure caused by immunoglobulin-a nephropathy patients was higher than the healthy controls (P<0.05)Conclusion:There is susceptibility association of HLA-A*2901, HLA-DRB1*1106, HLA-DRB1*1202, HLA-DRB 1*1401, HLA-DRB1*1602 with chronic renal failure caused by immunoglobulin-a nephropathy. It is concluded that there is a close genetic and immunological correlation between Human Leukocyte Antigens alleles and the pathogenesis of chronic renal failure caused by immunoglobulin-a nephropathy.