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Discovering Genes That Cause Disease
Published in Kenneth L. Brigham, Gene Therapy for Diseases of the Lung, 2020
So are such efforts doomed? In the spirit of recent experience, apparently insurmountable obstacles are still likely to yield to advancing genome technology. For the case of common diseases, the solution will likely be found in one of three approaches: (1) Identification of a prevalent predisposing haplotype (linkage disequilibrium) in a genetically homogeneous population. The recent use of this strategy to clone the gene for diastrophic dysplasia in Finland (21) lends strong support to the concept that such populations allow tracking of a much more refined predisposing region. Counting on such linkage disequilibrium to come to the rescue in a more outbred population may be risky, however. (2) Identification of a syntenic animal model. Animal models of human disease may not necessarily reflect the same predisposing loci, of course; but if genetic linkage analysis indicates that a small syntenic region is contributing relative risk in animals and humans, shifting the analysis to the animal species will be a highly attractive option. The ability to perform selective cross-breeding allows much more precise mapping of a polygene in animal experiments than in humans. (3) If all else fails, the availability of a highly dense transcript map (reducing the hunt for candidate genes to a computer exercise), coupled with powerful methods to search for sequence variation over large numbers of candidate DNA segments (where DNA chip hybridization (22) may greatly speed throughput), may still prevail.
Serological Typing of HLA-A, -B, and -C Antigens
Published in M. Kam, Jeffrey L. Bidwell, Handbook of HLA TYPING TECHNIQUES, 2020
In Tables 17 and 18 the antigen combinations or haplotypes observed to have a significant positive linkage disequilibrium are listed for these populations. The results in these tables are expressed as the delta values for the various haplotypes. Some haplotypes occur in many populations, while others appear to be restricted to particular ethnic groups. The extent to which a population study demonstrates the haplotypes in that population is obviously determined by the sample size. The haplotypes given in Tables 17 and 18 may not be definitive for those populations, but demonstrate the variation observed between different populations.
Human Genetic Variability and Susceptibility to Infectious Diseases
Published in Thomas R. O’Brien, Chemokine Receptors and AIDS, 2019
Linkage disequilibrium is the nonrandom association of alleles at linked loci. Two conditions must be fulfilled for M1 and G1 to be in linkage disequilibrium. First, there must be linkage between M and G (i.e., M and G lie close to one on the same chromosome, often within the same gene). Second, allele M1 must be preferentially associated with allele G1 (i.e., the frequency of the M1-G1 haplotype exceeds that which would be expected given the respective frequencies of M1 and G1). A classical explanation for linkage disequilibrium is that many people who bear the disease causing allele (G1) inherited that allele from a single common ancestor who bore the M1-G1 haplotype. It should be noted that linkage alone (fulfillment of condition one), even very close linkage, does not lead to association, and that the absence of association does not exclude linkage. Therefore, in the candidate gene approach, association studies are most useful for considering markers that lie within a gene that has a known relationship with the phenotype or for considering markers that are in close linkage with such a gene.
VEGF single nucleotide polymorphisms predict improved outcome in advanced non-small cell lung cancer patients treated with platinum-based chemotherapy
Published in Journal of Chemotherapy, 2023
Huijie Qi, Wenxin Zhang, Yan Wang, Mengxi Ge, Tianxiao Wang, Liudi Zhang, Mingkang Zhong, Xiaojin Shi, Xiaohua Liang, Qiong Zhan, Qunyi Li
Linkage disequilibrium is nonrandom association of alleles at different loci. It is a sensitive indicator of the population genetic forces that constitutes a genome [36]. Previous studies have demonstrated there was strong linkage disequilibrium between rs699947, rs833061 and rs2010963 [37, 38]. Furthermore, rs833061 and rs699947 were in full linkage disequilibrium in the genotyped population of gastric cancer [37] and metastatic renal cell carcinoma [39], which is consistent with our study. It is also reported that four VEGF gene polymorphisms (rs699947, rs1570360, rs833061 and rs2010963) are in strong linkage disequilibrium [26]. Moreover, the CTC haplotype (in the following order: rs699947, rs833061 and rs2010963) is associated with risk of the diffuse histological subtype of gastric cancer [37].
Association of Rs231775 Genetic Variant of Cytotoxic T-lymphocyte Associated Protein 4 with Alopecia Areata Disease in Males: A Case–Control Study
Published in Immunological Investigations, 2021
Nader Ali Ismail, Eman Ali Toraih, Hatem Mohamed Ameen, Amal Hussein Ahmed Gomaa, Radwa El- Sayed Mahmoud Marie
Our data suggest an important role of the CTLA4 gene in the pathogenesis of AA disorder. Thr17Ala polymorphism might be a marker for AA disease risk. However, some limitations need to be addressed. First, studies involving other geographical regions in Egypt are needed prior to the generalization of the results. Second, AA patients enrolled in the study had patchy and ophiasis distribution patterns, replication on cohorts with a wider variety of disease phenotypes is recommended. Moreover, the functional consequence of the polymorphism was not studied in the lab. Correlation analysis between the signal peptide variant and expression levels in patients would have added more value to the study outcomes. Additionally, only individual polymorphism was screened with lack of comprehensive linkage disequilibrium mapping. Haplotype analysis of CTLA4 will be more accurate to confirm true disease-causing alleles.
Genetic variations in the human immune system influence susceptibility to tegumentary leishmaniasis: a systematic review and meta-analysis
Published in Expert Review of Clinical Immunology, 2021
Daniele Stéfanie Sara Lopes Lera-Nonose, Larissa Ferreira De Oliveira, Aline Brustolin, Thais Silva Santos, Jully Oyama, Áquila Carolina Fernandes Herculano Ramos-Milaré, Mariana De Souza Terron-Monich, Izabel Galhardo Demarchi, Quirino Alves De Lima Neto, Jorge Juarez Vieira Teixeira, Maria Valdrinez Campana Lonardoni
This systematic review and meta-analysis was restricted by the contents of the included articles, primarily with respect to SNPs. However, the evidence was insufficient to provide a concrete answer about the influence of aforementioned polymorphism in the development of TL. The disease outcome requires the participation of many genes, which can be found in the same chromosome region forming haplotypes or under linkage disequilibrium. All these aspects are important for a complete understanding of genetic influences and disease outcomes. Another important point to better address the genetic influences requires the assessment of the impact on the phenotype [43]. This study could not provide a robust answer about the association of TL with all the polymorphisms that were studied, ascertain polymorphisms were shown by a single publication, others because of different study designs (clinical forms of leishmaniasis and study groups).