Linkage Disequilibrium In Patients Research Articles

Role of GSTP1 functional polymorphisms in molecular pathogenesis of colorectal cancer

Glutathione S-transferase P1 (GSTP1) plays a crucial role in the detoxification of harmful substances and cancer-causing agents. Single nucleotide polymorphisms (SNPs) in GSTP1 can affect its ability to catalyze reactions and detoxify, thereby influencing the risk of developing colorectal cancer (CRC). This study aimed to investigate the impact of functional SNPs (fSNPs) in GSTP1 on the risk of CRC, as well as their structural and functional consequences. We analyzed a total of 126 selected GSTP1 SNPs, including fSNPs rs1695 A > G (I105V) and rs1138272 C > T (A114V), in CRC patients (n = 103) and controls (n = 107) of south Indian origin using PCR-sequencing analysis with genomic DNA from blood samples. To assess the structural integrity of GSTP1 fSNPs, we conducted in silico analysis using various tools such as Swiss PDB Viewer, pyMOL mutagenesis wizard, ProSA-Web, and Pdbsum. Additionally, we performed functional characterization of GSTP1 fSNPs using cell and molecular biology techniques. Our findings revealed a significant association between the I105V fSNP and CRC risk, while the A114V fSNP did not show any significance. However, both fSNPs exhibited stronger linkage disequilibrium in patients compared to controls. In silico analysis indicated a loss of structural integrity and reduced electrostatic potential energy in the double mutant GSTP1 (V105/V114) compared to the native (I105/A114) or single mutant (V105/A114 and I105/V114) forms. Furthermore, FHC cells transfected with the GSTP1 I105V variant exhibited increased proliferation, invasion, and colony formation, along with decreased GST activity compared to carriers of the wild-type GSTP1. On the other hand, the GSTP1 A114V variant did not show a significant effect. Interestingly, FHC cells transfected with the double mutant GSTP1 variant (V105/V114) demonstrated synergistic and enhanced effects compared to the GSTP1 I105V variant. Consistent with these findings, plasma GST activity was significantly lower in haplogroups carrying both fSNPs compared to haplogroups with single or no fSNPs. To summarize, our findings indicate that while GSTP1 I105V alone contributes to the etiology of CRC, A114V does not; however, their combined presence has a more significant impact.

Association of Killer Cell Immunoglobulin-Like Receptors and Their HLA-Ligands with Type 1 Diabetes Among South Indian Population

ABSTRACT Background Type 1 diabetes (T1D) is a multifactorial autoimmune disease, involving strong genetic components with familial predisposition. Killer cell immunoglobulin-like receptors (KIRs) found on the surface of NK cells have ligands of human leukocyte antigen (HLA) class I that are associated with T1D. The present study evaluates the influence of KIR genes and their HLA-ligands in the aetiology of T1D among the South Indian population. Methods A total of 125 T1D patients, along with their parents (n = 126) and siblings (n = 52) were recruited. PCR-based genotyping was performed for KIR genes and HLA class I ligands. The gene frequencies were compared between patients and siblings/parents. Linkage-disequilibrium (LD) analysis was performed to assess the genetic association between KIR gene pairs. Results The results show significant differences in HLA-ligands of KIR genes between patients and parents. The HLA-C1C1 homozygosity was found to be a predisposing risk factor, and HLA-C1C2 heterozygosity was protective towards T1D along with either the activating KIR2DS2 or inhibitory KIRs 2DL1, 2DL2, 2DL3. However, the frequency of inhibitory KIR3DL1 significantly increased in the presence of HLA-B Bw4 Ile80 in parents when compared to patients showing a protective effect on T1D. Two pairs of KIR genes, 2DS4-3DL1 and 2DS1-2DL5, showed strong LD in patients, siblings and parents. Conclusion The KIR-HLA ligand combinations have a significant effect on T1D aetiology among the South Indian population. This study defines a pattern for family-based association studies with genotypic information about KIR genes and their HLA-ligands, providing the first evidence towards T1D among the South Indian population.

Triple Haplotypes of the TP53 Gene in Patients with Diffuse Small B-Cell Lymphoma

The role of genetic susceptibility to the development of lymphoma is confirmed by the accumulating data on common genetic variants of the genes involved in lymphomogenesis. The varieties of disease variants, as well as the small effect of each of the polymorphisms, require the analysis of these markers in individual histological lymphoma subtypes in haplotype groups. This study was carried out to analyze the frequencies of rs1042522, rs1625895, and rs17878362, their triple haplotypes, and linkage disequilibrium in patients with diffuse small B-cell lymphoma and a control group. The absence of pronounced linkage disequilibrium between the rs17878362, rs1042522, and rs1625895 markers of the TP53 gene in the population control sample was revealed. At the same time, data on significant linkage disequilibrium between rs1625895 and rs1042522, as well as rs1625895 and rs17878362, and on moderate linkage disequilibrium between rs17878362 and rs1042522 in the group of patients with lymphoma were obtained. An association of the haplotype wArgG in the homozygous state with a predisposition to the development of diffuse small B-cell lymphoma was found.

The association between MICA/MICB polymorphism and respiratory syncytial virus infection in children.

MICA/MICB gene polymorphisms are related to several cancers and infectious diseases, but there are no reports on the association between MICA/MICB gene polymorphisms and respiratory syncytial virus (RSV) infection. To clarify the association between MICA/MICB gene polymorphisms and infection of RSV in children, we collected fresh blood samples from paediatric patients with and without pneumonia after RSV infection. The MICA/MICB alleles were characterized by PCR sequence-specific primers (PCR-SSP) and PCR sequence-based genotyping (PCR-SBT), and then, the frequency of the MICA/MICB alleles and haplotypes was calculated. The results showed that the frequencies of MICA*002:01 and MICA-A9 in RSV-infected patients were significantly lower than in controls (9% vs. 20%, pc=0.04). The allele frequency of MICA*002:01 in pneumonia patients (8%) and nonpneumonia patients (9%) was significantly lower than in controls (20%, pc=0.02). MICA*002:01-MICB*008(Δrel=0.616), MICA*009-MICB*016 (Δrel=0.506), and MICA*045-MICB*014 (Δrel=0.700) showed linkage disequilibrium in patients infected with RSV. The haplotype frequency of MICA*002:01-MICB*005:02 in RSV-infected patients was significantly lower than in controls (10% vs. 16%, pc=0.033). In conclusion, allele MICA*002:01/A9 and haplotype MICA*002:01-MICB*005:02 were negatively associated with RSV respiratory tract infections.

Association of rs172378 C1q gene cluster polymorphism with lupus nephritis in Bulgarian patients.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that can affect substantially any organ in the body. One of its most severe manifestations is lupus nephritis. Hereditary C1q deficiency is strongly related to SLE but there are very few and inconsistent studies exploring the single nucleotide polymorphisms (SNPs) of the C1q gene cluster in relation to the pathogenesis of SLE. In the present study we evaluated the possible association of gene variants in complement C1q gene cluster with susceptibility to lupus nephritis in a Bulgarian population, focusing on five previously associated with SLE SNPs in other populations. Thirty-eight patients with lupus nephritis and 185 healthy controls, all from Bulgaria, were genotyped for the five C1q SNPs, rs587585, rs292001, rs172378, rs294179 and rs631090, by quantitive real-time PCR methods. We also determined C1q serum levels of C1q and haemolytic activity of C1q in relation to C1q genotypes. Lupus nephritis patients and healthy controls had statistically similar frequencies of genotypes and alleles of rs587585, rs292001, rs294179 and rs631090 SNPs. Nevertheless, minor G allele in rs172378 was significantly overrepresented in lupus nephritis patients when compared with healthy controls (36% vs. 23%, odds ratio = 1.80, 95% confidence interval = 1.06-3.06, p = 0.029). The SNP rs292001 showed a trend towards lower serum C1q levels in healthy controls. Two SNPs - rs294179 and rs292001 - were in a linkage disequilibrium in patients and healthy controls with different power (healthy controls: r (2 )= 0.6526, D' = 0.842; lupus nephritis patients: r (2 )= 0.491, D' = 0.686). The haplotype C-A-A-T-T in the patient group was associated with lupus nephritis: 7.7% vs. 0.8%, odds ratio = 10.81, 95% confidence interval = 1.45-80.57, p = 0.002. These results support the implication of the G allele in rs172378 as a risk factor for lupus nephritis in a homozygous status, at least for a Bulgarian population.

Estimation of risk and interaction of single nucleotide polymorphisms at angiotensinogen locus causing susceptibility to essential hypertension: a case control study

The risk conferred by the variants and haplotypes of single nucleotide polymorphisms (SNPs) at human angiotensinogen (AGT) gene to essential hypertension (EHT) have been described in several populations with variations in the results attributed to their ethnicity. We attempted to evaluate the risk of -217G>A, -152G>A, -20A>C, -6G>A, T174M, M235T and 15241A>G polymorphisms at AGT locus along with the analyses of haplotype and epistatic interactions in causing susceptibility to EHT. Two-hundred and forty-nine hypertensives and 248 controls were genotyped for the selected markers. Study of demographic parameters revealed significant association of obesity, positive family history and non-vegetarian diet habit, suggesting elevated risk of the condition when associated with these parameters. Significantly high risk for males with AA genotype of -217G>A polymorphism was observed for developing EHT (p = .07). Males with -217A (p = .01) showed a two-fold higher risk for EHT. Markers -217G>A and -6G>A were in strong linkage disequilibrium in patients as compared to controls. Strong epistatic interactions were found between -6G>A, M235T and -217G>A markers, supporting the synergistic effect between them leading to EHT. Our findings suggest that -217A variant is significantly associated with the risk for EHT in males. Further studies on the functional role of the marker -217 are recommended for understanding the cause of association with EHT.

Analysis of HLA haplotype frequency and linkage disequilibrium in patients with acute lymphoblastic leukemia from Northern Chinese Han

To analyze the difference between the frequencies of HLA-A-B, B-DRB1 and A-B-DRB1 haplotype, as well as their linkage disequilibrium pattern in patients with acute lymphoblastic leukemia(ALL) and healthy controls from Northern Chinese Han. The frequencies of HLA-A-B, B-DRB1, A-B-DR haplotypes and linkage disequilibrium were estimated by Expectation Maximization method based on the genotypes of 643 patients with ALL and 2 0359 unrelated healthy donors, and the statistical significance between the two groups were estimated by chi-square test. Linkage disequilibrium was analyzed with population genetic methods. The most common HLA-A-B, B-DRB1, and A-B-DR haplotypes were A30-B13, A2-B46, A33-B58, B13-DR7, B46-DR9, B52-DR15, B58-DR17, A30-B13-DR7, A33-B58-DR17 and A1-B37-DR10 in both groups. The frequencies of A30-B13, A2-B46, A33-B44, B13-DR7, A30-B13-DR7 and A2-B46-DR9 haplotypes and linkage disequilibrium value were significantly decreased (P<0.05) in the patient group than that in the control group. On the other hand, the frequencies of A2-B52, A31-B61, A24- B8, B60-DR9, B27-DR4, B52-DR14, B44-DR17, B27-DR12 and A11-B27-DR12 haplotypes and linkage disequilibrium value were significantly increased (P<0.05) in the patient group than that in the control group. There are some common and positive linkage disequilibrium haplotypes in both the ALL patients and the healthy donors in Northern Chinese Han. Interestingly, some haplotypes and their linkage disequilibrium patterns had significantly different distributions between the two groups. The study provided basic data for the relationship of ALL and HLA haplotype and for finding the HLA-A, B, DR matching donors.

Changes at the CYP2C locus and disruption of CYP2C8/9 linkage disequilibrium in patients with essential tremor

To identify low-penetrance genes related to sporadic essential tremor (ET) at the CYP2C locus, located in chromosome 10 q23.33. Leukocytary DNA from 200 ET patients and a control group of 300 unrelated healthy individuals with known CYP2C19 genotypes was studied for common CYP2C8 and CYP2C9 allelic variants by using amplification-restriction analyses. Patients with ET showed the following differences compared with healthy subjects: a 1.6-fold reduction in the frequency for CYP2C8*3 (p=0.006), a 1.35-fold reduction of CYP2C9*2 (p=0.05) and a 1.52-fold reduction in the frequency for CYP2C9*3 (p=0.07). The frequency for patients with ET carrying at least one defective allele was 1.33-fold reduced as compared with healthy subjects (p=0.002). In addition, a disruption of the CYP2C8*3/CYP2C9*2 linkage disequilibrium was observed in ET patients, with a 2.1-fold reduction in the percentage for carriers of the haplotype CYP2C8*3 plus CYP2C9*2 in ET patients (p=0.0001). These findings were independent of gender, age, age of onset, or clinical symptoms. These results suggest that alterations at the CYP2C gene locus are associated with the risk for ET.

Changes at the CYP2C locus and disruption of CYP2C8/9 linkage disequilibrium in patients with essential tremor

Changes at the CYP2C locus and disruption of CYP2C8/9 linkage disequilibrium in patients with essential tremor

Pairwise linkage disequilibrium under disease models

Many genetic studies of disease association rely heavily on linkage disequilibrium (LD) patterns between pairs of markers to detect susceptibility markers. This is true of large-scale positional mapping approaches as well as haplotype construction, selection of tagging single-nucleotide polymorphisms and population genetic analyses. Whereas the distribution of different LD measures has been investigated for randomly selected chromosomes from populations undergoing a variety of demographic effects, little is known about LD within disease-affected samples, and how various disease models influence the difference in LD between patients and the general population. As whole-genome efforts are now underway to characterize and utilize LD patterns in randomly sampled individuals, knowledge about the extent that LD differs between patients and the general population becomes crucial. Such information will allow investigators to design improved mapping experiments and better understand haplotype information arising from such experiments. In this paper, we explore two-site LD measures in the context of single gene disease models. Analytic expressions are presented for infinite populations and properties of sampling densities are reported for different disease models. Interestingly, results indicate that 'underdominant', some dominant, recessive and 'protective' disease models generate weaker LD levels in patients compared to the general population, whereas other models produce stronger LD among affected individuals. Analytic results are also presented for the ratio of LD in patients to the LD in the general population as a function of recombination fraction using a Haldane model. In addition, we explore the impact of various allele frequency combinations on LD differences.

HLA and psoriasis in the Chinese.

The HLA locus A, B and C antigen frequency of 70 unrelated Chinese patients with psoriasis were compared to that of 330 normal subjects. The frequency of 1, Aw30 and B13 were significantly elevated among patients compared to normals, even after correction for the number of antigens typed for. The joint occurrence of Aw30, B13 was observed in 20/70 (37.1%) patients compared to 8/330 /2.4%) normals (chi 2 = 60.7, RR = 16.1). Aw30 and B13 were found to be in significant linkage disequilibrium in patients as well as normals.