Background: Rheumatoid arthritis (RA) is a chronic, inflammatory autoimmune disease characterized by progressive destruction of peripheral joints. About 1% of the human population worldwide is suffering from this disease. The pathophysiology of RA is largely being influenced by immune dysregulation. Mannose-binding lectin (MBL), an acute-phase protein, has been reported to play an important role in pathogenesis of RA by the activation of complement pathway. Various studies documented the established the role of MBL in pathogenesis of various autoimmune diseases, including RA. MBL protein is encoded by gene MBL2, mapped on chromosome 10q11.2-q21. Objective: Both MBL serum levels and activity are mainly determined genetically by its variants. So considering the putative clinical role of MBL2, this case-control association study was designed to assess its six functional variants in a northwestern Indian cohort. Methods: Genetic typing of six MBL2 variants was done by amplification refractory mutation system-polymerase chain reaction. Data were analyzed using suitable statistical tools. Results: Significant difference has been observed in genotypic and allelic distribution between cases and controls for rs11003125. Comparison of allelic distribution for rs1800450 showed significantly high prevalence of A allele in cases than controls. Conclusion: These results indicate that MBL2 variants may act as plausible marker for susceptibility toward RA. Keeping this in view, it is pertinent to screen these variants in other population groups of India.
背景:类风湿性关节炎(RA)是一种慢性炎症性自身免疫疾病,其特征是外周关节的进行性破坏。全世界约有 1% 的人患有这种疾病。RA 的病理生理学在很大程度上受到免疫失调的影响。据报道,甘露糖结合凝集素(MBL)是一种急性期蛋白,可通过激活补体通路在风湿性关节炎的发病机制中发挥重要作用。多项研究证实,MBL 在包括 RA 在内的多种自身免疫性疾病的发病机制中发挥作用。MBL 蛋白由 MBL2 基因编码,该基因位于染色体 10q11.2-q21 上。目的:MBL 血清水平和活性主要由其变异基因决定。因此,考虑到 MBL2 的潜在临床作用,本病例对照关联研究旨在评估印度西北部队列中的六个功能变异体。研究方法通过扩增难治性突变系统聚合酶链反应对六种 MBL2 变体进行基因分型。使用合适的统计工具对数据进行分析。结果观察到 rs11003125 的基因型和等位基因分布在病例和对照组之间存在显著差异。比较 rs1800450 的等位基因分布发现,病例中 A 等位基因的患病率明显高于对照组。结论这些结果表明,MBL2 变异可作为 RA 易感性的合理标记。有鉴于此,在印度其他人群中筛查这些变异是有意义的。
{"title":"Mannose-Binding Lectin Gene Variants as Disease Susceptibility Biomarkers in Rheumatoid Arthritis.","authors":"Tarnjeet Kaur, Shreya Singh Kashyap, Sumeet Arora, Jatinder Singh, Manpreet Kaur","doi":"10.1089/gtmb.2024.0082","DOIUrl":"https://doi.org/10.1089/gtmb.2024.0082","url":null,"abstract":"<p><p><b><i>Background</i>:</b> Rheumatoid arthritis (RA) is a chronic, inflammatory autoimmune disease characterized by progressive destruction of peripheral joints. About 1% of the human population worldwide is suffering from this disease. The pathophysiology of RA is largely being influenced by immune dysregulation. Mannose-binding lectin (MBL), an acute-phase protein, has been reported to play an important role in pathogenesis of RA by the activation of complement pathway. Various studies documented the established the role of MBL in pathogenesis of various autoimmune diseases, including RA. MBL protein is encoded by gene <i>MBL2</i>, mapped on chromosome 10q11.2-q21. <b><i>Objective:</i></b> Both MBL serum levels and activity are mainly determined genetically by its variants. So considering the putative clinical role of <i>MBL2</i>, this case-control association study was designed to assess its six functional variants in a northwestern Indian cohort. <b><i>Methods:</i></b> Genetic typing of six <i>MBL2</i> variants was done by amplification refractory mutation system-polymerase chain reaction. Data were analyzed using suitable statistical tools. <b><i>Results:</i></b> Significant difference has been observed in genotypic and allelic distribution between cases and controls for rs11003125. Comparison of allelic distribution for rs1800450 showed significantly high prevalence of A allele in cases than controls. <b><i>Conclusion:</i></b> These results indicate that <i>MBL2</i> variants may act as plausible marker for susceptibility toward RA. Keeping this in view, it is pertinent to screen these variants in other population groups of India.</p>","PeriodicalId":12603,"journal":{"name":"Genetic testing and molecular biomarkers","volume":null,"pages":null},"PeriodicalIF":1.1,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141633066","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Introduction: The genetics of hereditary hemochromatosis (HH) is understudied in Iran. Here, we report the result of genetic screening of 854 individuals, referred as "suspected cases of HH," to a diagnostic laboratory in Iran over a 12-year period. Materials and Methods: From 2011 to 2012, 121 cases were screened for HH using Sanger sequencing of HFE exons. After 2012, this method was replaced by a commercial reverse hybridization assay (RHA) targeting 18 variants in the HFE, TFR2, and FPN1(SLC40A1) genes and 733 cases were screened using this method. Results: From the total studied population, HH was confirmed by genetic diagnosis in only seven cases (0.82%): two homozygotes for HFE:C282Y and five homozygotes for TFR2:AVAQ 594-597 deletion. In 254 cases (29.7%), H63D, C282Y, S65C, and four other HFE variants not targeted by RHA were identified. Although the resulting genotypes in the latter cases did not confirm HH, some of them were known modifying factors of iron overload or could cause HH in combination with a possibly undetected variant. No variant was detected in 593 cases (69.4%). Conclusion: This study showed that the spectrum of genetic variants of HH in the Iranian population includes HFE and TFR2 variants. However, HH was not confirmed in the majority (99.2%) of suspected cases. This could be explained by limitations of our genetic diagnostics and possible inaccuracies in clinical suspicion of HH. A cooperative clinical and genetic investigation is proposed as a solution to this issue.
{"title":"<i>HFE</i> and Non-<i>HFE</i> Hereditary Hemochromatosis Based on Screening of 854 Individuals: 12 Years of an Iranian Experience.","authors":"Razieh Zarifian Yeganeh, Masoumeh Akbari Kelishomi, Atiyeh Ahmadpour Jenaghard, Banafsheh Salmani, Zohreh Vahidi, Mina Makvand, Maryam Azad, Mahdieh Kooshki, Yassin Bouraqi, Azita Azarkeivan, Hossein Najmabadi, Maryam Neishabury","doi":"10.1089/gtmb.2023.0764","DOIUrl":"10.1089/gtmb.2023.0764","url":null,"abstract":"<p><p><b><i>Introduction:</i></b> The genetics of hereditary hemochromatosis (HH) is understudied in Iran. Here, we report the result of genetic screening of 854 individuals, referred as \"suspected cases of HH,\" to a diagnostic laboratory in Iran over a 12-year period. <b><i>Materials and Methods:</i></b> From 2011 to 2012, 121 cases were screened for HH using Sanger sequencing of <i>HFE</i> exons. After 2012, this method was replaced by a commercial reverse hybridization assay (RHA) targeting 18 variants in the <i>HFE</i>, <i>TFR2</i>, and <i>FPN1(SLC40A1)</i> genes and 733 cases were screened using this method. <b><i>Results:</i></b> From the total studied population, HH was confirmed by genetic diagnosis in only seven cases (0.82%): two homozygotes for <i>HFE</i>:C282Y and five homozygotes for <i>TFR2</i>:AVAQ 594-597 deletion. In 254 cases (29.7%), H63D, C282Y, S65C, and four other <i>HFE</i> variants not targeted by RHA were identified. Although the resulting genotypes in the latter cases did not confirm HH, some of them were known modifying factors of iron overload or could cause HH in combination with a possibly undetected variant. No variant was detected in 593 cases (69.4%). <b><i>Conclusion:</i></b> This study showed that the spectrum of genetic variants of HH in the Iranian population includes <i>HFE</i> and <i>TFR2</i> variants. However, HH was not confirmed in the majority (99.2%) of suspected cases. This could be explained by limitations of our genetic diagnostics and possible inaccuracies in clinical suspicion of HH. A cooperative clinical and genetic investigation is proposed as a solution to this issue.</p>","PeriodicalId":12603,"journal":{"name":"Genetic testing and molecular biomarkers","volume":null,"pages":null},"PeriodicalIF":1.1,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141563148","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-01Epub Date: 2024-05-09DOI: 10.1089/gtmb.2023.0304
Peshnyar M A Rashid, Gaza F Salih
Background: The global pandemic of Coronavirus Disease 2019 (COVID-19) has resulted in significant fatality rates. Clinical outcomes for affected individuals range from being asymptomatic to severe illnesses requiring intensive care unit (ICU) admission. Among the various factors contributing to the variation in clinical outcomes, host genetics play a prominent role. Interleukin-6 (IL6), a key player in immune responses, has been identified as having a crucial impact on viral infections, including the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Specifically, certain variations known as single nucleotide polymorphisms (SNPs) in the IL6 promoter region have been found to significantly influence IL6 expression and the severity of viral infections. Materials and Methods: To explore the relationship between these genetic variations and COVID-19 in asymptomatic and ICU-admitted Kurdish patients, genetic sequencing was performed to determine the genotypes of nine IL6 SNPs. Results: The study findings revealed that although the proportion of the GG genotype of rs1800795 was slightly higher in asymptomatic COVID-19 cases, the difference was not statistically significant (chi2 = 2.666, p = 0.236). Notably, Kurdish patients displayed a uniform genetic makeup (monomorphic) for the dominant alleles of rs2069830 (C), rs142759801 (C), rs2069857 (C), rs2069829 (G), rs2234683 (G), rs13447446 (T), rs527770772 (C), and rs13447445 (C). Furthermore, patients carrying the haplotype GCGGCTCCC were found to have a 0.481-fold higher likelihood of being asymptomatic with COVID-19 (p = 0.016, OR = 0.481). Conclusions: This study demonstrates that the rs1800795 SNP is not statistically associated with COVID-19 at the genotype level. However, the presence of the dominant G allele of rs1800795 in the haplotype was found to be statistically associated with asymptomatic COVID-19 patients.
{"title":"Genetic Polymorphism of Interleukin-6 in Asymptomatic and ICU-Admitted COVID-19 Patients in Sulaymaniyah Province, Kurdistan Region of Iraq.","authors":"Peshnyar M A Rashid, Gaza F Salih","doi":"10.1089/gtmb.2023.0304","DOIUrl":"10.1089/gtmb.2023.0304","url":null,"abstract":"<p><p><b><i>Background:</i></b> The global pandemic of Coronavirus Disease 2019 (COVID-19) has resulted in significant fatality rates. Clinical outcomes for affected individuals range from being asymptomatic to severe illnesses requiring intensive care unit (ICU) admission. Among the various factors contributing to the variation in clinical outcomes, host genetics play a prominent role. Interleukin-6 (IL6), a key player in immune responses, has been identified as having a crucial impact on viral infections, including the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Specifically, certain variations known as single nucleotide polymorphisms (SNPs) in the IL6 promoter region have been found to significantly influence IL6 expression and the severity of viral infections. <b><i>Materials and Methods:</i></b> To explore the relationship between these genetic variations and COVID-19 in asymptomatic and ICU-admitted Kurdish patients, genetic sequencing was performed to determine the genotypes of nine IL6 SNPs. <b><i>Results:</i></b> The study findings revealed that although the proportion of the GG genotype of rs1800795 was slightly higher in asymptomatic COVID-19 cases, the difference was not statistically significant (chi2 = 2.666, <i>p</i> = 0.236). Notably, Kurdish patients displayed a uniform genetic makeup (monomorphic) for the dominant alleles of rs2069830 (C), rs142759801 (C), rs2069857 (C), rs2069829 (G), rs2234683 (G), rs13447446 (T), rs527770772 (C), and rs13447445 (C). Furthermore, patients carrying the haplotype GCGGCTCCC were found to have a 0.481-fold higher likelihood of being asymptomatic with COVID-19 (<i>p</i> = 0.016, OR = 0.481). <b><i>Conclusions:</i></b> This study demonstrates that the rs1800795 SNP is not statistically associated with COVID-19 at the genotype level. However, the presence of the dominant G allele of rs1800795 in the haplotype was found to be statistically associated with asymptomatic COVID-19 patients.</p>","PeriodicalId":12603,"journal":{"name":"Genetic testing and molecular biomarkers","volume":null,"pages":null},"PeriodicalIF":1.1,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140891805","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: A high-altitude environment has inhibitory effects on obesity. Tibetans are not a high-risk population for obesity, but there are still obese individuals within that population. Obesity has become a worldwide health problem, and previous studies have found that obesity is closely associated with hereditary factors. Few studies have investigated obesity in Tibetans, and the association between gene polymorphisms and obesity in Tibetans remains unclear. Methods: Our study investigated the fat mass of 140 native Tibetan individuals (70 men and 70 women) from Lhasa and analyzed the associations between polymorphisms of melanocortin 4 receptor (MC4R), Src homology 2B adapter protein 1 (SH2B1), and neuronal growth regulator 1 (NEGR1) and obesity. Result: Among Tibetan individuals, there were differences in genotype and allele frequencies between those in the obesity group and those in the healthy group at MC4R (rs17782313) and SH2B1 (rs7359397). The polymorphisms of MC4R (rs17782313) were associated with fat mass and obesity in Tibetan men and women, and there was an association between SH2B1 (rs7359397) polymorphisms and fat mass and obesity in Tibetan men. However, polymorphisms of NEGR1 (rs3101336) were not associated with fat mass or obesity in Tibetan individuals. Conclusion: Among Tibetan individuals, polymorphisms of MC4R (rs17782313) and SH2B1 (rs7359397) were associated with obesity, but NEGR1 (rs3101336) polymorphisms were not associated with obesity.
{"title":"The Association between Obesity Susceptibility and Polymorphisms of MC4R, SH2B1, and NEGR1 in Tibetans.","authors":"Ting Huang, Xianpeng Zhang, Qiang Li, Xin Li, Jie Yao, Jia Song, Ying Chen, Liping Ye, Chunshan Li, Pingcuo Xiran, Youfeng Wen","doi":"10.1089/gtmb.2023.0546","DOIUrl":"10.1089/gtmb.2023.0546","url":null,"abstract":"<p><p><b><i>Background:</i></b> A high-altitude environment has inhibitory effects on obesity. Tibetans are not a high-risk population for obesity, but there are still obese individuals within that population. Obesity has become a worldwide health problem, and previous studies have found that obesity is closely associated with hereditary factors. Few studies have investigated obesity in Tibetans, and the association between gene polymorphisms and obesity in Tibetans remains unclear. <b><i>Methods:</i></b> Our study investigated the fat mass of 140 native Tibetan individuals (70 men and 70 women) from Lhasa and analyzed the associations between polymorphisms of melanocortin 4 receptor (MC4R), Src homology 2B adapter protein 1 (SH2B1), and neuronal growth regulator 1 (NEGR1) and obesity. <b><i>Result:</i></b> Among Tibetan individuals, there were differences in genotype and allele frequencies between those in the obesity group and those in the healthy group at MC4R (rs17782313) and SH2B1 (rs7359397). The polymorphisms of MC4R (rs17782313) were associated with fat mass and obesity in Tibetan men and women, and there was an association between SH2B1 (rs7359397) polymorphisms and fat mass and obesity in Tibetan men. However, polymorphisms of NEGR1 (rs3101336) were not associated with fat mass or obesity in Tibetan individuals. <b><i>Conclusion:</i></b> Among Tibetan individuals, polymorphisms of MC4R (rs17782313) and SH2B1 (rs7359397) were associated with obesity, but NEGR1 (rs3101336) polymorphisms were not associated with obesity.</p>","PeriodicalId":12603,"journal":{"name":"Genetic testing and molecular biomarkers","volume":null,"pages":null},"PeriodicalIF":1.1,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141733939","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Shan Cao, Dan Wang, Lixiao Liu, Junyan Yao, Lingli Wang, Yang Liao, Jinfeng Zhang, Jie Zhao, Ying Huang, Zhiyan Hao
Objective: To investigate the association between ACTN4 gene mutation and primary nephrotic syndrome (PNS) in children in Guangxi Autonomous Region, China. Methods: The high-throughput sequencing technology was used to sequence ACTN4 gene in 155 children with PNS in Guangxi Autonomous Region in China, with 98 healthy children serving as controls. Twenty-three exon-specific capture probes targeting ACTN4 were designed and used to hybridize with the genomic DNA library. The targeted genomic region DNA fragments were enriched and sequenced. The protein levels of ACTN4 in both case and control groups were quantified using ELISA method. Results: Bioinformatics analysis revealed five unique ACTN4 mutations exclusively in patients with PNS, including c.1516G>A (p.G506S) on one exon in 2 patients, c.1442 + 10G>A at the splice site in 1 patient, c.1649A>G (p.D550G) on exon in 1 patient, c.2191-4G>A at the cleavage site in 2 patients, and c.2315C>T (p.A772V) on one exon in 1 patient. The c.1649A>G (p.D550G) and c.2315C>T (p.A772V) were identified from the same patient. Notably, c.1649A>G (p.D550G) represents a novel mutation in ACTN4. In addition, three other ACTN4 polymorphisms occurred in both case and control groups, including c.162 + 6C>T (1 patient in case group and 2 patients in control group), c.572 + 11G>A (1 patient in case group and 2 patients in control group), and c.2191-5C>T (4 patients in the case group and 3 patients in control group). The serum ACTN4 concentration in the case group was markedly higher, averaging 544.7 ng/mL (range: 264.6-952.6 ng/mL), compared with 241.20 ng/mL (range: 110.75-542.35 ng/mL) in the control group. Conclusion: Five ACTN4 polymorphisms were identified among children with PNS in Guangxi Autonomous Region, China, including the novel mutation c.1649A>G. The lower serum levels of α-actinin-4 in the case group suggest that this protein might play a protective role in PNS.
{"title":"Association of <i>ACTN4</i> Gene Mutation with Primary Nephrotic Syndrome in Children in Guangxi Autonomous Region, China.","authors":"Shan Cao, Dan Wang, Lixiao Liu, Junyan Yao, Lingli Wang, Yang Liao, Jinfeng Zhang, Jie Zhao, Ying Huang, Zhiyan Hao","doi":"10.1089/gtmb.2023.0567","DOIUrl":"10.1089/gtmb.2023.0567","url":null,"abstract":"<p><p><b><i>Objective:</i></b> To investigate the association between <i>ACTN4</i> gene mutation and primary nephrotic syndrome (PNS) in children in Guangxi Autonomous Region, China. <b><i>Methods:</i></b> The high-throughput sequencing technology was used to sequence <i>ACTN4</i> gene in 155 children with PNS in Guangxi Autonomous Region in China, with 98 healthy children serving as controls. Twenty-three exon-specific capture probes targeting <i>ACTN4</i> were designed and used to hybridize with the genomic DNA library. The targeted genomic region DNA fragments were enriched and sequenced. The protein levels of <i>ACTN4</i> in both case and control groups were quantified using ELISA method. <b><i>Results:</i></b> Bioinformatics analysis revealed five unique <i>ACTN4</i> mutations exclusively in patients with PNS, including c.1516G>A (p.G506S) on one exon in 2 patients, c.1442 + 10G>A at the splice site in 1 patient, c.1649A>G (p.D550G) on exon in 1 patient, c.2191-4G>A at the cleavage site in 2 patients, and c.2315C>T (p.A772V) on one exon in 1 patient. The c.1649A>G (p.D550G) and c.2315C>T (p.A772V) were identified from the same patient. Notably, c.1649A>G (p.D550G) represents a novel mutation in <i>ACTN4</i>. In addition, three other <i>ACTN4</i> polymorphisms occurred in both case and control groups, including c.162 + 6C>T (1 patient in case group and 2 patients in control group), c.572 + 11G>A (1 patient in case group and 2 patients in control group), and c.2191-5C>T (4 patients in the case group and 3 patients in control group). The serum ACTN4 concentration in the case group was markedly higher, averaging 544.7 ng/mL (range: 264.6-952.6 ng/mL), compared with 241.20 ng/mL (range: 110.75-542.35 ng/mL) in the control group. <b><i>Conclusion:</i></b> Five <i>ACTN4</i> polymorphisms were identified among children with PNS in Guangxi Autonomous Region, China, including the novel mutation c.1649A>G. The lower serum levels of α-actinin-4 in the case group suggest that this protein might play a protective role in PNS.</p>","PeriodicalId":12603,"journal":{"name":"Genetic testing and molecular biomarkers","volume":null,"pages":null},"PeriodicalIF":1.1,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141476396","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-01Epub Date: 2024-06-25DOI: 10.1089/gtmb.2023.0365
Merve Aslantas, Onder Kilicaslan, Recep Eröz, Kenan Kocabay
Background and Objectives: Obesity is a major nutritional problem with an increasing prevalence among children and adolescents. The uridine-diphosphate-glucuronosyl-transferase1A1 (UGT1A1) gene encodes the UDP-glucuronosyl transferase enzyme, converting the toxic form of bilirubin to a soluble, nontoxic form. There are yet to be studies on the evaluation of the UGT1A1 variant types detected by next-generation sequencing (NGS) and their effects on bilirubin levels in nonsyndromic obese children. Methods: Forty-five children with body mass index (BMI) >95 percentile (p) constituted the obesity group and fourteen healthy children with BMI <85p constituted the control group. Anthropometric, clinical features, and biochemical parameters were evaluated. Furthermore, the UGT1A1 gene was sequenced by NGS. Results: The obese patients had lower total, direct, and indirect bilirubin levels (p = 0.422, 0.026, and 0.568, respectively). In addition, obese patients had more genetic variations in the UGT1A1 gene compared with the control group (62.2% and 50%, respectively). We found that children with variations had higher total direct and indirect bilirubin levels compared with those without variation (p = 0.016, 0.028, and 0.015, respectively). Children diagnosed with obesity in the first two years of their life had fewer genetic variations and lower total bilirubin levels (p = 0.000 and 0.013, respectively). Conclusions: It is assumed that bilirubin can be protective against many chronic diseases. Although bilirubin levels are found to be lower in obese children compared with the control group, some variations in the UGT1A1 gene may be supported by raising bilirubin. We suggest that high bilirubin levels caused by those UGT1A1 variations may be protective against obesity and its many negative effects.
{"title":"The Evaluation of the Genetic Variation Types of the <i>Uridine Diphosphate Glucuronosyl Transferase 1A1</i> Gene by Next-Generation Sequencing and Their Effects on Bilirubin Levels in Obese Children.","authors":"Merve Aslantas, Onder Kilicaslan, Recep Eröz, Kenan Kocabay","doi":"10.1089/gtmb.2023.0365","DOIUrl":"10.1089/gtmb.2023.0365","url":null,"abstract":"<p><p><b><i>Background and Objectives:</i></b> Obesity is a major nutritional problem with an increasing prevalence among children and adolescents. The <i>uridine-diphosphate-glucuronosyl-transferase1A1</i> (<i>UGT1A1</i>) gene encodes the UDP-glucuronosyl transferase enzyme, converting the toxic form of bilirubin to a soluble, nontoxic form. There are yet to be studies on the evaluation of the <i>UGT1A1</i> variant types detected by next-generation sequencing (NGS) and their effects on bilirubin levels in nonsyndromic obese children. <b><i>Methods:</i></b> Forty-five children with body mass index (BMI) >95 percentile (p) constituted the obesity group and fourteen healthy children with BMI <85p constituted the control group. Anthropometric, clinical features, and biochemical parameters were evaluated. Furthermore, the <i>UGT1A1</i> gene was sequenced by NGS. <b><i>Results:</i></b> The obese patients had lower total, direct, and indirect bilirubin levels (<i>p</i> = 0.422, 0.026, and 0.568, respectively). In addition, obese patients had more genetic variations in the <i>UGT1A1</i> gene compared with the control group (62.2% and 50%, respectively). We found that children with variations had higher total direct and indirect bilirubin levels compared with those without variation (<i>p</i> = 0.016, 0.028, and 0.015, respectively). Children diagnosed with obesity in the first two years of their life had fewer genetic variations and lower total bilirubin levels (<i>p</i> = 0.000 and 0.013, respectively). <b><i>Conclusions:</i></b> It is assumed that bilirubin can be protective against many chronic diseases. Although bilirubin levels are found to be lower in obese children compared with the control group, some variations in the <i>UGT1A1</i> gene may be supported by raising bilirubin. We suggest that high bilirubin levels caused by those <i>UGT1A1</i> variations may be protective against obesity and its many negative effects.</p>","PeriodicalId":12603,"journal":{"name":"Genetic testing and molecular biomarkers","volume":null,"pages":null},"PeriodicalIF":1.1,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11304751/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141446044","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: Castration-resistant prostate cancer (CRPC), which has developed resistance to next-generation antiandrogens, such as enzalutamide (Enz), is a lethal disease. Furthermore, transcriptional regulation by super enhancers (SEs) is crucial for the growth and spread of prostate cancer, as well as drug resistance. The functions of SEs, a significant class of noncoding DNA cis-regulatory elements, have been the subject of numerous recent studies in the field of cancer research. Materials and Methods: The goal of this research was to identify SEs associated with Enz resistance in C4-2B cells using chromatin immunoprecipitation sequencing and cleavage under targets and tagmentation (CUT&Tag). Using HOMER analysis to predict protein/gene-binding motifs, we identified master transcription factors (TFs) that may bind to SE sites. Using small interfering RNA, WST-1 assays, and qRT-PCR, we then confirmed the associations between TFs of SEs and Enz resistance. Results: A total of 999 SEs were screened from C4-2B EnzR cells in total. Incorporating analysis with RNA-seq data revealed 41 SEs to be strongly associated with the promotion of Enz resistance. In addition, we finally predicted that master TFs bind to SE-binding regions. Subsequently, we selected zinc finger protein 467 (ZFP467) and SMAD family member 3 to confirm the functional connections of master TFs with Enz resistance through SEs (ZNF467). Conclusions: In this study, SMAD3 and ZNF467 were found to be closely related to Enz-resistant CRPC. Our research uncovered a sizable group of SEs linked to Enz resistance in prostate cancer, dissected the mechanisms underlying SE Enz resistance, and shed light on potential clinical uses for SEs.
背景:对恩杂鲁胺(Enz)等新一代抗雄激素产生耐药性的阉割耐药前列腺癌(CRPC)是一种致命疾病。此外,超级增强子(SE)的转录调控对前列腺癌的生长和扩散以及耐药性至关重要。超级增强子是一类重要的非编码 DNA 顺式调控元件,其功能是近年来癌症研究领域大量研究的主题。材料与方法:本研究的目的是利用染色质免疫沉淀测序和靶标下裂解及标记(CUT&Tag)技术鉴定与C4-2B细胞中Enz耐药性相关的SEs。利用HOMER分析预测蛋白质/基因结合基序,我们确定了可能与SE位点结合的主转录因子(TF)。然后,我们利用小干扰 RNA、WST-1 试验和 qRT-PCR 确认了 SE 的 TFs 与 Enz 抗性之间的关联。结果:共从 C4-2B EnzR 细胞中筛选出 999 个 SE。结合 RNA-seq 数据分析发现,41 个 SE 与 Enz 抗性的增强密切相关。此外,我们最终预测了主控因子与 SE 结合区的结合。随后,我们选择了锌指蛋白467(ZFP467)和SMAD家族成员3,通过SEs(ZNF467)证实了主控因子与Enz抗性的功能联系。结论:本研究发现,SMAD3和ZNF467与Enz抗性CRPC密切相关。我们的研究发现了一大批与前列腺癌Enz耐药相关的SEs,剖析了SE Enz耐药的机制,并揭示了SEs的潜在临床用途。
{"title":"Aberrant Super-Enhancer Landscape in Enzalutamide-Resistant Prostate Cancer Cells.","authors":"Chao Cai, Qinwei Liu, Haoran Shan, Chuanfan Zhong, Guidong Chen, Zhouda Cai, Yu Zheng, Jianming Lu, Jiaojiao Tang, Zhuoyuan Lin","doi":"10.1089/gtmb.2023.0280","DOIUrl":"10.1089/gtmb.2023.0280","url":null,"abstract":"<p><p><b><i>Background:</i></b> Castration-resistant prostate cancer (CRPC), which has developed resistance to next-generation antiandrogens, such as enzalutamide (Enz), is a lethal disease. Furthermore, transcriptional regulation by super enhancers (SEs) is crucial for the growth and spread of prostate cancer, as well as drug resistance. The functions of SEs, a significant class of noncoding DNA cis-regulatory elements, have been the subject of numerous recent studies in the field of cancer research. <b><i>Materials and Methods:</i></b> The goal of this research was to identify SEs associated with Enz resistance in C4-2B cells using chromatin immunoprecipitation sequencing and cleavage under targets and tagmentation (CUT&Tag). Using HOMER analysis to predict protein/gene-binding motifs, we identified master transcription factors (TFs) that may bind to SE sites. Using small interfering RNA, WST-1 assays, and qRT-PCR, we then confirmed the associations between TFs of SEs and Enz resistance. <b><i>Results:</i></b> A total of 999 SEs were screened from C4-2B EnzR cells in total. Incorporating analysis with RNA-seq data revealed 41 SEs to be strongly associated with the promotion of Enz resistance. In addition, we finally predicted that master TFs bind to SE-binding regions. Subsequently, we selected zinc finger protein 467 (ZFP467) and SMAD family member 3 to confirm the functional connections of master TFs with Enz resistance through SEs (ZNF467). <b><i>Conclusions:</i></b> In this study, SMAD3 and ZNF467 were found to be closely related to Enz-resistant CRPC. Our research uncovered a sizable group of SEs linked to Enz resistance in prostate cancer, dissected the mechanisms underlying SE Enz resistance, and shed light on potential clinical uses for SEs.</p>","PeriodicalId":12603,"journal":{"name":"Genetic testing and molecular biomarkers","volume":null,"pages":null},"PeriodicalIF":1.4,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140896212","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: Matrix metalloproteinase (MMP) enzyme gene polymorphisms MMP-2-1575G/A and MMP-9-1562C/T promoter polymorphism, their serum levels, and activity are associated with aortic valve calcification (AVC). Materials and Methods: The synergistic link between the risk of AVC and the alleles T and A of MMP-9 and MMP-2 was investigated, respectively. Ninety-two cases with AVC and 92 healthy individuals from the west of Iran were included, and MMP- 2-1575G/A and MMP-9-1562C/T promoter polymorphisms were detected using PCR-RFLP. The serum levels and activity of MMP-2 and -9 were assessed using ELISA and gelatin zymography methods, respectively. In addition, serum biochemical markers, including FBS, urea and creatinine, cholesterol, triglyceride, HDL, LDL, calcium, phosphorus, and blood pressure: systolic blood pressure and diastolic blood pressure were measured. Results: Heart valve calcification disease was associated with a comparatively higher frequency of the A allele of the MMP2-1575 variation (p = 0.002). In addition, the frequency of T allele of the MMP9-1562 variant was higher than the control group (p = 0.007). Conclusion: MMP-2 and MMP-9 serum levels and activities were observed to be considerably higher in the experimental group than in the control group (p < 0.001). Patients are more susceptible to cardiovascular disease than the control group due to elevated serum levels and activity of MMP-2 and MMP-9.
{"title":"Association of Matrix Metalloproteinase-2 (MMP-2) and MMP-9 Promoter Variants, Their Serum Levels, and Activities with Aortic Valve Calcification (AVC) in a Population from Western Iran.","authors":"Reza Heidari Moghadam, Fatemeh Babajani, Afshin Karami, Daniel Elieh-Ali-Komi, Faeghe Hoseini, Nahid Salehi, Saeed Elahirad, Ehsan Mohammadi-Noori, Hossein Mohammadi, Amir Kiani","doi":"10.1089/gtmb.2023.0370","DOIUrl":"10.1089/gtmb.2023.0370","url":null,"abstract":"<p><p><b><i>Background:</i></b> Matrix metalloproteinase (MMP) enzyme gene polymorphisms MMP-2-1575G/A and MMP-9-1562C/T promoter polymorphism, their serum levels, and activity are associated with aortic valve calcification (AVC). <b><i>Materials and Methods:</i></b> The synergistic link between the risk of AVC and the alleles T and A of MMP-9 and MMP-2 was investigated, respectively. Ninety-two cases with AVC and 92 healthy individuals from the west of Iran were included, and MMP- 2-1575G/A and MMP-9-1562C/T promoter polymorphisms were detected using PCR-RFLP. The serum levels and activity of MMP-2 and -9 were assessed using ELISA and gelatin zymography methods, respectively. In addition, serum biochemical markers, including FBS, urea and creatinine, cholesterol, triglyceride, HDL, LDL, calcium, phosphorus, and blood pressure: systolic blood pressure and diastolic blood pressure were measured. <b><i>Results:</i></b> Heart valve calcification disease was associated with a comparatively higher frequency of the A allele of the MMP2-1575 variation (<i>p</i> = 0.002). In addition, the frequency of T allele of the MMP9-1562 variant was higher than the control group (<i>p</i> = 0.007). <b><i>Conclusion:</i></b> MMP-2 and MMP-9 serum levels and activities were observed to be considerably higher in the experimental group than in the control group (<i>p</i> < 0.001). Patients are more susceptible to cardiovascular disease than the control group due to elevated serum levels and activity of MMP-2 and MMP-9.</p>","PeriodicalId":12603,"journal":{"name":"Genetic testing and molecular biomarkers","volume":null,"pages":null},"PeriodicalIF":1.4,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140853078","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-01Epub Date: 2024-05-06DOI: 10.1089/gtmb.2024.0131
Hatem Kaseb, Genevieve Crane, Jane Gibson
{"title":"TP53-Mutated Myelodysplastic Syndrome: A Diagnostic Approach in Different Clinical Settings.","authors":"Hatem Kaseb, Genevieve Crane, Jane Gibson","doi":"10.1089/gtmb.2024.0131","DOIUrl":"10.1089/gtmb.2024.0131","url":null,"abstract":"","PeriodicalId":12603,"journal":{"name":"Genetic testing and molecular biomarkers","volume":null,"pages":null},"PeriodicalIF":1.4,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140853676","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-01Epub Date: 2024-05-09DOI: 10.1089/gtmb.2023.0550
Ahmed Bouhouche, Sara Sefiani, Hicham Charoute, Tibar Houyam, Naima Bouslam, Fatima-Zahra El Yousfi, Wadi Bnouhana, Ali Benomar, Fatima-Zahra Ouadghiri, Wafaa Regragui
Background: Wolfram syndrome (WFS) is an autosomal recessive disorder that often leads to diabetes, optic atrophy, and sensorineural hearing loss. The aim of this study was to determine the clinical characteristics and the genetic cause of the first two Moroccan families presenting with WFS. Methods: The clinical features of five members of two WFS families were evaluated. Whole-exome sequencing was conducted to explore the underlying genetic cause in the affected patients. Results: Two homozygous variants in the WFS1 gene were identified, each in one of the two families studied: a missense c.1329C>G variant (p.Ser443Arg) and a nonsense mutation c.1113G>A (p.Trp371Ter). These variants affected conserved amino acid residues, segregated well in the two families, and are absent from genetic databases and in controls of Moroccan origin. Bioinformatics analysis classified the two variants as pathogenic by in silico tools and molecular modeling. Conclusion: Our study identified for the first time two variants in Moroccan patients with WFS that extends the mutational spectrum associated with the disease.
{"title":"Novel <i>WFS1</i> Variants in Two Moroccan Families with Wolfram Syndrome.","authors":"Ahmed Bouhouche, Sara Sefiani, Hicham Charoute, Tibar Houyam, Naima Bouslam, Fatima-Zahra El Yousfi, Wadi Bnouhana, Ali Benomar, Fatima-Zahra Ouadghiri, Wafaa Regragui","doi":"10.1089/gtmb.2023.0550","DOIUrl":"10.1089/gtmb.2023.0550","url":null,"abstract":"<p><p><b><i>Background:</i></b> Wolfram syndrome (WFS) is an autosomal recessive disorder that often leads to diabetes, optic atrophy, and sensorineural hearing loss. The aim of this study was to determine the clinical characteristics and the genetic cause of the first two Moroccan families presenting with WFS. <b><i>Methods:</i></b> The clinical features of five members of two WFS families were evaluated. Whole-exome sequencing was conducted to explore the underlying genetic cause in the affected patients. <b><i>Results:</i></b> Two homozygous variants in the <i>WFS1</i> gene were identified, each in one of the two families studied: a missense c.1329C>G variant (p.Ser443Arg) and a nonsense mutation c.1113G>A (p.Trp371Ter). These variants affected conserved amino acid residues, segregated well in the two families, and are absent from genetic databases and in controls of Moroccan origin. Bioinformatics analysis classified the two variants as pathogenic by <i>in silico</i> tools and molecular modeling. <b><i>Conclusion:</i></b> Our study identified for the first time two variants in Moroccan patients with WFS that extends the mutational spectrum associated with the disease.</p>","PeriodicalId":12603,"journal":{"name":"Genetic testing and molecular biomarkers","volume":null,"pages":null},"PeriodicalIF":1.4,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140896353","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}