1.
Role of CTLA4 A49G polymorphism in systemic lupus erythematosus and its geographical distribution.
Kailashiya, V, Sharma, HB, Kailashiya, J
Journal of clinical pathology. 2019;(10):659-662
Abstract
CTLA-4 (cytotoxic T-lymphocyte-associated protein-4) or CD152 is an inhibitory receptor expressed constitutively on CD4+ CD25+ T regulatory lymphocytes and transiently on activated CD4+ and CD8+ T lymphocytes. Its inhibitory function promotes long-lived anergy in immune cells and prevents autoimmunity. Therefore, it plays a crucial role in T cell-mediated autoimmunity, and thus in susceptibility to autoimmune diseases, including systemic lupus erythematosus (SLE). It is encoded by CTLA4 gene in humans. AtoG polymorphism at position +49 of CTLA4 gene is the only polymorphism which changes amino acid sequence from alanine to threonine in the leader sequence, which may affect the function of CTLA-4. Association of CTLA4 polymorphisms with SLE has been investigated in several reports in different ethnic populations from different countries, which have shown highly inconsistent findings. In this review, we have compiled previous studies which have reported the association of CTLA4 A49G polymorphism in SLE and its geographical distribution.
2.
Discovery of common and rare genetic risk variants for colorectal cancer.
Huyghe, JR, Bien, SA, Harrison, TA, Kang, HM, Chen, S, Schmit, SL, Conti, DV, Qu, C, Jeon, J, Edlund, CK, et al
Nature genetics. 2019;(1):76-87
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Abstract
To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 × 10-8, bringing the number of known independent signals for CRC to ~100. New signals implicate lower-frequency variants, Krüppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development.
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The vitamin D receptor gene FokI polymorphism and Multiple Sclerosis in a Northern Portuguese population.
Bettencourt, A, Boleixa, D, Guimarães, AL, Leal, B, Carvalho, C, Brás, S, Samões, R, Santos, E, Costa, PP, Silva, B, et al
Journal of neuroimmunology. 2017;:34-37
Abstract
BACKGROUND The cause of Multiple Sclerosis (MS) remains poorly understood, but it is widely believed to be an autoimmune disease occurring in genetically susceptible individuals after exposure to as-yet undefined environmental factors. One of these environmental factors is vitamin D, a well-known immune modulator. The biologically active form of vitamin D, 1,25-dihydroxyvitamin D3, has been shown to exert its immune modulatory properties through its nuclear receptor (VDR) namely by inhibiting the proliferation of Th cells. The purpose of this study was to evaluate the influence of FokI VDR polymorphism in MS development and progression. METHODS A group of 533 unrelated Portuguese patients with a definitive diagnosis of MS and 446 ethnically matched healthy controls were included in the study. FokI was genotyped using a PCR-based TaqMan Genotyping Assay and serum 25-hydroxyvitamin D [25(OH)D] was also assessed. RESULTS A statistically significant higher frequency of the ff genotype was observed in MS patients (15.6% vs. 10.1%, p=0.012, OR (95% CI)=1.687(1.120-2.541)). No differences were observed in the frequencies of the FokI polymorphism according to disease course or with progression of disability. None of the genotypes was significantly associated with 25(OH)D serum levels. CONCLUSIONS An association between FokI ff genotype and MS susceptibility was found, but not with disease form or progression. Additional clinical and experimental studies should take the FokI VDR polymorphism into account, and further clarify the role of vitamin D, its metabolites and its receptor in MS.