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

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.

Interaction Effects of Lipoprotein Lipase Polymorphisms with Lifestyle on Lipid Levels in a Korean Population: A Cross-sectional Study.

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.

[Study on association between single nucleotide polymorphisms of MMP7, MMP8, MMP9 genes and development of gastric cancer and lymph node metastasis].

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.

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 FSHR and CYP19A1 polymorphisms is associated with premature ovarian failure.

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.

Epistasis between CYP19A1 and ESR1 polymorphisms is associated with premature ovarian failure.

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.

[Study on association between an H-RAS gene polymorphism and gastric cancer development].

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.