Wioleta Łuszczek

Does the KIR2DS5 Gene Protect from Some Human Diseases

Background KIR2DS5 gene encodes an activating natural killer cell receptor whose ligand is not known. It was recently reported to affect the outcome of hematopoietic stem cell transplantation. Methodology/Principal Findings In our studies on KIR2DS5 gene associations with human diseases, we compared the frequencies of this gene in patients and relevant controls. Typing for KIR2DS5 gene was performed by either individual or multiplex polymerase chain reactions which, when compared in the same samples, gave concordant results. We noted an apparently protective effect of KIR2DS5 gene presence in several clinical conditions, but not in others. Namely, this effect was observed in ankylosing spondylitis (p = 0.003, odds ratio [OR] = 0.47, confidence interval [CI] = 0.28–0.79), endometriosis (p = 0.03, OR = 0.25, CI = 0.07–0.82) and acute rejection of kidney graft (p = 0.0056, OR = 0.44, CI = 0.24–0.80), but not in non-small-cell lung carcinoma, rheumatoid arthritis, spontaneous abortion, or leukemia (all p>0.05). In addition, the simultaneous presence of KIR2DS5 gene and HLA-C C1 allotype exhibited an even stronger protective effect on ankylosing spondylitis (p = 0.0003, OR = 0.35, CI = 0.19–0.65), whereas a lack of KIR2DS5 and the presence of the HLA-C C2 allotype was associated with ankylosing spondylitis (p = 0.0017, OR = 1.92, CI = 1.28–2.89), whereas a lack of KIR2DS5 and presence of C1 allotype was associated with rheumatoid arthritis (p = 0.005, OR = 1.47, CI = 1.13–1.92). The presence of both KIR2DS5 and C1 seemed to protect from acute kidney graft rejection (p = 0.017, OR = 0.47, CI = 0.25–0.89), whereas lack of KIR2DS5 and presence of C2 seemed to favor rejection (p = 0.0015, OR = 2.13, CI = 1.34–3.37). Conclusions/Significance Our results suggest that KIR2DS5 may protect from endometriosis, ankylosing spondylitis, and acute rejection of kidney graft.

Strong association of HLA-Cw6 allele with juvenile psoriasis in Polish patients

Association of psoriasis vulgaris with HLA-C is not equally strong in different human populations. It has not yet been studied in Polish patients at DNA level, but only by serology that is inadequate for HLA-C. Therefore, we examined the distribution of HLA-C alleles by means of low resolution PCR-SSP in 102 Polish psoriatics and 123 healthy controls. We have found significantly higher representation of HLA-Cw*06 (odds ratio, 18.73; P(cor)<0.001) and significantly lower representation of HLA-Cw*07 (odds ratio, 0.41; P(cor)<0.038) in patients than in controls. Association of HLA-Cw*06 with psoriasis was even stronger in early age at onset (0-20 years) group: odds ratio, 77.71; P(cor)<0.001. Therefore, our population seems to belong to those with strong association of psoriasis with HLA-Cw*06.

Inhibitory and activatory KIR gene frequencies in the Polish population

Killer cell immunoglobulin‐like receptors (KIRs) present on natural killer cells and minor subpopulations of T cells recognize class I human leukocyte antigen (HLA) molecules on the surface of target cells. Human individuals differ by the presence or absence of some KIR genes on their chromosomes (haplotypic polymorphism). As KIRs (especially two‐immunoglobulin‐domain‐like containing, or KIR2D, molecules) are important for the outcome of tissue (particularly for haematopoietic stem cell) transplantation and possibly for pregnancy, the knowledge of KIR gene distribution in a given human population is of practical value. Therefore, we tested 175 healthy individuals from Poland for the presence or absence of these KIR genes which show haplotypic polymorphism and are expressed. Results were compared with those published for other human populations, showing close relations with other Caucasoids.

CTLA-4 gene polymorphisms and natural soluble CTLA-4 protein in psoriasis vulgaris.

CTLA‐4 molecule is an important inhibitor of T‐lymphocyte activation. Several single nucleotide polymorphisms (SNPs) in the CTLA‐4 gene were found, and their associations with many human diseases were described. So far, however, such studies have not been performed in psoriasis vulgaris in Caucasoids. Therefore, we examined the distribution of three CTLA‐4 SNPs: −1147C/T, −318C/T and +49 A/G in 116 patients with psoriasis vulgaris and 123 healthy blood donors using the polymerase chain reaction–restriction fragment length polymorphism method. For all three SNPs, the frequencies of alleles, genotypes and three‐point haplotypes were very similar in patients and controls, suggesting no contribution of these genetic variants to psoriasis.

Killer Immunoglobulin-like Receptor (KIR) and HLA Genotypes Affect the Outcome of Allogeneic Kidney Transplantation

Background Recipient NK cells may detect the lack of recipients (i.e., self) HLA antigens on donor renal tissue by means of their killer cell immunoglobulin-like receptors (KIRs). KIR genes are differently distributed in individuals, possibly contributing to differences in response to allogeneic graft. Methodology/Principal Findings We compared frequencies of 10 KIR genes by PCR-SSP in 93 kidney graft recipients rejecting allogeneic renal transplants with those in 190 recipients accepting grafts and 690 healthy control individuals. HLA matching results were drawn from medical records. We observed associations of both a full-length KIR2DS4 gene and its variant with 22-bp deletion with kidney graft rejection. This effect was modulated by the HLA-B,-DR matching, particularly in recipients who did not have glomerulonephritis but had both forms of KIR2DS4 gene. In contrast, in recipients with glomerulonephritis, HLA compatibility seemed to be much less important for graft rejection than the presence of KIR2DS4 gene. Simultaneous presence of both KIR2DS4 variants strongly increased the probability of rejection. Interestingly, KIR2DS5 seemed to protect the graft in the presence of KIR2DS4fl but in the absence of KIR2DS4del. Conclusions/Significance Our results suggest a protective role of KIR2DS5 in graft rejection and an association of KIR2DS4 with kidney rejection, particularly in recipients with glomerulonephritis.

HLA-C C1C2 heterozygosity may protect women bearing the killer immunoglobulin-like receptor AA genotype from spontaneous abortion.

Spontaneous abortion is the most common complication of human pregnancy. Natural killer (NK) cells expressing killer immunoglobulin-like receptors (KIRs), which may recognize HLA-C (i.e. its C1 or C2 groups) on trophoblast cells, constitute a large leukocyte population in the endometrium. This study investigated whether genetic polymorphisms in the KIR and HLA-C genes are risk factors for spontaneous abortion. One hundred and twenty-five couples with at least two spontaneous abortions, including eighty-five couples with idiopathic recurrent abortion (RSA; three or more abortions), and 117 control couples (with two or more healthy-born children) were tested. The frequencies of the individual KIR genes in the patients were similar to those in the controls. In the group of KIR AA women with HLA-C C2C2 partners, the HLA-C C1C2 heterozygotes were present in the controls but not in the patients (p=0.015 for all patients and p=0.0048 for RSA, but both comparisons lost significance after Bonferroni correction), whereas both homozygotes, C1C1 and C2C2, were absent in the control women but present among the aborting ones. Therefore, our results suggest that among KIR AA women who have HLA-C C2C2 partners, HLA-C heterozygous females show a trend towards an increased chance of successful pregnancy.

Distribution of LILRA3 (ILT6/LIR4) deletion in psoriatic patients and healthy controls

The leukocyte immunoglobulinlike receptor (LILRA3; ILT6) gene is localized on human chromosome 19 in the region 19q13.4, in the leukocyte receptor complex that encodes leukocyte receptors LILR (ILT/LIR), killer cell immunoglobulinlike receptors (KIR), LAIR, Fc IgA receptor, and others. The biologic role of the LILRA3 molecule and the nature of its ligand are not known. Comparison of LILRA3 gene sequence with those of other LILRs suggests LILRA3 is a soluble molecule. If LILRA3 binds human leukocyte antigen (HLA) class I molecules like other LILRs whose ligands are known, then it might block recognition of HLA by these receptors, influencing immune response and susceptibility to HLA class I associated disease. A deletion of LILRA3 gene was found in a minority of British population. We typed 108 healthy individuals from the Low Silesia region and 103 patients diagnosed with psoriasis vulgaris (a disease associated with HLA class I antigen, HLA-Cw6) for LILRA3 to examine whether LILRA3 deletion was distributed differently in patients affected with the disease. No differences in frequencies of the LILRA3 deletion were found between controls and patients or between HLA-Cw6(+) and HLA-Cw6(-) controls or patients, suggesting that LILRA3 has no role in psoriasis.

Distribution of the CTLA‐4 single nucleotide polymorphisms CT60G>A and +49A>G in psoriasis vulgaris patients and control individuals from a Polish Caucasian population

Psoriasis vulgaris is a multifactorial disease with an autoimmune component, and T lymphocytes seem to be involved in its aetiology. CTLA‐4 molecule is an important down‐regulator of T‐lymphocyte activation, and several polymorphisms of the CTLA‐4 gene were found to be associated with some autoimmune diseases. We examined whether single nucleotide polymorphisms (SNPs) in the CTLA‐4 gene, CT60A>G and +49A>G, are associated with psoriasis vulgaris. Alleles of these two SNPs were determined by the polymerase chain reaction–restriction fragment length polymorphism method. Both the CT60G>A and the +49A>G alleles and genotypes were distributed similarly in patients and controls. Although the two SNPs studied here in Poles were in linkage disequilibrium, all four possible two‐locus haplotypes were found, one of them rare; of the remaining three, the haplotype +49G, CT60G was significantly (P = 0.019, OR = 0.58, 95%CI = 0.37–0.91) less frequent in the patient group with disease onset between the ages of 21 and 40 years than in controls and the other patient groups, whereas the frequencies of the other haplotypes were similar in patients and controls. To the authors’ knowledge, this is the first study on CTLA‐4 CT60 allele frequencies in psoriasis.

Polymorphism of the TGFB1 gene is not associated with bronchial allergic asthma in a Polish population.

Allergic asthma is a complex genetic disorder that involves interactions between genetic and environmental factors. Some studies have indicated that transforming growth factor beta(1) (TGF-beta(1)), a pleiotropic cytokine regulating inflammatory reactions and airway remodeling, may participate in the pathogenesis of asthma. Several polymorphisms have been described in the TGFB1 gene; some were tested in allergic asthma, with conflicting results. The aim of this study was to investigate the possible associations of four TGFB1 gene polymorphisms (-800G>A, -509C>T, 869T>C, and 915G>C) with allergic asthma in a Polish population. These four single nucleotide polymorphisms were genotyped in 247 asthmatic patients (including 207 atopic individuals) and 287 unrelated healthy volunteers by means of the polymerase chain reaction-restriction fragment length polymorphism method. No significant differences between patients and controls in allele, genotype, and haplotype frequencies were reported. Logistic regression analysis of genotype distribution and allele positivity adjusted for age and sex did not reveal any significant differences between all patients or patients selected for atopy and controls. Thus, no evidence was reported for a contribution of the TGFB1 gene to allergic asthma in a Polish population. The results are discussed in the context of similar studies in other populations.

A single nucleotide polymorphism −35 kb T > C (rs9264942) is strongly associated with psoriasis vulgaris depending on HLA-Cw∗06

HLA class I molecules play a role both in viral infection control and in autoimmune diseases development. rs9264942T>C polymorphism in HLA-C gene was found to impact on HLA-C surface expression level and to be associated with HIV-1 control. It was found that these HLA alleles which protect against AIDS are associated with autoimmune disease e.g. psoriasis vulgaris (PsV). Whether rs9264942 SNP is associated with PsV was investigated here. rs9264942T>C was genotyped in 292 PsV patients, and 254 controls using TaqMan Genotyping Assay. PsV patients differed from controls in frequencies of rs9264942T>C alleles (p=3.62 × 10(-16)) and genotypes (5.67 × 10(-15)). However, rs9264942C allele was predisposing to PsV 3-fold weaker than HLA-Cw(∗)06 (OR=5.04 vs. OR=15.61, respectively). In addition, this SNP was described earlier to be in strong linkage disequilibrium (LD) with another SNP, rs67384697 ins/del, which by affecting a microRNA binding is responsible for regulating HLA-C expression. However, typing for is cheaper and simpler than that for rs67384697, therefore we think it may substitute for it to some extent.