ABSTRACT
Premature ovarian failure (POF) is characterized by heterogeneous genetic causes such as chromosomal abnormalities and variants in causal genes. Recently, development of techniques made next generation sequencing (NGS) possible to detect genome wide variants including chromosomal abnormalities. Among 37 Korean POF patients, XY karyotype with distal part deletions of Y chromosome, Yp11.32-31 and Yp12 end part, was observed in two patients through NGS. Six deleterious variants in POF genes were also detected which might explain the pathogenesis of POF with abnormalities in the sex chromosomes. Additionally, the two POF patients had no mutation in SRY but three non-synonymous variants were detected in genes regarding sex reversal. These findings suggest candidate causes of POF and sex reversal and show the propriety of NGS to approach the heterogeneous pathogenesis of POF.
Subject(s)
Chromosome Aberrations , Chromosomes, Human, Y , Primary Ovarian Insufficiency/genetics , Asian People/genetics , Female , High-Throughput Nucleotide Sequencing , Humans , Sequence Analysis, DNAABSTRACT
OBJECTIVE: This study investigated whether epistasis between single nucleotide polymorphisms (SNPs) within ACVR2B (activin A receptor, type IIB) and ADAMTS19 (ADAM metallopeptidase with thrombospondin type 1 motif, 19) genes is associated with premature ovarian failure (POF). METHODS: One hundred twenty women with POF and 152 controls were recruited for stage I, and 1,641 additional female controls participated in stage II. GoldenGate assay with VeraCode technology was used for genotyping ACVR2B and ADAMTS19 SNPs in stage I. In stage II, we obtained genotype data for SNPs using Affymetrix Genome-Wide Human SNP array 5.0 and imputed data using IMPUTE program from the Korean Genome Epidemiology Study. RESULTS: In stage I, five combinations showed significant synergistic interactions after Bonferroni correction. One SNP (rs1468077 within 5' flanking region) and two intronic SNPs (rs2268753 and rs2268757) in ACVR2B and three intronic SNPs within ADAMTS19 (rs13158524, rs1476083, and rs1972624) were involved in synergistic interactions in a recessive manner. In stage II and combined analyses, we could not find any significant interactions between the SNPs. However, diplotypes within ACVR2B and ADAMTS19 that consist of risk genotypes or alleles in the results of significant synergistic interactions between SNPs showed significant interactions after Bonferroni correction. Thirteen and nine significant synergistic interactions were found in a dominant model in stage II and combined analyses, respectively (strongest association in combined analysis: odds ratio, 5.93; 95% CI, 2.47-14.20; P = 6.65 × 10(-5)). CONCLUSIONS: Epistasis between polymorphisms within ACVR2B and ADAMTS19 is significantly associated with susceptibility to POF.
Subject(s)
ADAM Proteins/genetics , Activin Receptors, Type II/genetics , Epistasis, Genetic , Genetic Predisposition to Disease , Polymorphism, Single Nucleotide , Primary Ovarian Insufficiency/genetics , ADAMTS Proteins , Asian People/genetics , Female , Genome-Wide Association Study , Humans , Middle Aged , Odds Ratio , SeoulABSTRACT
OBJECTIVE: The aim of the present study was to examine whether interactions between polymorphisms in the thyroglobulin and ADAM metallopeptidase with thrombospondin type 1 motif, 16 (ADAMTS16) genes are associated with the development of premature ovarian failure (POF). METHODS: A total of 75 patients with POF and 196 controls were involved in this study. We used a GoldenGate assay to genotype single nucleotide polymorphisms (SNPs). Logistic regression analysis was performed to identify POF-associated polymorphisms and synergistic interactions between polymorphisms in the thyroglobulin and ADAMTS16 genes. RESULTS: Single gene analyses using logistic regression analysis showed no significant association between polymorphisms in the two genes and POF. In the results from interaction analyses, we found seven synergistic interactions between the polymorphisms in thyroglobulin and ADAMTS16, although there was no combination showing p-values lower than the significant threshold using the Bonferroni correction. When the AG genotype was present at the rs853326 missense SNP, the A and G alleles at the tagging SNPs rs16875268 and rs13168665 showed significant interactions (odds ratios=5.318 and 16.2 respectively; 95% confidence intervals, 1.64-17.28 and 2.08-126.4; p=0.0054 and 0.0079). CONCLUSION: Synergistic interactions between polymorphisms in the thyroglobulin and ADAMTS16 genes were associated with an increased risk of POF development in Korean women.
ABSTRACT
OBJECTIVE: This study examined whether epistasis between single nucleotide polymorphisms (SNPs) within proprotein convertase subtilisin/kexin type 1 (PCSK1) and dopamine ß-hydroxylase (DBH) genes is associated with premature ovarian failure (POF). METHODS: One hundred twenty women with POF and 222 female controls were recruited for this study. To genotype SNPs within PCSK1 and DBH, we used a GoldenGate assay with VeraCode technology, which uses an allele-specific primer extension method. RESULTS: Two SNPs (rs155979 and rs3762986) within PCSK1 and one SNP (rs1611114) within DBH, which were located in the 5' flanking region, were involved in synergistic interactions. The C allele in the rs155979 SNP showed an increased risk of POF in a dominant model when AA genotype in the rs1611114 SNP was present (odds ratio, 3.60; 95% CI, 1.82-7.14; P = 0.00024), whereas the G allele in the rs1611114 SNP showed a reduced risk of POF in a dominant model when at least one C allele at the rs155979 SNP was present (odds ratio, 0.24; 95% CI, 0.11-0.51; P = 0.00018) or one G allele at the rs3762986 SNP was present (odds ratio, 0.33; 95% CI, 0.19-0.60; P = 0.00023). CONCLUSIONS: Epistases between SNPs within PCSK1 and DBH genes are significantly associated with susceptibility or resistance to POF.
Subject(s)
Dopamine beta-Hydroxylase/genetics , Epistasis, Genetic , Primary Ovarian Insufficiency/genetics , Proprotein Convertase 1/genetics , Adult , Alleles , Female , Genetic Predisposition to Disease , Genotype , Humans , Polymorphism, Single Nucleotide/geneticsABSTRACT
OBJECTIVE: This study investigated whether epistasis between single nucleotide polymorphisms (SNPs) within the TSHB (thyroid-stimulating hormone ß) and ADAMTS16 (ADAM metallopeptidase with thrombospondin type 1 motif, 16) genes is associated with an increased risk of premature ovarian failure (POF) in Korean women. METHODS: In stage I, 120 women with POF and 222 controls participated. A GoldenGate assay with VeraCode technology was used to genotype SNPs within the TSHB and ADAMTS16 genes. For stage II, we obtained genotype data merged with imputed data for 1,641 female controls from the Korean Genome Epidemiology Study. RESULTS: In stage I, two SNPs (rs7530810 and rs1321108) in the 5' flanking region of the TSHB gene demonstrated significant synergistic interactions with one tagging intronic SNP (rs13172105) in the ADAMTS16 gene (odds ratios, 6.63 and 5.57; 95% CIs, 2.30-19.18 and 2.05-15.12; P = 0.00048 and 0.00074, respectively) although the SNPs were not significantly associated with POF in a single SNP model. When at least one G allele at rs7530810 or one A allele at rs1321108 was present in combination with a C allele at rs13172105, significant synergistic effects were observed in a recessive model. In stage II and combined analyses, the same combinations repeatedly showed significant synergistic interactions. CONCLUSIONS: Epistasis between SNPs within the TSHB and ADAMTS16 genes may increase the risk of POF in Korean women.
Subject(s)
ADAM Proteins/genetics , Primary Ovarian Insufficiency/genetics , Thyrotropin, beta Subunit/genetics , ADAMTS Proteins , Adult , Asian People , Case-Control Studies , Epistasis, Genetic , Female , Humans , Polymorphism, Single Nucleotide , Republic of KoreaABSTRACT
OBJECTIVE: This study investigated whether polymorphisms within the Fanconi anemia complementation group A (FANCA) gene contribute to the increased risk of premature ovarian failure (POF) in Korean women. METHODS: Ninety-eight women with POF and 218 controls participated in this study. Genomic DNA from peripheral blood was isolated, and GoldenGate genotyping assay was used to identify single nucleotide polymorphisms (SNPs) within the FANCA gene. RESULTS: Two significant SNPs (rs1006547 and rs2239359; P < 0.05) were identified by logistic regression analysis, but results were insignificant after Bonferroni correction. Six SNPs formed a linkage disequilibrium block, and three main haplotypes were found. Two of three haplotypes (AAAGAA and GGGAGG) distributed highly in the POF group, whereas the remaining haplotype (GGAAGG) distributed highly in the control group by logistic regression analysis (highest odds ratio, 2.515; 95% CI, 1.515-4.175; P = 0.00036). CONCLUSIONS: Our observations suggest that genetic variations in the FANCA gene may increase the risk for POF in Korean women.
Subject(s)
Fanconi Anemia Complementation Group A Protein/genetics , Polymorphism, Single Nucleotide/genetics , Primary Ovarian Insufficiency/genetics , Adult , Asian People/genetics , Female , Genetic Predisposition to Disease , Genome-Wide Association Study , Humans , Logistic ModelsABSTRACT
OBJECTIVE: The aim of this study was to identify polymorphisms and gene-gene interactions that are significantly associated with age at menarche and age at menopause in a Korean population. METHODS: A total of 3,452 and 1,827 women participated in studies of age at menarche and age at natural menopause, respectively. Linear regression analyses adjusted for residence area were used to perform genome-wide association studies (GWAS), candidate gene association studies, and interactions between the candidate genes for age at menarche and age at natural menopause. RESULTS: In GWAS, four single nucleotide polymorphisms (SNPs; rs7528241, rs1324329, rs11597068, and rs6495785) were strongly associated with age at natural menopause (lowest P = 9.66 × 10). However, GWAS of age at menarche did not reveal any strong associations. In candidate gene association studies, SNPs with P < 0.01 were selected to test their synergistic interactions. For age at natural menopause, there was a significant interaction between intronic SNPs on ADAM metallopeptidase with thrombospondin type I motif 9 (ADAMTS9) and SMAD family member 3 (SMAD3) genes (P = 9.52 × 10). For age at menarche, there were three significant interactions between three intronic SNPs on follicle-stimulating hormone receptor (FSHR) gene and one SNP located at the 3' flanking region of insulin-like growth factor 2 receptor (IGF2R) gene (lowest P = 1.95 × 10). CONCLUSIONS: Novel SNPs and synergistic interactions between candidate genes are significantly associated with age at menarche and age at natural menopause in a Korean population.
Subject(s)
Epistasis, Genetic , Menarche/genetics , Menopause/genetics , Polymorphism, Single Nucleotide/genetics , ADAM Proteins/genetics , ADAMTS9 Protein , Adult , Asian People , Female , Genome-Wide Association Study , Humans , Middle Aged , Receptor, IGF Type 2/genetics , Receptors, FSH/genetics , Smad3 Protein/genetics , Young AdultABSTRACT
Lipoprotein lipase (LPL) plays an essential role in the regulation of high-density lipoprotein cholesterol (HDLC) and triglyceride levels, which have been closely associated with cardiovascular diseases. Genetic studies in European have shown that LPL single-nucleotide polymorphisms (SNPs) are strongly associated with lipid levels. However, studies about the influence of interactions between LPL SNPs and lifestyle factors have not been sufficiently performed. Here, we examine if LPL polymorphisms, as well as their interaction with lifestyle factors, influence lipid concentrations in a Korean population. A two-stage association study was performed using genotype data for SNPs on the LPL gene, including the 3' flanking region from 7,536 (stage 1) and 3,703 (stage 2) individuals. The association study showed that 15 SNPs and 4 haplotypes were strongly associated with HDLC (lowest p = 2.86 × 10(-22)) and triglyceride levels (lowest p = 3.0 × 10(-15)). Interactions between LPL polymorphisms and lifestyle factors (lowest p = 9.6 × 10(-4)) were also observed on lipid concentrations. These findings suggest that there are interaction effects of LPL polymorphisms with lifestyle variables, including energy intake, fat intake, smoking, and alcohol consumption, as well as effects of LPL polymorphisms themselves, on lipid concentrations in a Korean population.
ABSTRACT
OBJECTIVES: Common variations with modest effect in complex and polygenic disease such as premature ovarian failure (POF) can be detected by a genome wide association study. We performed a genome wide association study to identify predisposing genes associated with an increased risk of POF. STUDY DESIGN: In stage I, genome wide association study was performed using 24 POF patients and 24 matched controls. A strongly associated region was re-tested to confirm the association with POF in stage II using 98 patients and 218 matched controls. RESULTS: In the stage I, we found a strongly associated region that was located on chromosome 1q31 and encoded the laminin gamma 1 (LAMC1) gene. All 22 single nucleotide polymorphisms (SNPs) in the LAMC1 formed a linkage disequilibrium block and two haplotypes were significantly associated with POF. In the stage II, 14 SNPs, the majority of which were SNPs located in coding region and tagging SNPs, were genotyped. Distributions of 9 SNPs of them including one nonsynonymous SNP (rs20558) and one haplotype (HT1, C-C-T-G-C-C-A-T-T-C) were significantly higher in POF patients than in control group (86.6% and 74.5%, respectively, OR=2.209, CI: 1.139-4.284, P=0.017). CONCLUSIONS: We showed for the first time that LAMC1 is significantly associated with POF, and specifically, possession of at least one HT1 was associated with susceptibility to POF. This result means that HT1 may co-exist with causative variant for susceptibility to POF in linkage disequilibrium and that the LAMC1 may be involved in POF pathogenesis.
Subject(s)
Chromosomes, Human, Pair 1 , Genotype , Laminin/genetics , Linkage Disequilibrium , Polymorphism, Single Nucleotide , Primary Ovarian Insufficiency/genetics , Case-Control Studies , Female , Genetic Predisposition to Disease , Genome-Wide Association Study , Haplotypes , Humans , Risk FactorsABSTRACT
OBJECTIVE: To identify whether epistasis between TG and HSD17B4 and whether polymorphisms in HSD17B4 are associated with premature ovarian failure (POF). DESIGN: Case-control genetic association study. SETTING: Research laboratory of a university. PATIENT(S): Female patients with POF (98) and controls (218) of Korean ethnicity participated in this study. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Genotype distribution, haplotype (HT) inference, and gene-gene interaction. RESULT(S): Distribution of one haplotype (A-G-A-A-G-G) on the HSD17B4 gene was significantly different between the POF group and the control group in a dominant model. In addition, the combined effect of the single nucleotide polymorphisms (SNPs) HSD17B4 rs28943592 and TG rs2076740 was significantly associated with POF (odds ratio = 7.74, 95% confidence interval = 1.67-35.94), although a significant association was not observed in the single SNP model. CONCLUSION(S): A haplotype in the HSD17B4 gene was identified that was significantly associated with resistance to POF. In addition, epistasis between two missense SNPs (rs28943592, rs2076740) located in HSD17B4 and TG was significantly associated with susceptibility to POF.
Subject(s)
17-Hydroxysteroid Dehydrogenases/genetics , Epistasis, Genetic , Hydro-Lyases/genetics , Polymorphism, Single Nucleotide , Primary Ovarian Insufficiency/genetics , Thyroglobulin/genetics , Case-Control Studies , Chi-Square Distribution , Female , Gene Frequency , Genetic Predisposition to Disease , Haplotypes , Humans , Odds Ratio , Peroxisomal Multifunctional Protein-2 , Primary Ovarian Insufficiency/enzymology , Republic of Korea , Risk Assessment , Risk FactorsABSTRACT
BACKGROUND/AIMS: Matrix metallopeptidase (MMP) is known to be involved in tumor invasion and metastasis of cancer. This study investigated the association of MMP7 rs11568818, MMP8 rs11225395, MMP9 rs17576 and rs2250889 with gastric cancer (GC) development and lymph node metastasis (LNM). METHODS: Samples were obtained from 326 chronic gastritis (CG) and 153 GC patients and genotyped by using the GoldenGate® method. Chi-square test was performed to identify the difference of allele distribution between each group (CG vs. GC; CG vs. with LNM GC). The associations of genotype with risk of GC and LNM were estimated by odds ratio and the 95% confidence interval was calculated by logistic regression adjusting for age and sex. RESULTS: The allele and genotype frequencies of MMP7 rs11568818, MMP8 rs11225395, MMP9 rs17576 and rs2250889 were not associated with the development of GC and LNM. CONCLUSIONS: In summary, MMP7 rs11568818, MMP8 rs11225395 MMP9 rs17576 and rs2250889 were not associated with the GC development and LNM in Korean population.
Subject(s)
Matrix Metalloproteinase 7/genetics , Matrix Metalloproteinase 8/genetics , Matrix Metalloproteinase 9/genetics , Stomach Neoplasms/genetics , Adult , Age Factors , Aged , Alleles , Chronic Disease , Female , Genotype , Humans , Logistic Models , Lymphatic Metastasis , Male , Middle Aged , Neoplasm Staging , Odds Ratio , Polymorphism, Single Nucleotide , Risk Factors , Sex FactorsABSTRACT
Poly (ADP-ribose) polymerase 1 (PARP1), which plays a critical role in the base excision DNA repair mechanism, and matrix metallopeptidase 2 (MMP2), a member of the matrix metalloprotease family, are involved in tumor formation and metastasis, respectively. In the present study, the possible association of single nucleotide polymorphisms (SNPs) and gene-gene interaction between PARP1 and MMP2 with the increased incidence of gastric cancer (GC) development and lymph node metastasis (LNM) was investigated in a Korean population. Samples were obtained from 326 patients with chronic gastritis and 153 patients with GC and genotyped using the GoldenGate® method. The PARP1 rs1136410 genotype showed a significant association with the frequency of LNM of GC (odds ratio [OR] = 2.19, p = 0.02), LNM stage (p = 0.035), and tumor invasion (p = 0.035). The allele frequency of MMP2 rs243865 was not associated with the development of GC or with the development of LNM of GC. Epistasis between the PARP1 SNP and the MMP2 SNP was associated with the development of LNM of GC. The combination of the MMP2 rs243865 CC genotype and the PARP1 rs1136410 CC or CC+CT genotypes showed a high risk of LNM of GC (OR = 2.47, p = 0.01; OR = 2.28, p = 0.01, respectively). In summary, PARP1 is associated with the risk of LNM of GC and the stage of LNM and tumor invasion. Epistasis between PARP1 rs1136410 and MMP2 rs243865 increased the risk of LNM of GC.
Subject(s)
Epistasis, Genetic , Lymphatic Metastasis/genetics , Matrix Metalloproteinase 2/genetics , Neoplasm Proteins/genetics , Poly(ADP-ribose) Polymerases/genetics , Stomach Neoplasms/genetics , Adult , Aged , Aged, 80 and over , Alleles , Case-Control Studies , Chronic Disease , Female , Gastritis/enzymology , Gastritis/genetics , Gene Frequency , Genotype , Humans , Male , Middle Aged , Neoplasm Invasiveness , Neoplasm Staging , Poly (ADP-Ribose) Polymerase-1 , Polymorphism, Single Nucleotide , Republic of Korea/epidemiology , Stomach Neoplasms/enzymology , Stomach Neoplasms/epidemiology , Stomach Neoplasms/pathologyABSTRACT
Follicle-stimulating hormone secreted from the pituitary gland plays a key role in human reproduction and regulates estrogen production by acting on the regulatory region of CYP19A1. We observed a significant association between premature ovarian failure and the combined genetic effect of single nucleotide polymorphism (SNP) rs4646 (CA+AA) in the 3' untranslated region of CYP19A1 and the missense FSHR SNP rs6166 (AG+GG) genotype (odds ratio 5.42, 95% confidence interval 1.96-14.98), and we identified a significant association between premature ovarian failure and the combined genetic effect of the FSHR missense SNP rs6166 (AA) and the rs4646-rs10046 haplotype (C-T)+(C-C) (odds ratio 5.47, 95% confidence interval 2.03-14.75), suggesting that two biochemical pathways may be involved in the regulation of folliculogenesis.
Subject(s)
Aromatase/genetics , Epistasis, Genetic , Ovary/physiopathology , Polymorphism, Single Nucleotide , Primary Ovarian Insufficiency/genetics , Receptors, FSH/genetics , 3' Untranslated Regions , Case-Control Studies , Chi-Square Distribution , Female , Gene Frequency , Genetic Predisposition to Disease , Haplotypes , Humans , Mutation, Missense , Odds Ratio , Phenotype , Primary Ovarian Insufficiency/enzymology , Primary Ovarian Insufficiency/physiopathology , Republic of Korea , Risk Assessment , Risk FactorsABSTRACT
Because an interaction between CYP19A1 and ESR1 may play a key role in determining the level of circulating E2 by way of the hypothalamus-hypophysis-ovarian axis, the effect of single nucleotide polymorphism (SNP)-SNP interactions between CYP19A1 and ESR1 on the development of premature ovarian failure (POF) was investigated by comparing the polymorphisms of 98 patients with POF and 218 matched controls of Korean ethnicity. A significant association with POF risk was found for the combined genetic effect between the CYP19A1 3'untranslated region (UTR) SNP rs10046 (CT+TT) and the intronic ESR1 SNP rs1569788 (CC) genotype (odds ratio=12.67, 95% confidence interval: 1.61-99.71), and a statistically significant association was also observed between POF and the CYP19A1 3'UTR SNP rs10046 under a dominant model (odds ratio=2.51, 95% confidence interval: 1.33-4.76), suggesting that epistasis between ESR1 and CYP19A1 may be involved in the regulation of folliculogenesis.
Subject(s)
Aromatase/genetics , Epistasis, Genetic , Estrogen Receptor alpha/genetics , Polymorphism, Single Nucleotide , Primary Ovarian Insufficiency/epidemiology , Primary Ovarian Insufficiency/genetics , 3' Untranslated Regions/genetics , Asian People/genetics , Female , Humans , Introns/genetics , Ovarian Follicle/physiology , Republic of Korea/epidemiology , Risk FactorsABSTRACT
Variants of the thyroglobulin gene were significantly associated with premature ovarian failure in a Korean population. Three single nucleotide polymorphisms and one haplotype were found to be associated with a significant increase in the risk for premature ovarian failure.
Subject(s)
Hypothyroidism/epidemiology , Hypothyroidism/genetics , Primary Ovarian Insufficiency/epidemiology , Primary Ovarian Insufficiency/genetics , Thyroglobulin/genetics , Adult , Asian People/genetics , Female , Gene Frequency , Haplotypes , Humans , Polymorphism, Single Nucleotide , Risk FactorsABSTRACT
BACKGROUND/AIMS: Oncogenic RAS gene mutations have been frequently observed in many tumor types, and their associations with various cancers were reported. This study was conducted to evaluate the association between H-RAS T81C polymorphism and gastric cancer development. METHODS: H-RAS T81C polymorphism was genotyped in 321 chronic gastritis (ChG) and 151 gastric cancer (GC) patients using GoldenGate Assay kit. Logistic regression analysis adjusted for age and gender was performed to identify the differences of genotype and allele distributions between the each group. RESULTS: All ChG and GC patients were in Hardy-Weinberg equilibrium. When the frequencies of H-RAS T81C genotype in each group were compared, the homozygous type of major allele TT was more frequent in GC group (62.9%) than ChG group (57.3%), while the frequencies of heterozygous type TC and homozygous type of minor allele CC were higher in ChG group than GC group (39.3% vs. 33.8%, 3.4% vs. 3.3%, respectively). In the results of logistic regression analyses adjusted for age and gender, the odds ratios were 0.845 (0.604-1.182), 0.799 (0.556-1.147), 0.741 (0.493-1.114) and 1.094 (0.366-3.270) for allele, codominant, dominant and recessive models, respectively. However, significant difference was not observed between two groups in any models. CONCLUSIONS: H-RAS T81C polymorphism was not associated with gastric cancer development in a Korean population.
Subject(s)
Polymorphism, Single Nucleotide , Stomach Neoplasms/genetics , ras Proteins/genetics , Adult , Aged , Alleles , Amino Acid Substitution , Chronic Disease , Female , Gastritis/genetics , Genetic Predisposition to Disease , Genotype , Humans , Logistic Models , Male , Middle Aged , Republic of KoreaABSTRACT
We found that four polymorphisms in the protein L-isoaspartyl-O-methyltransferase (PCMT1) gene, encoding a protein repair enzyme, are associated with premature ovarian failure (POF). All four polymorphisms were in strong linkage disequilibrium. The frequencies of two haplotypes were statistically significantly different between the POF group and the matched control group.