Genetics of randomly bred cats support the cradle of cat domestication being in the Near East.

Cat domestication likely initiated as a symbiotic relationship between wildcats (Felis silvestris subspecies) and the peoples of developing agrarian societies in the Fertile Crescent. As humans transitioned from hunter-gatherers to farmers ~12,000 years ago, bold wildcats likely capitalized on increased prey density (i.e., rodents). Humans benefited from the cats' predation on these vermin. To refine the site(s) of cat domestication, over 1000 random-bred cats of primarily Eurasian descent were genotyped for single-nucleotide variants and short tandem repeats. The overall cat population structure suggested a single worldwide population with significant isolation by the distance of peripheral subpopulations. The cat population heterozygosity decreased as genetic distance from the proposed cat progenitor's (F.s. lybica) natural habitat increased. Domestic cat origins are focused in the eastern Mediterranean Basin, spreading to nearby islands, and southernly via the Levantine coast into the Nile Valley. Cat population diversity supports the migration patterns of humans and other symbiotic species.

Whole genome sequencing in cats, identifies new models for blindness in AIPL1 and somite segmentation in HES7.

BACKGROUND: The reduced cost and improved efficiency of whole genome sequencing (WGS) is drastically improving the development of cats as biomedical models. Persian cats are models for Leber's congenital amaurosis (LCA), the most severe and earliest onset form of visual impairment in humans. Cats with innocuous breed-defining traits, such as a bobbed tail, can also be models for somite segmentation and vertebral column development. METHODS: The first WGS in cats was conducted on a trio segregating for LCA and the bobbed tail abnormality. Variants were identified using FreeBayes and effects predicted using SnpEff. Variants within a known haplotype block for cat LCA and specific candidate genes for both phenotypes were prioritized by the predicted variant effect on the proteins and concordant segregation within the trio. The efficiency of WGS of a single trio of domestic cats was evaluated. RESULTS: A stop gain was identified at position c.577C > T in cat AIPL1, a predicted p.Arg193*. A c.5A > G variant causing a p.V2A was identified in HES7. The variants segregated concordantly in a Persian - Japanese bobtail pedigree. Over 1700 cats from 40 different breeds and populations were genotyped for the AIPL1 variant, defining an allelic frequency in only Persian -related breeds of 1.15%. A sub-set of cats was genotyped for the HES7 variant, supporting the variant as private to the Japanese bobtail breed. Approximately 18 million SNPs were identified for application in cat research. The cat AIPL1 variant would have been considered a high priority variant for evaluation, regardless of a priori knowledge from previous genetic studies. CONCLUSIONS: This study represents the first effort of the 99 Lives Cat Genome Sequencing Initiative to identify disease--causing variants in the domestic cat using WGS. The current cat reference assembly is efficient for gene and variant identification. However, as the feline variant database improves, development of cats as biomedical models for human disease will be more efficient, providing an alternative, large animal model for drug and gene therapy trials. Undiagnosed human patients with early-onset blindness should be screened for this AIPL1 variant. The HES7 variant should further calibrate the somite segmentation clock.

Genetic variants of vascular endothelial growth factor are associated with recurrent implantation failure in Korean women.

Vascular endothelial growth factor (VEGF) is involved in embryonic development, decidual vascularization and placenta angiogenesis. This study was performed to determine whether there is an association between genetic polymorphisms in the VEGF gene and the development of recurrent implantation failure (RIF) in Korean women. A total of 119 women diagnosed with RIF and 236 control subjects were genotyped for VEGF polymorphic sites including rs833061 (-460T>C), rs25648 (-7C>T) and rs3025020 (-583C>T) using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assays and real-time PCR. The VEGF rs833061 C allele and rs25648 T allele were significantly associated with increased RIF risk (odds ratio [OR] = 1.813 [1.161-2.831], P = 0.009, OR = 2.213 [1.254-3.903], P = 0.005). The rs833061/rs25648 TC/CT, TC/CT+TT, and rs833061/rs3025020 TC+CC/TT genotypes were more frequent in the RIF group compared with the control group (OR = 2.130 [1.092-4.156], P = 0.025, OR = 2.130 [1.092-4.156], OR = 4.261 [1.163-15.620], P = 0.028, respectively). The results of this study suggests that VEGF polymorphisms are associated with RIF development. Therefore, we postulate that VEGF polymorphisms might be useful markers to predict RIF development. Further studies are warranted to elucidate the role of VEGF variants and RIF development.

Genome-wide association and linkage analyses localize a progressive retinal atrophy locus in Persian cats.

Hereditary eye diseases of animals serve as excellent models of human ocular disorders and assist in the development of gene and drug therapies for inherited forms of blindness. Several primary hereditary eye conditions affecting various ocular tissues and having different rates of progression have been documented in domestic cats. Gene therapy for canine retinopathies has been successful, thus the cat could be a gene therapy candidate for other forms of retinal degenerations. The current study investigates a hereditary, autosomal recessive, retinal degeneration specific to Persian cats. A multi-generational pedigree segregating for this progressive retinal atrophy was genotyped using a 63 K SNP array and analyzed via genome-wide linkage and association methods. A multi-point parametric linkage analysis localized the blindness phenotype to a ~1.75 Mb region with significant LOD scores (Z ≈ 14, θ = 0.00) on cat chromosome E1. Genome-wide TDT, sib-TDT, and case-control analyses also consistently supported significant association within the same region on chromosome E1, which is homologous to human chromosome 17. Using haplotype analysis, a ~1.3 Mb region was identified as highly associated for progressive retinal atrophy in Persian cats. Several candidate genes within the region are reasonable candidates as a potential causative gene and should be considered for molecular analyses.

Divergent and dynamic activity of endogenous retroviruses in burn patients and their inflammatory potential.

Genes constitute ~3% of the human genome, whereas human endogenous retroviruses (HERVs) represent ~8%. We examined post-burn HERV expression in patients' blood cells, and the inflammatory potentials of the burn-associated HERVs were evaluated. Buffy coat cells, collected at various time points from 11 patients, were screened for the expression of eight HERV families, and we identified their divergent expression profiles depending on patient, HERV, and time point. The population of expressed HERV sequences was patient-specific, suggesting HERVs' inherent genomic polymorphisms and/or differential expression potentials depending on characteristics of patients and courses of injury response. Some HERVs were shared among the patients, while the others were divergent. Interestingly, one burn-associated HERV gag gene from a patient's genome induced IL-6, IL-1ß, Ptgs-2, and iNOS. These findings demonstrate that injury stressors initiate divergent HERV responses depending on patient, HERV, and disease course and implicate HERVs as genetic elements contributing to polymorphic injury pathophysiology.

Association of the miR-146aC>G, miR-149T>C, miR-196a2T>C, and miR-499A>G polymorphisms with gastric cancer risk and survival in the Korean population.

We investigated whether four common microRNA polymorphisms (miR-146aC>G [rs2910164], miR-149T>C [rs2292832], miR-196a2T>C [rs11614913], and miR-499A>G [rs3746444]) are associated with the susceptibility and prognosis of gastric cancer in the Korean population. The four microRNA single-nucleotide polymorphisms (SNPs) were identified in a case-control study (461 patients; 447 controls) by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis in the Korean population. When patients were stratified into diffuse and intestinal-type gastric cancer groups, subjects with the miR-499AG and AG + GG genotypes had reduced adjusted odds ratios (AORs) for diffuse-type gastric cancer (AOR = 0.54 with 95% confidence interval [CI] = 0.31-0.97; AOR = 0.57 with 95% CI = 0.33-0.97). In the stratified analyses for gastric cancer risk, the miR-146aGG and CG + GG genotypes were associated with increased risk of gastric cancers among the non-smokers, whereas the miR-149TC and TC + CC genotypes showed lower risk of gastric cancer in males. The miR-196a2CC genotype was associated with elevated gastric cancer risk among females. For gastric cancer prognosis, intestinal-type gastric cancer patients with miR-146aCG + GG genotypes had significantly higher survival rates (log-rank P = 0.030) than patients with the CC genotype, and patients with the miR-499AA genotype had significantly increased survival rates compared to patients with the AG + GG genotypes (log-rank P = 0.013). When miR-146aCG + GG and miR-499AA genotypes were combined, the survival rate of intestinal-type gastric cancer patients was elevated (log-rank P < 0.001). No association was found between gastric or diffuse-type cancer prognosis and other miRNAs. Our data demonstrate that specific miRNA SNPs are associated with gastric cancer susceptibility (miR-499A>G) and prognosis (miR-146aC>G and miR-499A>G) in the Korean population depending on gastric cancer type.

Are Veterinary Costs and Socioeconomic Status Risk Factors for Companion Animal Relinquishment in the Republic of Korea?

More than 110,000 companion animals are sent to shelters each year due to abandonment in Republic of Korea, and there is a need to analyze the causes of the relinquishment of animals and implement appropriate policies. Veterinary costs have been blamed for this issue in Republic of Korea above the reported leading causes of socioeconomic status of owners, cost and behavior issues of the animals, or housing restrictions. However, it is rare to find supporting evidence. In this study, we aimed to determine whether veterinary costs and socioeconomic factors are related to animal relinquishment in Republic of Korea. Multiple regression models were used to test if veterinary costs and socioeconomic indicators can account for relinquishment in 128 regions of Republic of Korea in 2020 and 2021. When five independent variables (two veterinary cost data and three socioeconomic indicators) were included, the regression model showed significance in explaining pet relinquishment in 2020, with an adjusted coefficient of determination of 0.3956. Pet relinquishment can also be explained by the same five variables for 2021, with an adjusted coefficient of determination of 0.391 with p < 0.0001. The findings suggest that intervention to reduce companion animal relinquishment in Republic of Korea should focus on lightening the financial burdens of owners as the socioeconomic status of a community worsens.

Recurrence risk prediction of acute coronary syndrome per patient as a personalized ACS recurrence risk: a retrospective study.

Acute coronary syndrome (ACS) has been one of the most important issues in global public health. The high recurrence risk of patients with coronary heart disease (CHD) has led to the importance of post-discharge care and secondary prevention of CHD. Previous studies provided binary results of ACS recurrence risk; however, studies providing the recurrence risk of an individual patient are rare. In this study, we conducted a model which provides the recurrence risk probability for each patient, along with the binary result, with two datasets from the Korea Health Insurance Review and Assessment Service and Chungbuk National University Hospital. The total data of 6,535 patients who had been diagnosed with ACS were used to build a machine learning model by using logistic regression. Data including age, gender, procedure codes, procedure reason, prescription drug codes, and condition codes were used as the model predictors. The model performance showed 0.893, 0.894, 0.851, 0.869, and 0.921 for accuracy, precision, recall, F1-score, and AUC, respectively. Our model provides the ACS recurrence probability of each patient as a personalized ACS recurrence risk, which may help motivate the patient to reduce their own ACS recurrence risk. The model also shows that acute transmural myocardial infarction of an unspecified site, and other sites and acute transmural myocardial infarction of an unspecified site contributed most significantly to ACS recurrence with an odds ratio of 97.908 as a procedure reason code and with an odds ratio of 58.215 as a condition code, respectively.

Identification of a unique library of complex, but ordered, arrays of repetitive elements in the human genome and implication of their potential involvement in pathobiology.

Approximately 2% of the human genome is reported to be occupied by genes. Various forms of repetitive elements (REs), both characterized and uncharacterized, are presumed to make up the vast majority of the rest of the genomes of human and other species. In conjunction with a comprehensive annotation of genes, information regarding components of genome biology, such as gene polymorphisms, non-coding RNAs, and certain REs, is found in human genome databases. However, the genome-wide profile of unique RE arrangements formed by different groups of REs has not been fully characterized yet. In this study, the entire human genome was subjected to an unbiased RE survey to establish a whole-genome profile of REs and their arrangements. Due to the limitation in query size within the bl2seq alignment program (National Center for Biotechnology Information [NCBI]) utilized for the RE survey, the entire NCBI reference human genome was fragmented into 6206 units of 0.5M nucleotides. A number of RE arrangements with varying complexities and patterns were identified throughout the genome. Each chromosome had unique profiles of RE arrangements and density, and high levels of RE density were measured near the centromere regions. Subsequently, 175 complex RE arrangements, which were selected throughout the genome, were subjected to a comparison analysis using five different human genome sequences. Interestingly, three of the five human genome databases shared the exactly same arrangement patterns and sequences for all 175 RE arrangement regions (a total of 12,765,625 nucleotides). The findings from this study demonstrate that a substantial fraction of REs in the human genome are clustered into various forms of ordered structures. Further investigations are needed to examine whether some of these ordered RE arrangements contribute to the human pathobiology as a functional genome unit.

miR-27a and miR-449b polymorphisms associated with a risk of idiopathic recurrent pregnancy loss.

OBJECTIVE: MicroRNAs (miRNAs) regulate gene expression during the peri-implantation period. The purpose of this study was to investigate whether genetic polymorphisms in the four miRNAs associated with fetal or placental development play roles in the development of idiopathic recurrent pregnancy loss (RPL) in Korean females. STUDY DESIGN: A case-control study involving 225 controls and 387 women with at least two consecutively recurrent pregnancy losses between 1999 and 2012 was performed. The genotypes of the four miRNA polymorphisms, including miR-27a rs895819, miR-423 rs6505162, miR-449b rs10061133, and miR-605 rs2043556, were analyzed by the polymerase chain reaction-restriction fragment length polymorphism assay. Odds ratios and 95% confidence intervals were estimated using multivariate analyses after maternal age adjustments. The relationships between each of the four microRNA genotypes and each of the six clinical parameters of the RPL patients (plasma homocysteine and folate levels, natural killer cell number, platelet count, prothrombin time, and, activated partial thromboplastin time) were analyzed using multiple linear regression analyses. RESULTS: Our results suggest that weak associations between decreased RPL risk and the genotypes of miR-27a (AG and AG+GG), combination genotype of miR-27a/miR-423 (AG/GC), and haplotypes of miR-27a/miR-423/miR-449b/miR-605 (G-C-A-G) and miR-27a/miR-449b/miR-605 (G-A-G), whereas weak associations between increased RPL risk and genotypes of miR-449b (GG and AG+GG), combination genotypes of miR-423/miR-449b (CC/GG and CA/AG), miR-449b/miR-605 (AG/AG), haplotypes of miR-27a/miR-423/miR-449b/miR-605 (A-C-G-A, A-A-A-G, and G-C-G-G), miR-27a/miR-423/miR-449b (A-C-G), miR-27a/miR-449b/miR-605 (A-A-G, A-G-A, and G-G-G), miR-423/miR-449b/miR-605 (C-G-G and A-A-G), and miR-423/miR-449b (C-G and A-A). The genotypes of miR-27a (AG and AG+GG) also showed significant contributions to the prediction of folate levels in RPL patients. CONCLUSIONS: The study showed associations between miRNA polymorphisms (miR-27a rs895819 and miR-449b rs10061133) and RPL development, and between the miRNA polymorphism (miR-27a rs895819) and plasma folate levels.

Single nucleotide polymorphisms at miR-146a/196a2 and their primary ovarian insufficiency-related target gene regulation in granulosa cells.

MicroRNAs post-transcriptionally regulate gene expression in animals and plants. The aim of this study was to identify new target genes for microRNA polymorphisms (miR-146aC>G and miR-196a2T>C) in primary ovarian insufficiency (POI). We cloned and transfected miR-146aC>G and miR-196a2T>C into human granulosa cells and used microarrays and qPCR-arrays to examine the changes in the messenger RNA expression profile. We show miR-146aC>G and miR-196a2T>C change the mRNA expression patterns in granulosa cell. In each case, mRNAs were up or down-regulated after treatments with miR-146a C or G and miR-196a2 T or C. We found that miR-146a led to a significantly altered regulation of the mRNA levels of FOXO3, FOXL2 and CCND2 compared to controls. We also found that the polymorphisms of miR-146a led to a significantly altered regulation of CCND2 and FOXO3. Our results suggest that miR-146aC>G and miR-196a2T>C can regulate the levels of many of their target transcripts. In addition, specific target genes of miR-146aC>G polymorphisms may be involved in granulosa cell regulation.

Lack of genetic association among coat colors, progressive retinal atrophy and polycystic kidney disease in Persian cats.

An inherited form of progressive retinal atrophy (PRA) is recognized in Persian cats; however, the prevalence of PRA in the breed has not been determined. Breeders suggest that cats from only brown ('chocolate') or Himalayan ('pointed') lines are at risk for PRA, suggesting the disease is not widespread. This study was designed to evaluate whether PRA in Persian cats is associated with three coat colors, including chocolate, or with a highly prevalent inherited disease in this breed--polycystic kidney disease (PKD). Sixty related cats were evaluated for PRA by ophthalmic examination and genetically typed for PKD and the mutations that cause coat color variants in agouti, brown and color (producing the pointed coloration in Himalayan). No associations were identified among any of the traits, including between PRA and chocolate. These data suggest that PRA is not limited to cats with chocolate coat coloration and breeders and veterinarians should be aware that the prevalence of the disease may be higher than currently claimed.

Polymorphisms in tumor necrosis factor-alpha (-863C>A, -857C>T and +488G>A) are associated with idiopathic recurrent pregnancy loss in Korean women.

Polymorphisms in TNF-a have been reported as genetic risk factors for recurrent spontaneous abortion and TNF-α may be immunologically important. We therefore examined the contribution of several TNF-a mutations to this phenomenon. The study participants consisted of 388 patients with idiopathic recurrent pregnancy loss (RPL), which was diagnosed on the basis of at least two consecutive spontaneous abortions; control subjects were 224 healthy women with a history of successful pregnancies. Polymerase chain reaction-restriction fragment length polymorphism analysis was performed to determine the TNF-α -863C>A, -857C>T, and +488G>A genotypes. The TNF-α -863C>A variants correlated with increased risk of RPL (CA+AA; adjusted odds ratio [AOR], 2.142; 95% confidence interval [CI], 1.493-3.074). These data did not differ in a stratified analysis according to number of consecutive spontaneous abortions. In haplotype analysis, there were similar trends of data for combination analysis, but in patients with 3+ pregnancy losses, a stratified analysis revealed that this correlation did not increase directly with the number of pregnancy losses. The TNF-α -863C>A variant is a possible genetic risk factor for idiopathic RPL in Korean women.

Early-onset, autosomal recessive, progressive retinal atrophy in Persian cats.

PURPOSE: An early-onset retinal degenerative disease has been identified in Persian cats. This study genetically, clinically, and histologically characterized the disease. A breeding colony was established to assist with identification of the causative gene and to provide a resource for vision research. METHODS: Cats were produced from testcross breedings. Kittens underwent serial ophthalmic and neuro-ophthalmic examinations. Globes were harvested from age-matched affected, obligate carrier, and control cats and were evaluated by light microscopy. Fluorescein angiography assessed retinal and choroidal vasculature. RESULTS: Test breedings confirmed an autosomal recessive mode of inheritance. Rate and extent of disease progression were similar among individual affected cats. The earliest clinical signs (reduced pupillary light reflexes) were seen at 2 to 3 weeks of age. Retinal degeneration was virtually complete by 16 weeks of age. Histologic changes progressed rapidly and paralleled clinical findings. Histologic lesions were limited to the photoreceptors, outer plexiform layer, and retinal pigment epithelium in all but the terminal stages, when subtle changes were noted within the inner nuclear layer. CONCLUSIONS: Characterized in this study was an autosomal recessive, early-onset, retinal degenerative disease in Persian cats that is likely to be more prevalent in this breed than previously suspected. This feline disease model may identify a new gene or provide biological insight into some forms of early-onset retinitis pigmentosa (RP) in humans and genetic retinal degenerations in other species. A breeding colony that will assist in the identification of the causative gene has been established and is available for studies in vision research.

Association of breast cancer-related microRNA polymorphisms with idiopathic primary ovarian insufficiency.

OBJECTIVE: The aim of our study was to investigate whether breast cancer-related microRNA polymorphisms are associated with primary ovarian insufficiency (POI) risk. METHODS: Four breast cancer-related microRNA polymorphisms (miR-27aA > G [rs895819], miR-135bC > T [rs74141216], miR-423C > A [rs6505162], and miR-608G > C [rs4919510]) were genotyped in 136 women with idiopathic POI and 224 controls of Korean ethnicity using polymerase chain reaction-restriction fragment length polymorphism analysis. Differences in genotype frequencies between cases and controls were compared. Odds ratios and 95% CIs were determined as measures of the strength of association between genotype and POI. RESULTS: Two haplotypes (G-C-A-G and A-T-C-C) of miR-27a/miR-135b/miR-423/miR-608 were associated with increased POI risk. The haplotypes G-A-G of miR-27a/miR-423/miR-608 and A-T-C of miR-27a/miR-135b/miR-608 were associated with higher POI risk, whereas the G-T haplotype of miR-27a/miR-135b was associated with decreased POI risk. The association between POI risk and the G-A-G haplotype of miR-27a/miR-423/miR-608 remained significant after false discovery rate correction for multiple comparisons. The combined genotypes AA/CT/CC/CC, AG/CC/CA/GC, GG/CC/CC/CC, and GG/CC/CA/GG of miR-27a/miR-135b/miR-423/miR-608 were also associated with higher POI risk. Increased POI risk was observed in combined genotypes GG/CC/GG of miR-27a/miR-135b/miR-608; AA/CC/GC, AG/CA/GC, GG/CC/GG, GG/CC/CC, and GG/CA/GG of miR-27a/miR-423/miR-608; and GG/GG of miR-27a/miR-608; however, these associations were not significant after false discovery rate correction. None of the four microRNA polymorphisms alone was associated with POI risk. CONCLUSIONS: Our data suggest that breast cancer-related microRNA polymorphisms, including miR-27aA > G, miR-423C > A, and miR-608G > C, are associated with increased POI risk via interactions between miR-27aG, miR-423A, and miR-608G variants. However, our results should be interpreted cautiously because of our small sample size and the low statistical power of our study design.

Association of inhibin α gene promoter polymorphisms with risk of idiopathic primary ovarian insufficiency in Korean women.

OBJECTIVE: The aim of this study was to investigate whether two polymorphisms in the promoter region of inhibin alpha (INHA) are associated with risk of idiopathic primary ovarian insufficiency (POI) in Korean women, which is a controversial topic. STUDY DESIGN: We genotyped the INHA polymorphisms c.-16C>T (rs35118453) and c.-124A>G (rs11893842) of 136 POI patients and 225 controls in Korean women by polymerase chain reaction and restriction fragment length polymorphism analysis. We then compared differences in genotype and allele frequencies (AF) of the polymorphisms between the two groups to determine odds ratios (OR) and 95% confidence intervals (CI) as measures of the strength of association between genotype and POI. RESULTS: There were no significant differences in genotype or AF of the polymorphisms between the POI patients and controls. Haplotype analysis revealed that the T-G haplotype of the two variant alleles was more frequent in POI patients than in the controls (OR=1.630, 95% CI=1.081-2.457). Combination genotype analysis showed that the CT+TT/GG genotype frequency was higher in POI patients than in the controls (OR=2.414, 95% CI=1.190-4.895). CONCLUSIONS: We provide evidence to suggest that when the two variant alleles are combined, the c.-16C>T and c.-124A>G polymorphisms are associated with increased POI risk in Korean women. We postulate that interactions between the INHA polymorphisms may affect POI risk.

Genetic variants in microRNA machinery genes are associated [corrected] with idiopathic recurrent pregnancy loss risk.

OBJECTIVE: Key molecules involved in microRNA (miRNA) biogenesis, such as DROSHA, XPO5, and DICER, have been identified in trophoblast cells, confirming that the miRNA biogenesis pathway is active in human placenta. In addition, miRNAs regulate uterine gene expression associated with inflammatory responses during the peri-implantation period and participate in maternal-fetal immune tolerance. The purpose of this study was to demonstrate whether genetic polymorphisms in miRNA machinery genes show an association with idiopathic recurrent pregnancy loss (RPL) in Korean women. STUDY DESIGN: We performed a case-control study with 238 controls and 338 women who had experienced at least two consecutive pregnancy losses between 1999 and 2010. Genotypes of miRNA machinery genes, including DICER rs3742330, DROSHA rs10719, RAN GTPase (RAN) rs14035, and exportin-5 (XPO5) rs11077 were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. The logistic odds ratios (ORs) of RPL were estimated with a 95% confidence interval (CI) in multivariate analysis after maternal age adjustment. Gene-gene interactions among the loci of the four gene polymorphisms were evaluated using the multifactor dimensionality reduction (MDR) method. RESULTS: The RAN rs14035 CC genotype and DICER rs3742330/DROSHA rs10719 GG/TC+CC, rs3742330/RAN rs14035 GG/CC, and DICER rs3742330/XPO5 rs11077 GG/AC+CC combinations were significantly associated with increased RPL risk, whereas the RAN rs14035 CT, DICER rs3742330/RAN rs14035 AA+AG/CT+TT, DROSHA rs10719/RAN rs14035 TC+CC/CT+TT, and RAN rs14035/XPO5 rs11077 CT+TT/AA combinations reduced RPL risk. The A-T-T-C and G-C-T-A allele combinations (DICER/DROSHA/RAN/XPO5) were 20 times more frequent in the RPL group than in the control group. CONCLUSION: Our study demonstrates the relationship between RPL development and the polymorphism of the miRNA machinery gene RAN and combined genotype of DROSHA/DICER.

Transcobalamin II (TCN2 67A>G and TCN2 776C>G) and transcobalamin II receptor (TCblR 1104C>T) polymorphisms in Korean patients with idiopathic recurrent spontaneous abortion.

PROBLEM: The transcobalamin II (TCN2) 776C>G polymorphism has been reported to be a genetic risk factor for idiopathic recurrent spontaneous abortion (RSA). However, the sample size in previous studies was small, and other TCN2 polymorphisms have not been studied. Moreover, the TCN2 67A>G and 776C>G polymorphisms, and the transcobalamin II receptor (TCblR/CD320) 1104C>T polymorphism, have demonstrated associations with immune responses. METHOD OF STUDY: Three hundred and seventy-eight RSA patients who had at least two consecutive spontaneous abortions were enrolled. Two hundred and seven control subjects were collected from a convenience sample. Polymerase chain reaction and restriction fragment length polymorphism analysis were performed to identify the TCN2 67A>G and 776C>G polymorphisms, and the TCblR 1104C>T polymorphism. RESULTS: RSA patients showed significantly different frequencies of the TCN2 67AG+GG genotypes compared with control subjects. CONCLUSION: The TCN2 67G allele is a possible risk factor for idiopathic RSA.

Association of kinase insert domain-containing receptor (KDR) gene polymorphisms with idiopathic recurrent spontaneous abortion in Korean women.

OBJECTIVE: To investigate whether kinase insert domain-containing receptor (KDR) gene polymorphisms are risk factors for recurrent spontaneous abortion (RSA) in Korean women. DESIGN: Case-control study. SETTING: University hospital. PATIENT(S): Three hundred twenty-seven idiopathic RSA patients and 230 controls with Korean ethnicity. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The KDR -604T→C (rs2071559), 1192G→A (rs2305948), and 1719A→T (rs1870377) polymorphisms were assessed. RESULT(S): KDR -604TC and TC+CC genotypes were more prevalent in RSA patients than in controls (adjusted odds ratio [AOR] = 2.091 and 2.076, respectively). KDR -604TC+CC/1192GG, -604TC+CC/1719AA, and -604TC+CC/1719TA+TT combined genotypes exhibited higher frequencies in RSA patients (AOR = 2.422, 2.611, and 2.216, respectively). KDR -604C/1192G/1719A, -604C/1192G/1719T, -604C/1192G, -604C/1719A, and -604C/1719T haplotype frequencies were higher in RSA patients (OR = 1.778, 2.659, 2.089, 1.678, and 1.806, respectively), whereas -604T/1192G/1719A, -604T/1192G, and -604T/1719A haplotype frequencies were lower in RSA patients (OR = 2.422, 2.611, and 2.216, respectively). No association was found between RSA and KDR 1192G→A or 1719A→T. CONCLUSION(S): An association between the KDR -604T→C polymorphism and RSA was found in Korean women. Carriers of the -604C variant allele were more frequent among RSA patients than among controls, suggesting that KDR -604C may confer RSA risk. The association of 1719A→T with RSA that was found in Taiwanese Han women was not observed in Korean women.

Association between polymorphisms in renin-angiotensin system genes and primary ovarian insufficiency in Korean women.

OBJECTIVE: The purpose of this study was to evaluate the relationship between angiotensin-converting enzyme (ACE; insertion/deletion), angiotensinogen (AGT M235T), and angiotensin II type 1 receptor (AT1R 1166A>C) and the prevalence of primary ovarian insufficiency (POI) in Korean women. METHODS: A total of 133 women with POI and 238 controls were genotyped for polymorphic sites in each gene using polymerase chain reaction-restriction fragment length polymorphism analysis. RESULTS: ACE ID and ID + II variants occurred more frequently in women with POI than in controls (odds ratio [OR], 1.830; 95% CI, 1.040-3.221; P = 0.040; and OR, 1.797; 95% CI, 1.055-3.060; P = 0.031, respectively). The AT1R 1166AC genotype occurred more frequently in participants with POI than in controls (OR, 3.171; 95% CI, 1.562-6.436; P = 0.002). Comparing the combined genotype frequencies of ACE/AT1R revealed that the frequencies of ID/AA, ID/AC, and II/AC were higher in participants than in controls (OR, 1.916; 95% CI, 1.053-3.485; P = 0.043; OR, 3.544; 95% CI, 1.207-10.407; P = 0.036; and OR, 7.875; 95% CI, 2.224-27.881; P = 0.001, respectively). The TT/AC genotype for combined genotyping of AGT/AT1R was more frequently observed in the POI group than in the control group (OR, 3.472; 95% CI, 1.450-8.313; P = 0.006). In multifactor dimensionality reduction-based haplotype analysis, the I-T-C genotype of ACE/AGT/AT1R was a possible predisposing factor for POI (OR, 4.678; 95% CI, 1.721-12.717; P = 0.002). CONCLUSIONS: This study demonstrates that polymorphisms in the renin-angiotensin system are related to the prevalence of POI. Thus, these renin-angiotensin system genes may serve as a novel marker for predicting the development of POI.