1) To perform the first comprehensive systematic review of genetic association studies (GASs) in idiopathic recurrent spontaneous abortion (IRSA); 2) to analyze studies according to recurrent ...spontaneous abortion (RSA) definition and selection criteria for patients and control subjects; and 3) to perform meta-analyses for the association of candidate genes with IRSA.
Systematic review and meta-analysis.
Not applicable.
Couples with IRSA and their spontaneously aborted embryos.
Summary odds ratios (ORs) were calculated by means of fixed- or random-effects models.
Association of genetic variants with IRSA.
The systematic review included 428 case-control studies (1990–2015), which differed substantially regarding RSA definition, clinical evaluation of patients, and selection of control subjects. In women, 472 variants in 187 genes were investigated. Meta-analyses were performed for 36 variants in 16 genes. Association with IRSA defined as three or more spontaneous abortions (SAs) was detected for 21 variants in genes involved in immune response (IFNG, IL10, KIR2DS2, KIR2DS3, KIR2DS4, MBL, TNF), coagulation (F2, F5, PAI-1, PROZ), metabolism (GSTT1, MTHFR), and angiogenesis (NOS3, VEGFA). However, ORs were modest (0.51–2.37), with moderate or weak epidemiologic credibility. Minor differences in summary ORs were detected between IRSA defined as two or more and as three or more SAs. Male partners were included in 12.1% of studies, and one study included spontaneously aborted embryos.
Candidate gene studies show moderate associations with IRSA. Owing to large differences in RSA definition and selection criteria for participants, consensus is needed. Future GASs should include both partners and spontaneously aborted embryos. Genome-wide association studies and large-scale replications of identified associations are recommended.
Parkinson's disease (PD) is neurodegenerative disease with a multifactorial etiopathogenesis with accumulating evidence identifying microbiota as a potential factor in the earliest, prodromal phases ...of the disease. Previous research has already shown a significant difference between gut microbiota composition in PD patients as opposed to healthy controls, with a growing number of studies correlating gut microbiota changes with the clinical presentation of the disease in later stages, through various motor and non-motor symptoms. Our aim in this systematic review is to compose and assess current knowledge in the field and determine if the findings could influence future clinical practice as well as therapy in PD.
We have conducted a systematic review according to PRISMA guidelines through MEDLINE and Embase databases, with studies being selected for inclusion via a set inclusion and exclusion criteria.
20 studies were included in this systematic review according to the selected inclusion and exclusion criteria. The search yielded 18 case control studies, 1 case study, and 1 prospective case study with no controls. The total number of PD patients encompassed in the studies cited in this review is 1,511.
The link between gut microbiota and neurodegeneration is a complex one and it depends on various factors. The relative abundance of various microbiota taxa in the gut has been consistently shown to have a correlation with motor and non-motor symptom severity. The answer could lie in the products of gut microbiota metabolism which have also been linked to PD. Further research is thus warranted in the field, with a focus on the metabolic function of gut microbiota in relation to motor and non-motor symptoms.
Mitochondrial DNA (mtDNA) has been used for decades as a predominant tool in population genetics and as a valuable addition to forensic genetic research, owing to its unique maternal inheritance ...pattern that enables the tracing of individuals along the maternal lineage across numerous generations. The dynamic interplay between evolutionary forces, primarily genetic drift, bottlenecks, and the founder effect, can exert significant influence on genetic profiles. Consequently, the Adriatic islands have accumulated a subset of lineages that exhibits remarkable absence or rarity within other European populations. This distinctive genetic composition underscores the islands’ potential as a significant resource in phylogenetic research, with implications reaching beyond regional boundaries to contribute to a global understanding. In the initial attempt to expand the mitochondrial forensic database of the Croatian population with haplotypes from small isolated communities, we sequenced mitogenomes of rare haplogroups from different Croatian island and mainland populations using next-generation sequencing (NGS). In the next step and based on the obtained results, we refined the global phylogeny of haplogroup N1a, HV2, and X by analyzing rare haplotypes, which are absent from the current phylogenetic tree. The trees were based on 16 novel and 52 previously published samples, revealing completely novel branches in the X and HV2 haplogroups and a new European cluster in the ancestral N1a variant, previously believed to be an exclusively African–Asian haplogroup. The research emphasizes the importance of investigating geographically isolated populations and their unique characteristics within a global context.
Parkinson's disease is a neurological disorder that affects motor function, autonomic functions, and cognitive abilities. It is likely that both genetic and environmental factors, along with age, ...contribute to the cause. However, there is no comprehensive guideline for genetic testing for Parkinson's disease, and more research is needed to understand genetic variations in different populations. There has been no research on the genetic background of Parkinson's disease in Croatia so far. Therefore, with the GiOPARK project, we aimed to investigate the genetic variants responsible for Parkinson's disease in 153 Croatian patients with early onset, familial onset, and sporadic late-onset using whole-exome sequencing, along with multiplex ligation-dependent probe amplification and Sanger sequencing in select patients. We found causative variants in 7.84% of the patients, with GBA being the most common gene (4.58%), followed by PRKN (1.96%), ITM2B (0.65%), and MAPT (0.65%). Moreover, variants of uncertain significance were identified in 26.14% of the patients. The causative variants were found in all three subgroups, indicating that genetic factors play a role in all the analyzed Parkinson's disease subtypes. This study emphasizes the need for more inclusive research and improved guidelines to better understand the genetic basis of Parkinson's disease and facilitate more effective clinical management.
Down syndrome (DS, also known as trisomy 21) most often results from chromosomal nondisjunction during oogenesis. Numerous studies sustain a causal link between global DNA hypomethylation and genetic ...instability. It has been suggested that DNA hypomethylation might affect the structure and dynamics of chromatin regions that are critical for chromosome stability and segregation, thus favouring chromosomal nondisjunction during meiosis. Maternal global DNA hypomethylation has not yet been analyzed as a potential risk factor for chromosome 21 nondisjunction. This study aimed to asses the risk for DS in association with maternal global DNA methylation and the impact of endogenous and exogenous factors that reportedly influence DNA methylation status. Global DNA methylation was analyzed in peripheral blood lymphocytes by quantifying LINE-1 methylation using the MethyLight method. Levels of global DNA methylation were significantly lower among mothers of children with maternally derived trisomy 21 than among control mothers (P = 0.000). The combination of MTHFR C677T genotype and diet significantly influenced global DNA methylation (R2 = 4.5%, P = 0.046). The lowest values of global DNA methylation were observed in mothers with MTHFR 677 CT+TT genotype and low dietary folate. Although our findings revealed an association between maternal global DNA hypomethylation and trisomy 21 of maternal origin, further progress and final conclusions regarding the role of global DNA methylation and the occurrence of trisomy 21 are facing major challenges.
Increasing evidence points to host genetics as a factor in COVID-19 prevalence and outcome. CCR5 is a receptor for proinflammatory chemokines that are involved in host responses, especially to ...viruses. The CCR5-Δ32 minor allele is an interesting variant, given the role of CCR5 in some viral infections, particularly HIV-1. Recent studies of the impact of CCR5-Δ32 on COVID-19 risk and severity have yielded contradictory results. This ecologic study shows that the CCR5-Δ32 allelic frequency in a European population was significantly negatively correlated with the number of COVID-19 cases (p=0.035) and deaths (p=0.006) during the second pandemic wave. These results suggest that CCR5-Δ32 may be protective against SARS-CoV-2 infection, as it is against HIV infection, and could be predictive of COVID-19 risk and severity. Further studies based on samples from populations of different genetic backgrounds are needed to validate these statistically obtained findings.
Abstract Idiopathic recurrent spontaneous abortion (IRSA) has been associated with abnormalities in the remodelling of endometrial extracellular matrix, as well as aberrant matrix metalloproteinase ...(MMP) gene expression in endometrium of IRSA women and chorionic villi of IRSA concepti. This study investigated the association of five functional MMP gene promoter polymorphisms (MMP1 −1607 1G/2G, MMP2 −735 C/T, MMP2 −1306 C/T, MMP3 −1612 5A/6A and MMP9 −1562 C/T) with IRSA. A total of 149 couples with at least three consecutive IRSA and 149 fertile couples were included in a case–control study. Genotype analysis was performed using PCR restriction fragment length polymorphism. Statistically significant differences were found in distributions of MMP2 −735 CT (chi-squared 10.21, P = 0.006; OR 2.15, 95% CI 1.34–3.45, P = 0.001), and MMP9 −1562 CC (chi-squared 9.06, P = 0.010; OR 2.21, 95% CI 1.30–3.80, P = 0.004) between IRSA women and controls. Combined analysis of MMP gene polymorphisms did not increase their predictive value. There were no statistically significant differences in genotype and allele frequencies of any polymorphism between IRSA men and controls. MMP2 −735 C/T and MMP9 −1562 C/T functional gene polymorphisms might be associated with an increased risk of IRSA in women. Considering the insufficient knowledge on genetic contribution to pregnancy loss, studies on genetic causes of idiopathic recurrent spontaneous abortion (IRSA) are of great importance. Development of a histologically and functionally normal endometrium is critical for subsequent endometrial decidualization, receptivity and implantation. The proper communication and interaction between maternal decidual cells and the embryo is essential for the establishment of a functional fetal–maternal interface. IRSA has been associated with abnormalities in the remodelling of endometrial extracellular matrix, as well as aberrant matrix metalloproteinase (MMP) gene expression in endometrium of IRSA women and chorionic villi of IRSA concepti. The aim of this study was to investigate the association of five functional MMP gene promoter polymorphisms with IRSA. A total of 149 couples with at least three consecutive IRSA and 149 fertile couples were included in a case–control study. Genotype analysis was performed using polymerase chain reaction and restriction fragment length polymorphism. Statistically significant differences were found in distribution of MMP2 −735 CT and MMP9 −1562 CC genotypes between IRSA and control women. Combined analysis of MMP gene polymorphisms did not increase their predictive value. There were no statistically significant differences in distribution of genotype and allele frequencies of any polymorphism between IRSA men and controls. Our results demonstrate that MMP2 −735 C/T and MMP9 −1562 C/T functional gene polymorphisms might be associated with an increased risk of IRSA in women.
Abstract The insertion/deletion (I/D) polymorphism in intron 16 of the angiotensin I-converting enzyme gene ( ACE ) has been extensively studied as a predisposing factor for idiopathic recurrent ...spontaneous abortion (IRSA). A case-control study including 149 women with ≥3 spontaneous abortions and 149 controls was performed to test the association of ACE I/D polymorphism with IRSA. A systematic review was conducted of previous case-control studies, with strict selection criteria for meta-analyses. We also aimed to evaluate the potential differences in summary estimates between studies defining IRSA as ≥2 and ≥3 spontaneous abortions. Genotyping was performed by PCR, and systematic review conducted using PubMed and Scopus. There was no association of the polymorphism with IRSA in Slovenian women. Sixteen case-control studies, showing substantial differences regarding IRSA definition and selection criteria for women were identified. Meta-analysis was performed and included four studies defining IRSA as ≥2 spontaneous abortions and the current study, which defined IRSA as ≥3 spontaneous abortions. Based on random effects model, meta-analysis conducted on 1192 patients and 736 controls showed no association with IRSA under dominant(DD+IDvsII) and recessive(DDvsID+II) genetic models. Well-designed studies are needed to evaluate the role of ACE I/D polymorphism in IRSA defined as ≥3 spontaneous abortions.
OBJECTIVE: To investigate the potential association of tissue inhibitor of metalloproteinases (TIMP) 1, 2, 3, and 4 gene polymorphisms with idiopathic recurrent spontaneous abortion (IRSA). DESIGN: ...Case-control and association study. SETTING: Departments of gynecology and obstetrics and university-based research laboratory. PATIENT(S): A total of 149 couples with a history of three or more idiopathic spontaneous pregnancy losses and 149 fertile men and 149 fertile women with at least two live births and no history of pregnancy pathologies. INTERVENTION(S): Polymerase chain reaction and restriction-fragment-length polymorphism methods. MAIN OUTCOME MEASURE(S): Detection of TIMP-1 −372 C/T, TIMP-2 −303 C/T, TIMP-3 −915 A/G, TIMP-3 −1296 C/T, and TIMP-4 −3′-UTR C/T genotypes and allele frequencies. RESULT(S): There were no statistically significant differences in the distribution of any genotype and allele frequencies or any genetic model between IRSA patients and controls. Additionally, no significant associations occurred between combinations of TIMP polymorphisms and the risk of IRSA. CONCLUSION(S): We found no evidence for the association of TIMP-1, -2, -3, and -4 with IRSA in a Slovenian population.
Purpose
The aim of this study was to investigate the potential association of
matrix metalloproteinase 7
(
MMP7
) -181 A/G and
MMP12
-82 A/G functional single nucleotide polymorphisms (SNP) with ...idiopathic recurrent spontaneous abortion (IRSA) in Slovenian reproductive couples.
Methods
A case–control study was conducted on 149 couples with 3 or more consecutive idiopathic spontaneous pregnancy loses and 149 women and men with at least 2 live births and no history of pregnancy complications. Genotyping of
MMP7
-181 A/G and
MMP12
-82 A/G SNPs was performed using polymerase chain reaction and restriction fragment length polymorphism methods.
Results
There were no statistically significant differences in the distribution of
MMP7
-181 A/G and
MMP12
-82 A/G genotype, allele, or haplotype frequencies between IRSA patients and controls, as well as patients’ primary and secondary IRSA. We also found no association of
MMP7
-181 A/G and
MMP12
-82 A/G genotypes, alleles, and haplotypes with IRSA.
Conclusions
We found no evidence to support the association between IRSA and
MMP7
-181 A/G and
MMP12
-82 A/G SNPs in Slovenian reproductive couples.
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