Jung-A Pyun

LAMC1 gene is associated with premature ovarian failure

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.

Epistasis between IGF2R and ADAMTS19 polymorphisms associates with premature ovarian failure

STUDY QUESTION Do single nucleotide polymorphisms (SNPs) or synergistic interactions between SNPs and diplotypes within the insulin-like growth factor 2 receptor (IGF2R) and ADAM metallopeptidase with thrombospondin type 1 motif, 19 (ADAMTS19), contribute to premature ovarian failure (POF)? SUMMARY ANSWER Synergistic interactions were detected between SNPs, including a non-synonymous SNP, and diplotypes within IGF2R and ADAMTS19 which may contribute to POF; however, there was no correlation with POF in a single SNP model after Bonferroni correction. WHAT IS KNOWN ALREADY IGF2R regulates free IGF2 level, which is involved in steroidogenesis in bovine granulosa cells. ADAMTS19 expression is higher in the murine embryonic ovary than in the embryonic testis during sexual differentiation, and an ADAMTS19 SNP (rs246246) showed a possible association with POF in a genome-wide association study in Caucasian women. STUDY DESIGN, SIZE, DURATION This study analyzed interactions between SNPs and diplotypes within IGF2R and ADAMTS19 as well as SNPs within the two genes. In Stage I, a total of 120 patients with POF and 152 female controls were recruited. All patients were diagnosed with POF at the CHA hospital in Seoul, Korea, and were recruited between 1994 and 2004. The 152 controls were recruited from Chungju, Korea, as part of another study that was conducted from April 2002 to March 2004. For Stage II, we obtained genotype data for an additional 1641 female controls, recruited in Ansung and Ansan from 2001 to 2008, from the Korean Genome Epidemiology Study (KoGES). PARTICIPANTS/MATERIALS, SETTING, METHODS In Stage I, the GoldenGate assay with VeraCode technology was used to genotype SNPs in IGF2R and ADAMTS19. In Stage II, we obtained genotype data for IGF2R and ADAMTS19 using Affymetrix Genome-Wide Human SNP array 5.0 and imputed data by the IMPUTE program from the KoGES. To identify POF-associated SNPs, logistic regression analysis in an additive model was performed using the PLINK tool. Synergistic interactions between SNPs and diplotypes within IGF2R and ADAMTS19 were analyzed by logistic regression analysis in three alternative models. MAIN RESULTS AND THE ROLE OF CHANCE In Stage I, 13 combinations of SNPs showed significant synergistic interactions after Bonferroni correction [the strongest association had odds ratio (OR) = 5.77, 95% confidence interval (CI): 2.26-14.75, P = 0.00025]. In Stage II and combined analyses, two and four combinations, respectively, of the significant results in Stage I showed significant synergistic interactions after Bonferroni correction. For interactions between diplotypes in block 2 of IGF2R and block 3 of ADAMTS19 in Stage I, we found 17 synergistic interactions with P < 0.0001, but there was no significant interaction after Bonferroni correction. In Stage II and combined analyses, we found that three and seven combinations in the same blocks, respectively, showed significant synergistic interactions after Bonferroni correction (strongest association: OR = 4.12, 95% CI: 2.22-7.62, P = 6.74E-06). LIMITATIONS, REASONS FOR CAUTION The sample size for patients with POF in this study was small but, compared with recent reports describing associations between SNPs and POF and considering the low prevalence of POF (1%), the sample size is considered to be reasonable. These results should be confirmed in large-scale studies involving different ethnic groups. WIDER IMPLICATIONS OF THE FINDINGS Our results may ultimately provide predictive markers for women at a high risk of POF. STUDY FUNDING/COMPETING INTERESTS This study was supported by grants from Basic Science Research Program through the National Research Foundation of Korea (NRF), which is funded by the Ministry of Education (2009-0093821, 2011-0010637). There are no competing interests.

Lymph Node Metastasis of Gastric Cancer Is Associated with the Interaction Between Poly (ADP-Ribose) Polymerase 1 and Matrix Metallopeptidase 2

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.

Epistasis between polymorphisms in TSHB and ADAMTS16 is associated with premature ovarian failure.

ObjectiveThis study investigated whether epistasis between single nucleotide polymorphisms (SNPs) within the TSHB (thyroid-stimulating hormone &bgr;) 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. MethodsIn 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. ResultsIn 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. ConclusionsEpistasis between SNPs within the TSHB and ADAMTS16 genes may increase the risk of POF in Korean women.

Epistasis between the HSD17B4 and TG polymorphisms is associated with premature ovarian failure

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.

Association between polymorphisms in the protein L-isoaspartate (D-aspartate) O-methyltransferase gene and premature ovarian failure

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.

Interaction between thyroglobulin and ADAMTS16 in premature ovarian failure

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.

Thyroglobulin gene is associated with premature ovarian failure

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.

Polymorphisms within the FANCA gene associate with premature ovarian failure in Korean women.

ObjectiveThis 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. MethodsNinety-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. ResultsTwo 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). ConclusionsOur observations suggest that genetic variations in the FANCA gene may increase the risk for POF in Korean women.

Epistasis between polymorphisms in PCSK1 and DBH is associated with premature ovarian failure.

ObjectiveThis study examined whether epistasis between single nucleotide polymorphisms (SNPs) within proprotein convertase subtilisin/kexin type 1 (PCSK1) and dopamine &bgr;-hydroxylase (DBH) genes is associated with premature ovarian failure (POF). MethodsOne 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. ResultsTwo 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). ConclusionsEpistases between SNPs within PCSK1 and DBH genes are significantly associated with susceptibility or resistance to POF.