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Polymorphism in clinical immunology – From HLA typing to immunogenetic profiling
Ping Jin, Ena Wang
Journal of Translational Medicine , 2003, DOI: 10.1186/1479-5876-1-8
Abstract: Genetic polymorphism is the hallmark of human biology. Scientists who address the pathophysiology of disease are well aware of this and often resort to the simplification of human pathology through the development of animal models that eliminate this confounding dimension through generations of inbreeding. The immune system is clearly most profoundly affected by the genetic variation of the human species. This is why Jean Dausset observed in 1952 that individuals who had received several transfusions from strangers developed antibodies against the donor's leukocytes. This observation eventually led to the identification of the Human Leukocyte Antigen (HLA) system [1], a nomenclature that refers to the human Major Histocompatibility Complex (MHC) [2]. It turned out that the MHC complex includes the most polymorphic genes in the human and wild animals' genomes and the implications of this polymorphism in relation to transplantation, immune response and autoimmune disease had stirred an ongoing debate [3-6]. Conservation is generally considered in biology a structural requirement for function: protein domains that are most conserved are also most likely to be those that are most critical to the function of that protein. Conversely, polymorphism is regarded as a dispensable component of the human genome where random mutations are not erased by evolutionary pressure. This concept may very well apply to functions that do not require extensive adaptability of the specie to environmental pressure. Molecules like insulin which responds to a well defined and invariable stimulus (blood glucose) by reducing its circulating levels with almost mathematical predictability do not need much adaptation and are affected by minimal genetic variation across mammalian species.The immune system, on the other hand, has the more complex task of responding to ever evolving environmental components that enter the organism through different routes in the form of pathogens. This adaptation can
Frecuencia de alelos HLA de clase I y II en una cohorte de pacientes con espondiloartritis provenientes del noroccidente colombiano
Velásquez,Eliana Patricia; Quintero,Julio César; Aristizábal,Beatriz Helena; Rincón,Olga Lucía; Velásquez,Carlos Jaime; Pinto,Luis Fernando; Márquez,Javier Darío;
Biomédica , 2012,
Abstract: introduction. spondyloarthritis is a chronic rheumatic disease that affect the axial skeleton and peripheral joints, along with several extra-articular manifestations. the association with hla-b27 remains one of the strongest known links between these entities and the major histocompatibility complex. however, the global distribution of hla-b27 varies considerably and furthermore, associations with non-hla-b27 genes have been described. objective. the frequency of hla class i and ii was determined in a population of patients with spondyloarthritis with respect to detection in the clinical setting and by radiology. materials and methods. a descriptive, observational, cross-sectional, retrospective and prospective study was conducted in 56 patients from northwestern colombia. each was diagnosed with spondyloarthritis between 2005 and 2008. in each case, alleles were identified for the loci hla class i and ii (hla-b; hladqb1 and hladrb). the frequency of these alleles in the axial, peripheral, extraarticular and radiological manifestations. results.the frequency of hla-b27 was 50% overall, and it was the most frequent allele. the two other alleles were hla.drb4*01 at 35.7% and hla-dqb1*0501 at 28.6%, as detected in each of the clinical and radiological manifestations. a high frequency of hla-b27 and hla-drb4*01 (64.3%) was noted in patients with dactylitis. conclusion. the alleles hla-b27, hla-drb4*01 and hla-dqb1*0501 were common in the different subtypes of spondyloarthritis and were frequent in the specific clinical axial, peripheral and extraarticular clinical manifestations, as well as radiological sacroiliitis.
Lack of Influence of the Androgen Receptor Gene CAG-Repeat Polymorphism on Clinical and Electrocardiographic Manifestations of the Brugada Syndrome in Man
S. Mariani, B. Musumeci, S. Basciani, D. Fiore, P. Francia, A. Persichetti, M. Volpe, C. Autore, C. Moretti, S. Ulisse, and L. Gnessi
Clinical Medicine Insights: Cardiology , 2012, DOI: 10.4137/CMC.S10553
Abstract: Background: Clinical studies suggest that testosterone (T) plays an important role in the male predominance of the clinical manifestations of the Brugada syndrome (BS). However, no statistically significant correlations have been observed between T levels and electrocardiogram (ECG) parameters in the BS patients. We investigated whether the hormonal pattern and the variation within CAG repeat polymorphism in exon 1 of the androgen receptor (AR) gene, affecting androgen sensitivity, are associated with the Brugada ECG phenotype in males. Methods and Results: 16 male patients with BS (mean age 45.06 ± 11.3 years) were studied. 12-lead ECG was recorded. Blood levels of follicle-stimulating hormone, luteinizing hormone, prolactin, testosterone, free-T, dihydrotestosterone, 17- -estradiol, estrone, 3-alpha-androstanediol-glucuronide, delta-4-androstenedione, dehydroepiandrosterone sulphate, progesterone, 17-hydroxyprogesterone, and sex hormone binding globulin were assayed. Genotyping of CAG repeats on DNA extracted from leukocytes was carried out. No relationship was found between hormone values and ECG parameters of BS. BS patients showed the CAG length normally recognized in the human polymorphism range and the number of CAG repeats did not correlate with the ECG pattern of BS. Conclusions: The AR CAG repeat length does not correlate with the ECG features of the patients affected by BS. The search for genes downstream AR activation as possibly responsible for the increased risk of spontaneous arrhythmias in BS males after puberty is warranted.
Frequency of HLA alleles class I and II in a cohort of northwestern Colombian patients with spondyloarthritis Frecuencia de alelos HLA de clase I y II en una cohorte de pacientes  [cached]
Eliana Patricia Velásquez,Julio César Quintero,Beatriz Helena Aristizábal,Olga Lucía Rincón
Biomédica , 2011,
Abstract: Introduction. Spondyloarthritis is a chronic rheumatic disease that affect the axial skeleton and peripheral joints, along with several extra-articular manifestations. The association with HLA-B27 remains one of the strongest known links between these entities and the major histocompatibility complex. However, the global distribution of HLA-B27 varies considerably and furthermore, associations with non-HLA-B27 genes have been described. Objective. The frequency of HLA class I and II was determined in a population of patients with spondyloarthritis with respect to detection in the clinical setting and by radiology. Materials and methods. A descriptive, observational, cross-sectional, retrospective and prospective study was conducted in 56 patients from northwestern Colombia. Each was diagnosed with spondyloarthritis between 2005 and 2008. In each case, alleles were identified for the loci HLA class I and II (HLA-B; HLADQB1 and HLADRB). The frequency of these alleles in the axial, peripheral, extraarticular and radiological manifestations. Results.The frequency of HLA-B27 was 50% overall, and it was the most frequent allele. The two other alleles were HLA.DRB4*01 at 35.7% and HLA-DQB1*0501 at 28.6%, as detected in each of the clinical and radiological manifestations. A high frequency of HLA-B27 and HLA-DRB4*01 (64.3%) was noted in patients with dactylitis. Conclusion. The alleles HLA-B27, HLA-DRB4*01 and HLA-DQB1*0501 were common in the different subtypes of spondyloarthritis and were frequent in the specific clinical axial, peripheral and extraarticular clinical manifestations, as well as radiological sacroiliitis. Introducción. Las espondiloartritis son enfermedades reumatológicas crónicas que afectan el esqueleto axial y las articulaciones periféricas, con varias manifestaciones extraarticulares. La asociación con el HLA-B27 sigue siendo uno de los vínculos más fuertes conocidos entre estas entidades y el complejo mayor de histocompatibilidad; sin embargo, la distribución mundial del HLA-B27 varía considerablemente y se han descrito asociaciones con genes no HLA-B27. Objetivo. Conocer la frecuencia de alelos HLA de clase I y II en pacientes con espondiloartritis provenientes del noroccidente colombiano y su frecuencia en las manifestaciones clínicas y radiológicas específicas. Materiales y métodos. Se condujo un estudio descriptivo, observacional, de corte transversal, retrospectivo y prospectivo entre 2005 y 2008 de 56 pacientes colombianos con espondiloartritis. Se identificaron los alelos correspondientes a los loci HLA de clase I y II (HLA-B, HLADQ
H. Kalanie,G.R. Shamsai
Iranian Journal of Child Neurology , 2007,
Abstract: Multiple sclerosis (MS) is a demyelinating disease of the central nervous system, with unknown etiology in which both genetic and environmental factors are thought to be involved. The HLA system provides a set of genetic markers which lend themselves to systematic study. The disease also has variable clinical manifestations, ranging from a relapsing-remitting course to a chronic progressive disease. In this article we review HLA profile and clinical presentation of the disease from current available data in Iran.
Associations between Brain-derived Neurotrophic Factor G196A Gene Polymorphism and Clinical Phenotypes in Schizophrenia Patients  [PDF]
Tiao-Lai Huang,Chien-Te Lee
Chang Gung Medical Journal , 2007,
Abstract: Background: Brain-derived neurotrophic factor (BDNF) had been chosen as a candidategene for schizophrenia. This study investigated the relationships betweenBDNF G196A gene polymorphism and clinical phenotypes in schizophreniapatients in the Taiwanese population.Methods: During a one year period, 132 schizophrenic patients and 103 healthy controlswere recruited. Psychiatric diagnoses were made according to DSM-IVcriteria. Genotyping of the G196A polymorphism of BDNF was performedby polymerase chain reaction amplification and restriction fragment lengthpolymorphism.Results: The data showed that the BDNF G196A genotypes and their allele distributionsdid not differ between patients with schizophrenia and healthy controls.No significant differences were noted in the BDNF G196A genotypes andallele distribution between schizophrenia patients with and without a familytendency for schizophrenia or between those with an age of onset before orafter 25 years old. However, there was a significant difference in BDNFG196A genotype distribution between schizophrenia patients with and withouta suicide history.Conclusions: These analytical results suggest that BDNF G196A gene polymorphism isassociated with a susceptibility to a suicide history in schizophrenia patientsin the Taiwanese population. Further study with a larger number of samplesis needed to prove these findings.
Prognostic Significance of Comparison of Clinical Indicators with Manifestations of Genetic Polymorphism of Glutathione-S-Transferases in Non-Small Cell Lung Cancer  [PDF]
Mikhail N. Shapetska, Evelina V. Krupnova, Alena P. Mikhalenka, Natalia V. Chebotareva, Anna N. Shchayuk, Svetlana G. Pashkevich, Alexander V. Prokhorov
Journal of Cancer Therapy (JCT) , 2018, DOI: 10.4236/jct.2018.912080
Abstract: The article presented the results of comparison of polymorphic variants of the genes GSTM1, GSTT1, GSTP1 and clinical manifestations of non-small cell lung carcinoma. The association of the genotype GSTT1 (del) with the risk of developing squamous cell lung cancer has been revealed (OR = 2.54 CI: 1.13 - 5.72, p = 0.035). Analysis of patient survival rate (n = 173) in groups of various histological types of lung cancer showed that in the group of squamous cell lung cancer (n = 91) in patients with genotype GSTT1 (del), the survival rate median was significantly higher—84 months (95% CI 12.4 - 155.7) than in patients with the genotype GSTT1 (+)—36 months (95% CI 25.2 - 46.8, p = 0.045). In contrast, in the adenocarcinoma group (n = 82), the survival rate median in patients with the genotype GSTT1 (del) was 19 months. (95% CI 6.2 - 33.5), and in patients with genotype GSTT1 (+)—67 months (95% CI 50.1 - 84.0), which is the basis for continuing this comparison in an additional group of testees, as the sampling did not achieve the reliability of p = 0.12. Hypothetically, these differences may be due to differences in the gender composition of squamous cell lung cancer and adenocarcinoma and the involvement of GST enzymes in the metabolism of estrogens in adenocarcinoma in women and other hormonal background and reactivity of the male body with squamous cell carcinoma. Further research and subsequent analysis of the results will be aimed at confirming this hypothesis.
Different HLA-DRB1 allele distributions in distinct clinical subgroups of sarcoidosis patients
Johan Grunewald, Boel Brynedal, Pernilla Darlington, Magnus Nisell, Kerstin Cederlund, Jan Hillert, Anders Eklund
Respiratory Research , 2010, DOI: 10.1186/1465-9921-11-25
Abstract: In this study we HLA typed a large patient population (n = 754) recruited from one single centre. Patients were sub-grouped into those with L?fgren's syndrome (LS) (n = 302) and those without (non-L?fgren's) (n = 452), and the majority of them were clinically classified into those with recovery within two years (resolving) and those with signs of disease for more than two years (non-resolving). PCR was used for determination of HLA-DRB1 alleles. Swedish healthy blood donors (n = 1366) served as controls.There was a dramatic difference in the distribution of HLA alleles in LS compared to non-LS patients (p = 4 × 10-36). Most notably, DRB1*01, DRB1*03 and DRB1*14, clearly differed in LS and non-LS patients. In relation to disease course, DRB1*07, DRB1*14 and DRB1*15 generally associated with, while DRB1*01 and DRB1*03 protected against, a non-resolving disease. Interestingly, the clinical influence of DRB1*03 (good prognosis) dominated over that of DRB1*15 (bad prognosis).We found several significant differences between LS and non-LS patients and we therefore suggest that genetic association studies in sarcoidosis should include a careful clinical characterisation and sub-grouping of patients, in order to reveal true genetic associations. This may be particularly accurate to do in the heterogeneous non-LS group of patients.Sarcoidosis is an inflammatory disease of unknown aetiology. A genetic influence has been suggested by reports showing different susceptibilities and clinical manifestations between distinct ethnic groups [1]. In addition genetic linkage analyses have pointed out a significant linkage for the major histocompatibility complex (MHC) region [2], but also with minor peaks in specific regions of some other chromosomes [3]. One recently published genome wide association study described an association with the gene coding for Annexin A11, a protein with several important functions, including for apoptosis [4].Sarcoidosis is thus influenced by a multitude o
Risk Alleles for Systemic Lupus Erythematosus in a Large Case-Control Collection and Associations with Clinical Subphenotypes  [PDF]
Kimberly E. Taylor,Sharon A. Chung,Robert R. Graham,Ward A. Ortmann,Annette T. Lee,Carl D. Langefeld,Chaim O. Jacob,M. Ilyas Kamboh,Marta E. Alarcón-Riquelme,Betty P. Tsao,Kathy L. Moser,Patrick M. Gaffney,John B. Harley,Michelle Petri,Susan Manzi,Peter K. Gregersen,Timothy W. Behrens,Lindsey A. Criswell
PLOS Genetics , 2011, DOI: 10.1371/journal.pgen.1001311
Abstract: Systemic lupus erythematosus (SLE) is a genetically complex disease with heterogeneous clinical manifestations. Recent studies have greatly expanded the number of established SLE risk alleles, but the distribution of multiple risk alleles in cases versus controls and their relationship to subphenotypes have not been studied. We studied 22 SLE susceptibility polymorphisms with previous genome-wide evidence of association (p<5×10?8) in 1919 SLE cases from 9 independent Caucasian SLE case series and 4813 independent controls. The mean number of risk alleles in cases was 15.1 (SD 3.1) while the mean in controls was 13.1 (SD 2.8), with trend p = 4×10?128. We defined a genetic risk score (GRS) for SLE as the number of risk alleles with each weighted by the SLE risk odds ratio (OR). The OR for high-low GRS tertiles, adjusted for intra-European ancestry, sex, and parent study, was 4.4 (95% CI 3.8–5.1). We studied associations of individual SNPs and the GRS with clinical manifestations for the cases: age at diagnosis, the 11 American College of Rheumatology classification criteria, and double-stranded DNA antibody (anti-dsDNA) production. Six subphenotypes were significantly associated with the GRS, most notably anti-dsDNA (ORhigh-low = 2.36, p = 9e?9), the immunologic criterion (ORhigh-low = 2.23, p = 3e?7), and age at diagnosis (ORhigh-low = 1.45, p = 0.0060). Finally, we developed a subphenotype-specific GRS (sub-GRS) for each phenotype with more power to detect cumulative genetic associations. The sub-GRS was more strongly associated than any single SNP effect for 5 subphenotypes (the above plus hematologic disorder and oral ulcers), while single loci are more significantly associated with renal disease (HLA-DRB1, OR = 1.37, 95% CI 1.14–1.64) and arthritis (ITGAM, OR = 0.72, 95% CI 0.59–0.88). We did not observe significant associations for other subphenotypes, for individual loci or the sub-GRS. Thus our analysis categorizes SLE subphenotypes into three groups: those having cumulative, single, and no known genetic association with respect to the currently established SLE risk loci.
Identification of Novel Genetic Markers Associated with Clinical Phenotypes of Systemic Sclerosis through a Genome-Wide Association Strategy  [PDF]
Olga Gorlova equal contributor ,Jose-Ezequiel Martin equal contributor,Blanca Rueda equal contributor,Bobby P. C. Koeleman equal contributor,Jun Ying,Maria Teruel,Lina-Marcela Diaz-Gallo,Jasper C. Broen,Madelon C. Vonk,Carmen P. Simeon,Behrooz Z. Alizadeh,Marieke J. H. Coenen,Alexandre E. Voskuyl,Annemie J. Schuerwegh,Piet L. C. M. van Riel,Marie Vanthuyne,Ruben van 't Slot,Annet Italiaander,Roel A. Ophoff,Nicolas Hunzelmann,Vicente Fonollosa,Norberto Ortego-Centeno,Miguel A. González-Gay,Francisco J. García-Hernández,María F. González-Escribano,Paolo Airo,Jacob van Laar,Jane Worthington,Roger Hesselstrand,Vanessa Smith,Filip de Keyser,Fredric Houssiau,Meng May Chee,Rajan Madhok,Paul G. Shiels,Rene Westhovens,Alexander Kreuter,Elfride de Baere,Torsten Witte,Leonid Padyukov,Annika Nordin,Raffaella Scorza,Claudio Lunardi,Benedicte A. Lie,Anna-Maria Hoffmann-Vold,?yvind Palm,Paloma García de la Pe?a,Patricia Carreira,Spanish Scleroderma Group equal contributor,John Varga,Monique Hinchcliff,Annette T. Lee,Pravitt Gourh,Christopher I. Amos,Frederick M. Wigley,Laura K. Hummers,J. Hummers,J. Lee Nelson,Gabriella Riemekasten,Ariane Herrick,Lorenzo Beretta,Carmen Fonseca,Christopher P. Denton,Peter K. Gregersen,Sandeep Agarwal,Shervin Assassi,Filemon K. Tan,Frank C. Arnett ?,Timothy R. D. J. Radstake ?,Maureen D. Mayes ?,Javier Martin ?
PLOS Genetics , 2011, DOI: 10.1371/journal.pgen.1002178
Abstract: The aim of this study was to determine, through a genome-wide association study (GWAS), the genetic components contributing to different clinical sub-phenotypes of systemic sclerosis (SSc). We considered limited (lcSSc) and diffuse (dcSSc) cutaneous involvement, and the relationships with presence of the SSc-specific auto-antibodies, anti-centromere (ACA), and anti-topoisomerase I (ATA). Four GWAS cohorts, comprising 2,296 SSc patients and 5,171 healthy controls, were meta-analyzed looking for associations in the selected subgroups. Eighteen polymorphisms were further tested in nine independent cohorts comprising an additional 3,175 SSc patients and 4,971 controls. Conditional analysis for associated SNPs in the HLA region was performed to explore their independent association in antibody subgroups. Overall analysis showed that non-HLA polymorphism rs11642873 in IRF8 gene to be associated at GWAS level with lcSSc (P = 2.32×10?12, OR = 0.75). Also, rs12540874 in GRB10 gene (P = 1.27 × 10?6, OR = 1.15) and rs11047102 in SOX5 gene (P = 1.39×10?7, OR = 1.36) showed a suggestive association with lcSSc and ACA subgroups respectively. In the HLA region, we observed highly associated allelic combinations in the HLA-DQB1 locus with ACA (P = 1.79×10?61, OR = 2.48), in the HLA-DPA1/B1 loci with ATA (P = 4.57×10?76, OR = 8.84), and in NOTCH4 with ACA P = 8.84×10?21, OR = 0.55) and ATA (P = 1.14×10?8, OR = 0.54). We have identified three new non-HLA genes (IRF8, GRB10, and SOX5) associated with SSc clinical and auto-antibody subgroups. Within the HLA region, HLA-DQB1, HLA-DPA1/B1, and NOTCH4 associations with SSc are likely confined to specific auto-antibodies. These data emphasize the differential genetic components of subphenotypes of SSc.
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