The association of 17q23.1 locus with advanced carotid atherosclerosis

Проведен анализ ассоциаций rs8078424 (chr17:59873104) с риском развития клинически выраженного атеросклероза сонных артерий и патогенетически значимыми для развития данной патологии количественными признаками, а также оценена связь данного генетического варианта с экспрессией гена MIR21 в лейкоцитах периферической крови пациентов. В группу обследования включены пациенты с клинически выраженным атеросклерозом сонных артерий (стеноз при ультразвуковом исследовании более 80%; n=104). В качестве контроля использованы популяционная выборка жителей г. Томска (n=161) и группа, состоящая из относительно здоровых индивидов, которые имели начальные стадии атеросклероза сонных артерий, но без гемодинамически значимых изменений (стеноз не более 24%; n=84). Генотипирование rs8078424 выполняли методом MALDI-TOF масс-спектрометрии на приборе Sequenom MassARRAY® (США). Уровень экспрессии гена MIR21 в лейкоцитах крови оценивался методом капельной цифровой ПЦР на приборе QX200 Droplet Digital PCR System (Bio-Rad). Выявлено, что генотип GG rs8078424 является протективным относительно развития клинически выраженного атеросклероза сонных артерий (OR=0,023, 95%CI:0,08-0,62; р=0,003), ассоциирован с меньшим уровнем общего холестерина в сыворотке крови и повышенной экспрессией гена MIR21 в лейкоцитах крови пациентов. Потенциальными молекулярными механизмами ассоциации rs8078424 с атеросклерозом являются изменение сайта связывания транскрипционных факторов (FOXP1, SOX18, GATA3, HOXD9, HOXD10 и C/EBPalpha), а также связь с экспрессией гена MIR21 в клетках органов-мишеней патологии. Полиморфизм локуса 17q23.1 (в области генов TUBD1, VMP1/MIR21) представляет интерес для более детального изучения подверженности к сердечно-сосудистым заболеваниям в контексте эпигенетических механизмов в отдельных клетках органов-мишеней патологии. In this study, we analyzed the association of rs8078424 (chr17:59873104) with the risk of advanced carotid atherosclerosis and disease-related traits. We also assessed the association of this genetic variant with the expression of MIR21 gene in peripheral blood leukocytes of patients. Methods. A group of cases included patients with advanced carotid atherosclerosis who had artery stenosis with 80% or more by ultrasound examination (n=104). We used two control groups. Resident population of Tomsk was the first group (n=161). A second group consists of relatively healthy individuals who had non-hemodynamically significant carotid atherosclerosis (24% or less; n=84). Genotyping of rs8078424 was performed using MALDI-TOF mass spectrometry on a Sequenom MassARRAY® (USA) platform. The expression level of the MIR21 gene in peripheral blood leukocytes was assessed by droplet digital PCR on a QX200 Droplet Digital PCR System (Bio-Rad). Results. The GG rs8078424 genotype was found to be protective against of advanced carotid atherosclerosis (OR=0.023, 95%CI:0.08-0.62; p=0.003) and associated with a lower level of total cholesterol in the serum and increased MIR21 gene expression in peripheral blood leukocytes of the patients. Potential molecular mechanisms of the association of rs8078424 with atherosclerosis include alteration of transcription factors binding sites (FOXP1, SOX18, GATA3, HOXD9, HOXD10, and C/EBPalpha) as well as relationship with the MIR21 gene expression in cells of target organs. Conclusion. The polymorphism of the 17q23.1 locus (in the region of the TUBD1, VMP1/MIR21 genes) is of interest for a more detailed study of susceptibility to cardiovascular diseases in the context of epigenetic mechanisms in single cells of the target organs.

Epigenetic Regulation of Mitochondrial Quality Control Genes in Multiple Myeloma: A Sequenom MassARRAY Pilot Investigation on HMCLs

The mitochondrial quality control network includes several epigenetically-regulated genes involved in mitochondrial dynamics, mitophagy, and mitochondrial biogenesis under physiologic conditions. Dysregulated expression of such genes has been reported in various disease contexts, including cancer. However, their expression pattern and the possible underlying epigenetic modifications remain to be defined within plasma cell (PC) dyscrasias. Herein, we compared the mRNA expression of mitochondrial quality control genes from multiple myeloma, plasma cell leukemia patients and human myeloma cell lines (HMCLs) with healthy plasma cells; moreover, by applying the Sequenom MassARRAY EpiTYPER technology, we performed a pilot investigation of their CpG methylation status in HMCLs. Overall, the results provided indicate dysregulated expression of several mitochondrial network’s genes, and alteration of the CpG methylation profile, underscoring novel potential myeloma biomarkers deserving in-depth functional investigation in the future.

Genes of different molecular classes and their relationship with type 1 diabetes an age of manifestation

В работе изучена генетическая составляющая возраста манифестации сахарного диабета 1-го типа (СД1). В общей группе больных СД1 (n=330), а также в подгруппах с разным возрастом манифестации СД1 (до 30 лет, n=269, с 31 года, n=61) и популяционной выборке (n=289) изучено 58 однонуклеотидных полиморфизмов (SNPs), локализованных в 47 генах, продукты которых участвуют в различных метаболических путях и вовлечены в процессы фиброгенеза, эндотелиальную дисфункцию, иммунный ответ и воспаление. Генотипирование выполнено методом масс-спектрометрии на приборе «Sequenom MassARRAY» (США). В результате выявлена ассоциация с возрастом манифестации СД1 до 30 лет rs1007856 гена ITGB5 (генотип TT, р=0,02), rs3765124 гена ADAMDEC1 (генотип AA, р=0,01). При сравнении подгрупп СД1 с разным возрастом манифестации отличия получены для rs1107946 гена COL1A1 (генотип AA, р=0,03) и rs514921 гена MMP1 (генотип AA, р=0,03). Гены, SNPs которых показали ассоциацию с возрастом манифестации СД1, кодируют белковые продукты, вовлеченные в метаболизм экстрацеллюлярного матрикса и коллагена. Данные варианты могут рассматриваться в качестве маркеров возраста дебюта СД1. We have studied the genetic component of the age of onset of type 1 diabetes (T1D). We examined a group of patients with T1D (n = 330), which was divided into subgroups with different ages of manifestation of T1D (up to 30 years, n = 269, from 31 years old, n=61). A total of 289 healthy population individuals were enrolled in this study. We studied 58 SNPs of 47 genes whose products are involved in various metabolic pathways as well as fibrogenesis, endothelial dysfunction, the immune response and inflammation. We performed genotyping by mass spectrometry using a Sequenom MassARRAY (USA). As a result, we identified an association with the manifestation age of T1D up to 30 years for rs1007856 of the gene ITGB5 (genotype TT, p=0,02), rs3765124 of the gene ADAMDEC1 (genotype AA, p=0,01). Differences received when comparing subgroups of T1D with different ages of manifestation: for rs1107946 of the gene COL1A1 (genotype AA, p=0,03) and rs514921 of the gene MMP1 (genotype AA, p=0,03). Genes whose SNPs have been associated with an age of manifestation of T1D are involved in the metabolism of extracellular matrix and collagen. Identified genetic variants can be considered as markers of the age of onset of T1D.

LRCH1 polymorphisms linked to delayed encephalopathy after acute carbon monoxide poisoning identified by GWAS analysis followed by Sequenom MassARRAY® validation

Background We explored the association of leucine-rich repeats and calponin homology domain containing 1 (LRCH1) gene polymorphisms with genetic susceptibility to delayed encephalopathy after acute carbon monoxide poisoning (DEACMP), which might provide a theoretical basis for the pathogenesis, diagnosis, and prognosis research of DEACMP. Methods Four single nucleotide polymorphisms, rs1539177 (G/A), rs17068697 (G/A), rs9534475 (A/C), and rs2236592 (T/C), of LRCH1, selected as candidate genes through genome-wide association analysis, were genotyped in 661 patients (DEACMP group: 235 cases; ACMP group: 426 cases) using Sequenom Massarray®. The association analysis of four SNPs and LRCH1 was performed under different genetic models. Results LRCH1 polymorphisms (rs1539177, rs17068697, rs9534475) under additive and dominant genetic models were significantly associated with an increased risk of DEACMP, but no significant association under allele and recessive models was found. The LRCH1 rs2236592 polymorphism was susceptible to DEACMP only under the dominant model (TT/TC + CC, OR = 1.616, 95% CI: 1.092–2.390, P = 0.015784). In addition, the A allele gene of rs9534475 polymorphism in LRCH1 might increase the risk for DEACMP (OR = 1.273, 95% CI: 1.013–1.601, P = 0.038445). Conclusions We found a significant association between the four LRCH1 polymorphisms and DEACMP. The allelic A of rs9534475 polymorphism in LRCH1 might be a risk factor for DEACMP.

Correction to: Assessment of intratumor immune-microenvironment in colorectal cancers with extranodal extension of nodal metastases

Following publication of the original article [1], it has been brought to our attention that an incorrect Sequenom MassArray trace and an incorrect nomenclature were used to represent the PIK3CA p.E545A mutation in Fig. 2b. The correct Fig. 2b is shown in this erratum. The authors apologize for the confusion.