Role of Single Nucleotide Variants in FSHR, GNRHR, ESR2 and LHCGR Genes in Adolescents with Polycystic Ovary Syndrome.

BACKGROUND: Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women, affecting up to 16.6% of reproductive-age women. PCOS symptoms in adolescents comprise oligomenorrhoea/amenorrhoea and biochemical and/or clinical hyperandrogenism. Long-term health risks of PCOS patients include infertility, metabolic syndrome, type 2 diabetes and cardiovascular disease. Genetic factors have been proven to play a role in development of the syndrome and its symptoms. OBJECTIVE: To investigate single nucleotide variants (SNVs) in the GNRHR, ESR2, LHCGR and FSHR genes in adolescent patients with PCOS and their association with PCOS symptoms. METHODS: We conducted a cross-sectional study comprising of 152 adolescents: 63 patients with PCOS, 22 patients at risk of developing PCOS and 67 healthy controls. Participants were recruited from out-patients attending a gynaecologist at the Children's Clinical University Hospital, Riga, Latvia, between January 2017 and December 2020. Genomic DNA was extracted from whole blood, and SNVs in the GNRHR, ESR2, LHCGR and FSHR genes were genotyped. The distributions of SNV genotypes were compared among the three groups and genotype-phenotype associations within the PCOS group were evaluated. RESULTS: No statistically significant differences were found in the distributions of genotypes for GNRHR (rs104893837), ESR2 (rs4986938), LHCGR (rs2293275) and FSHR (rs6166, rs6165, rs2349415) among PCOS patients, risk patients and healthy controls. Within the PCOS group, ESR2 rs4986938 minor allele homozygous patients had a significantly higher level of total testosterone than major allele homozygous patients and heterozygous patients. A significantly higher total testosterone level was also observed in PCOS patients carrying the LHCGR rs2293275 minor allele compared with major allele homozygous patients. CONCLUSIONS: The SNVs ESR2 rs4986938 and LHCGR rs2293275 play a role in the phenotypic characteristics of PCOS. To fully uncover their influence on the development of PCOS and its symptoms, further studies of larger cohorts and a follow up of this study sample through to adulthood are required. Furthermore, studies of adolescent PCOS patients conducted prior to the latest European Society of Human Reproduction and Embryology (ESHRE) criteria (2018) should be re-evaluated as the study groups might include risk patients according to these updated criteria, thereby potentially significantly impacting the published results.

PKP2 and DSG2 genetic variations in Latvian arrhythmogenic right ventricular dysplasia/cardiomyopathy registry patients.

OBJECTIVE: The Latvian arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD-C) registry was established to determine the genetic background of ARVD-C for analyzing discovered genetic variation frequencies in the European and Latvian populations. METHODS: In total, 38 patients with suspected ARVD-C were selected. The clinical parameters were defined according to the ARVD-C guidelines, PKP2 and DSG2 gene analysis was performed using the Sanger sequencing. Additionally, large deletions/duplications were analyzed using the multiplex ligation-dependent probe amplification (MLPA) analysis. RESULTS: Twenty symptomatic patients were enrolled in the study. Typical ARVD abnormalities were found in electrocardiography for 10 (50%) patients, in Holter monitoring for 19 (95%), in transthoracic echocardiography for 20 (100%), and in cardiac magnetic resonance for 6 (30%). Different benign genetic variations were found. Three novel, unregistered, possibly benign variations were found in the PKP2 gene: c.2489+131G>A, c.2489+72delA, and c.1035-5T>C and three in the DSG2 gene: c.404G>A, c.1107G>A, and c.379-15A>G. Two genetic variations in the PKP2 gene: c.1592T>G, c.2489+1G>A are possibly pathogenic. For the first time, variation c.1592T>G, has been discovered in the homozygote form. Using the MLPA analysis, large deletions or duplications were not found. CONCLUSION: The prevalence of the majority of non-pathological genetic variations is similar in the Latvian ARVD-C patients and the European population. Possibly, pathogenic variations were found only in 10% of our registry patients, which could mean that PKP2 and DSG2 are not the most commonly affected genes in the Latvian population.

Analysis of possible genetic risk factors contributing to development of childhood acute lymphoblastic leukaemia in the Latvian population.

INTRODUCTION: Childhood acute lymphoblastic leukaemia (ALL) is a complex disease caused by a combination of genetic susceptibility and environmental exposure. Previous genome-wide association studies have reported several single nucleotide polymorphisms (SNPs) associated with the incidence of ALL. Several variations in genes encoding enzymes involved in carcinogenesis are suggested as being associated with an increased risk of ALL development. MATERIAL AND METHODS: We enrolled 77 paediatric ALL patients and 122 healthy controls, and in addition parental DNA was also available for 45 probands. SNPs rs10821936 (ARID5B), rs4132601 (IKZF1), rs2239633 (CEBPE), rs3731217 (CDKN2A) and rs1800566 (NQO1) and the presence of GSTT1 and GSTM1 null variants were detected. For statistical analysis the hybrid method of two designs 'Haplin' was used as well as linkage disequilibrium for family-based association studies. RESULTS: We identified the SNP rs10821936 in the ARID5B gene as being statistically significantly associated with childhood ALL, especially if the C allele is in a homozygous state, relative risk (RR) 4.65, 95% CI: 2.03-10.6, p = 0.0006. Statistically significant differences were not found in other SNPs. We found risk combinations including all five variations, the strongest association being found in a combination where all five genetic variants are in a homozygous state, CCTTTTTTCC, p = 0.032. CONCLUSIONS: The identified SNP rs10821936 could serve as a potential risk marker for childhood ALL development. Further studies in an independent population are needed for verification.