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1.
Vitamin D Receptor Polymorphisms Associated with Autism Spectrum Disorder.
Guerini, FR, Bolognesi, E, Chiappedi, M, Mensi, MM, Fumagalli, O, Rogantini, C, Zanzottera, M, Ghezzo, A, Zanette, M, Agliardi, C, et al
Autism research : official journal of the International Society for Autism Research. 2020;(5):680-690
Abstract
Vitamin D is endowed with a number of biological properties, including down-regulation of inflammation, and might contribute to the pathogenesis of autism spectrum disorders (ASD). Vitamin D binds to the vitamin D Receptor (VDR); the biological activity of the ensuing complex depends on VDR FokI, BsmI, ApaI, and TaqI gene polymorphisms. We evaluated such Single Nucletoide Polymorphismsm (SNPs) in a cohort of 100 Italian families with ASD children. FokI genotype distribution was skewed in ASD children compared with their healthy sibs (Pc = 0.03 2 df) and to a group of 170 Italian healthy women (HC) (Pc = 0.04 2 df). FokI genotype and allelic distribution skewing were also observed in mothers of ASD children compared to HC (Pc = 0.04 2 df). Both Transmission Disequilibrium Test for single loci and haplotype analysis distribution revealed a major FokI (C) allele-mediated protective effect, which was more frequently transmitted (73%) than not transmitted to healthy sibs (P = 0.02). A protective FokI-, BsmI-, ApaI-, and TaqI (CCAG) haplotype was more frequently carried by healthy sibs than by ASD children (P = 1 × 10-4 ; OR: 0.1, 95% CI: 0.03-0.4) too. Finally, a strong gene-dose association of FokI (T) allele with both higher Childhood Autism Rating Scale score (Pc = 0.01) and, particularly, with hyperactivity behavior (Pc = 0.006) emerged in ASD children. Because the protein produced by the FokI (T) allele is transcriptionally less active than that produced by the FokI (C) allele, the reduced biological activity of the vitamin D/VDR complex prevalent in ASD could favor ASD- and maternal immune activation- associated inflammation. Vitamin D supplementation might be useful in preventative and rehabilitation protocols for ASD. Autism Res 2020, 13: 680-690. © 2020 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY Vitamin D deficiency and Vitamin D receptor (VDR) polymorphisms are associated with structural and functional brain abnormalities and behavioral disorders. We analyzed the association of VDR gene polymorphisms in a cohort of 100 Italian families with ASD children. A strong correlation between one of the VDR polymorphisms and hyperactivity behavior was evidenced in ASD children. In healthy mothers, the same VDR polymorphism was also correlated with an increased risk of giving birth to children with ASD.
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2.
The Research Progress of Host Genes and Tuberculosis Susceptibility.
Cai, L, Li, Z, Guan, X, Cai, K, Wang, L, Liu, J, Tong, Y
Oxidative medicine and cellular longevity. 2019;:9273056
Abstract
BACKGROUND/AIMS: Nucleotide diversity may affect the immune regulation of tuberculosis (TB) patients, leading to the individual susceptibility to TB. In recent years, there are a lot of researches on the association of host genetic factors and TB susceptibility which has attracted increasing attention, and the in-depth study of its mechanism is gradually clear. MATERIALS We made a minireview on the association of many candidate genes with TB based on recent research studies systematically, such as the human leukocyte antigen (HLA) gene, the solute carrier family 11 member 1 (SLC11A1) gene system, the vitamin D receptor (VDR) gene, the mannan-binding lectin (MBL) gene, the nitric oxide synthase 2A (NOS2A) gene, the speckled 110 (SP110) gene, and the P2X7 receptor (P2X7) gene. The discovery of these candidate genes could reveal the pathogenesis of TB comprehensively and is crucial to provide scientific evidence for formulating the related measures of prevention and cure. DISCUSSION The host genes play important roles in the development of TB, and the host genes may become new targets for the prevention and treatment of TB. Effective regulation of host genes may help prevent or even treat TB. CONCLUSION This minireview focuses on the association of host genes with the development of TB, which may supply some clues for future therapies and novel drug targets for TB.
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3.
Genetically-determined hyperfunction of the S100B/RAGE axis is a risk factor for aspergillosis in stem cell transplant recipients.
Cunha, C, Giovannini, G, Pierini, A, Bell, AS, Sorci, G, Riuzzi, F, Donato, R, Rodrigues, F, Velardi, A, Aversa, F, et al
PloS one. 2011;(11):e27962
Abstract
Invasive aspergillosis (IA) is a major threat to the successful outcome of hematopoietic stem cell transplantation (HSCT), although individual risk varies considerably. Recent evidence has established a pivotal role for a danger sensing mechanism implicating the S100B/receptor for advanced glycation end products (RAGE) axis in antifungal immunity. The association of selected genetic variants in the S100B/RAGE axis with susceptibility to IA was investigated in 223 consecutive patients undergoing HSCT. Furthermore, studies addressing the functional consequences of these variants were performed. Susceptibility to IA was significantly associated with two distinct polymorphisms in RAGE (-374T/A) and S100B (+427C/T) genes, the relative contribution of each depended on their presence in both transplantation counterparts [patient SNP(RAGE), adjusted hazard ratio (HR), 1.97; P = 0.042 and donor SNP(RAGE), HR, 2.03; P = 0.047] or in donors (SNP(S100B), HR, 3.15; P = 7.8e-(4)) only, respectively. Functional assays demonstrated a gain-of-function phenotype of both variants, as shown by the enhanced expression of inflammatory cytokines in RAGE polymorphic cells and increased S100B secretion in vitro and in vivo in the presence of the S100B polymorphism. These findings point to a relevant role of the danger sensing signaling in human antifungal immunity and highlight a possible contribution of a genetically-determined hyperfunction of the S100B/RAGE axis to susceptibility to IA in the HSCT setting.
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4.
Genetic polymorphisms in vitamin D receptor, vitamin D-binding protein, Toll-like receptor 2, nitric oxide synthase 2, and interferon-gamma genes and its association with susceptibility to tuberculosis.
Leandro, AC, Rocha, MA, Cardoso, CS, Bonecini-Almeida, MG
Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas. 2009;(4):312-22
Abstract
Mycobacterium tuberculosis kills more people than any other single pathogen, with an estimated one-third of the world's population being infected. Among those infected, only 10% will develop the disease. There are several demonstrations that susceptibility to tuberculosis is linked to host genetic factors in twins, family and associated-based case control studies. In the past years, there has been dramatic improvement in our understanding of the role of innate and adaptive immunity in the human host defense to tuberculosis. To date, attention has been paid to the role of genetic host and parasitic factors in tuberculosis pathogenesis mainly regarding innate and adaptive immune responses and their complex interactions. Many studies have focused on the candidate genes for tuberculosis susceptibility ranging from those expressed in several cells from the innate or adaptive immune system such as Toll-like receptors, cytokines (TNF-alpha, TGF-beta, IFN-gamma, IL-1b, IL-1RA, IL-12, IL-10), nitric oxide synthase and vitamin D, both nuclear receptors and their carrier, the vitamin D-binding protein (VDBP). The identification of possible genes that can promote resistance or susceptibility to tuberculosis could be the first step to understanding disease pathogenesis and can help to identify new tools for treatment and vaccine development. Thus, in this mini-review, we summarize the current state of investigation on some of the genetic determinants, such as the candidate polymorphisms of vitamin D, VDBP, Toll-like receptor, nitric oxide synthase 2 and interferon-gamma genes, to generate resistance or susceptibility to M. tuberculosis infection.
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5.
Reduced endocannabinoid immune modulation by a common cannabinoid 2 (CB2) receptor gene polymorphism: possible risk for autoimmune disorders.
Sipe, JC, Arbour, N, Gerber, A, Beutler, E
Journal of leukocyte biology. 2005;(1):231-8
Abstract
Immune system responsiveness results from numerous factors, including endogenous cannabinoid signaling in immunocytes termed the "immunocannabinoid" system. This system can be an important signaling pathway for immune modulation. To assess the immunomodulating role of the cannabinoid 2 (CB2) receptor, we sought polymorphisms in the human gene, identified a common dinucleotide polymorphism, and investigated its effect on endocannabinoid-induced inhibition of T lymphocyte proliferation. The CB2 cDNA 188-189 GG/GG polymorphism predicts the substitution of glutamine at amino acid position 63 by arginine. T lymphocytes from CB2 188-189 GG/GG homozygotes had approximately twofold reduction of endocannabinoid-induced inhibition of proliferation compared with cells from CB2 188-189 AA/AA homozygotes. In GG/GG subjects, the reduced endocannabinoid inhibitory response was highly significant for N-arachidonylglycine and nearly significant for 2-arachidonylglycerol, and a specific CB2 receptor antagonist partially blocked these effects. Also, patients with autoimmune diseases had an increased prevalence of the homozygous GG/GG genotype. Collectively, these results demonstrate reduced endogenous fatty acid amide immunomodulatory responses in individuals with the CB2 188-189 GG/GG genotype and suggest that this CB2 gene variation may be a risk factor for autoimmunity. The results also support the proposition that the CB2 receptor may represent a novel pharmacological target for selective agonists designed to suppress autoreactive immune responses while avoiding CB1 receptor-mediated cannabinoid adverse effects.
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6.
Association between chronic fatigue syndrome and the corticosteroid-binding globulin gene ALA SER224 polymorphism.
Torpy, DJ, Bachmann, AW, Gartside, M, Grice, JE, Harris, JM, Clifton, P, Easteal, S, Jackson, RV, Whitworth, JA
Endocrine research. 2004;(3):417-29
Abstract
Chronic fatigue syndrome (CFS) is characterized by idiopathic fatigue of greater than 6 months' duration with postexertional exacerbation and many other symptoms. A trend toward relative hypocortisolism is described in CFS. Twin and family studies indicate a substantial genetic etiologic component to CFS. Recently, severe corticosteroid-binding globulin (CBG) gene mutations have been associated with CFS in isolated kindreds. Human leukocyte elastase, an enzyme important in CBG catabolism at inflammatory sites, is reported to be elevated in CFS. We hypothesized that CBG gene polymorphisms may act as a genetic risk factor for CFS. A total of 248 patients with CFS defined by Centers for Disease Control criteria, and 248 controls were recruited. Sequencing and restriction enzyme testing of the CBG gene coding region allowed detection of severe CBG gene mutations and a common exon 3 polymorphism (c.825G-->T, Ala-Ser224). Plasma CBG levels were measured in 125 CFS patients and 198 controls by radioimmunoassay. Total and free (calculated and measured) cortisol levels were ascertained in single samples between 8-10 a.m. The age of onset (mid 30s) and gender ratio (2.2:1, female:male) of the patients were similar to those reported in U.S. epidemiologic studies. A trend toward a preponderance of serine224 homozygosity among the CFS patients was noted, compared with controls (chi2 = 5.31, P = 0.07). Immunoreactive-CBG (IR-CBG) levels were higher in Serine/Alanine (Ser/Ala) than Ala/Ala subjects and higher again in Ser/Ser subjects, this effect was strongest in controls; Ser/Ser: 46.1+/-1.8 (n = 31, P = 0.03) vs. Ser/Ala: 42.4+/-1.0 (n = 56, P = 0.05) vs. Ala/Ala: 40.8+/-1.7 microg/mL (n = 21). Despite higher CBG levels, there was a nonsignificant trend toward lower total and free plasma cortisol in serine allele positive patients, total cortisol: Ser/Ser: 13.3+/-1.4 (n = 34) vs. Ser/Ala: 14.0+/-0.7 (n = 66) vs. Ala/Ala: 15.4+/-1.0 (n = 23). Homozygosity for the serine allele of the CBG gene may predispose to CFS, perhaps due to an effect on hypothalamic-pituitary-adrenal axis function related to altered CBG-cortisol transport function or immune-cortisol interactions.
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7.
[Histocompatibility HLA system of man. Consideration in the light of current concepts. I. Organization and polymorphism].
Kedzierska, A, Turowski, G
Przeglad lekarski. 2001;(5):459-62
Abstract
The HLA system, which represents the major histocompatibility complex (MHC) of man, encompasses approximately one thousandth of the human genome and is localised on the short arm of chromosome 6 (band 6p 21.3). The HLA gene complex shows an extreme polymorphism which can be demonstrated by molecular genetic methods. The genes so far recognised in the HLA can be subdivided into three major classes: 1) the HLA class I (HLA-ABC) and class II genes (HLA-D); 2) immune function related genes (C2, C4A, C4B, TNFA and TNFB, transporter and proteasome genes); 3) other genes apparently not related to immune functions (CYP 21, valyl-tRNA synthetase). The loci HLA-A, -B, and -C represent the classical HLA class I loci with gene products expressed on nearly all nucleated cells; HLA-E, -F and -G the non-classical HLA class I loci, code for products with a limited tissue distribution and a restricted polymorphism. Classical class I and II MHC antigens are integral membrane proteins composed of two pairs of structurally similar extracellular domains. The X-ray studies indicated the presence of peptides bound to HLA molecules within the groove. The groove has on its floor several amino acids where peptides, derived from the antigen being presented, are bound. Although the principle of allele specific motives ruling the peptide binding seems to be become more established, the further biological impact of the allelic variation remains subject for future studies.