Angiotensin I-converting enzyme insertion-related genotypes and allele are associated with higher susceptibility of endometriosis and leiomyoma.

Endometriosis and leiomyoma display features similar to malignancy, requiring neovascularization to proliferation and growth. Altered vascular-related genes might be related to the development of endometriosis and leiomyoma. Polymorphisms of the angiotensin-converting enzyme (ACE) insertion/deletion (I/D) genes have been linked with some vascular diseases. This study investigates whether ACE I/D gene polymorphisms could be used as markers of susceptibility in endometriosis and leiomyoma. Women were divided into three groups: (1) endometriosis (n = 125); (2) leiomyoma (n = 120); (3) normal controls (n = 128). Genomic DNA was obtained from peripheral leukocyte. ACE I/D gene polymorphisms in intron 16 were amplified by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) Genotypes and allelic frequencies in both groups were compared. We observed the genotype distribution and allele frequency of ACE I/D gene polymorphisms in both groups were significantly different. Proportions of ACE*I homozygote/heterozygote/D homozygote in both groups were: (1) 50.4/24/25.6%; (2) 25/23.33/51.67%; (3) 10.2/29.7/60.1%. Proportions of I/D alleles in each group were: (1) 62.4/37.6%; (2) 36.7/63.3%; (3) 25/75%. We concluded that ACE*I/D gene polymorphisms are associated with endometriosis and leiomyoma susceptibilities. ACE*I-related genotypes and allele are strongly related to the occurrence of endometriosis and moderately related to the occurrence of leiomyoma.

Polymorphism for transforming growth factor beta 1-509 (TGF-B1-509): association with endometriosis.

Transforming growth factor beta (TGF-B) family members are multi-functional cytokines that play a key role in cellular growth, proliferation, and differentiation. The aim of the study was to investigate whether the TGF-B1-509 gene polymorphism could be used as a marker of susceptibility in endometriosis. Women were divided into two groups: endometriosis (n = 150) and non-endometriosis (n = 159). Polymorphisms for TGF-B 1-509 genes were amplified by polymerase chain reaction and detected after restriction enzyme digestion. Genotypes and allelic frequencies in both groups were compared. Genotype proportions and allele frequencies of TGF-B1 gene polymorphisms differed significantly in both groups. Proportions of C homozygote, heterozygote, and T homozygote for TGF-B1 gene polymorphisms were 9.3/61.3/29.4% in the endometriosis group and 41.3158.510% in the non-endometriosis group. Alleles C and T for TGF-B1 gene polymorphism were 40/60% (endometriosis) and 70.8/29.2% (non-endometriosis). Association of endometriosis with TGF-B 1-509 gene polymorphism exists. T homozygote and T allele for TGF-B1 are associated with higher susceptibility to endometriosis.

Tumor necrosis factor-alpha-308 promoter and p53 codon 72 gene polymorphisms in women with leiomyomas.

OBJECTIVE: Tumor necrosis factor-alpha (TNF-alpha), a proinflammatory cytokine, plays an important role in the process of autoimmune diseases. p53 is related to the regulation of cell growth and prevention of carcinogenesis. We propose to investigate whether gene polymorphisms for TNF-alpha-308 promoter and p53 could be used as markers of susceptibility in leiomyomas. DESIGN: Prospective basic study. SETTING: Departments of gynecology and genetics in a medical center. PATIENT(S): Group 1: leiomyoma (n = 159); group 2: non-leiomyoma (n = 131). INTERVENTION(S): Genomic DNA was obtained from peripheral leukocyte. The TNF-alpha and p53 gene polymorphisms were amplified by polymerase chain reaction (PCR), enzyme restriction, and electrophoresis. MAIN OUTCOME MEASURE(S): Two gene polymorphisms were identified: [1] the A (cuttable)/G (uncuttable) polymorphisms of the TNF-alpha gene on chromosome 6p21.3; [2] A (cuttable)/P (uncuttable) polymorphisms of the p53 gene on chromosome 17p. Genotype and allelic frequencies in both groups were compared. RESULT(S): Genotype distribution and allele frequency of TNF-alpha gene polymorphism in both groups were significantly different. Proportions of A homozygote/heterozygote/G homozygote for TNF-alpha in both groups were: (group 1) 61%/34.6%/4.4% and (group 2) 81.7%/14.5%/3.8%. Proportions of allele A/G for TNF-alpha in both groups were: (group 1) 78.3%/21.7% and (group 2) 88.9%/11.1%. Distributions of p53 polymorphisms in both groups were not different. The proportions of A homozygotes/heterozygotes/P homozygotes for p53 were (group 1) 32.7%/42.1%/25.2% and (group 2) 28.2%/48.9%/22.9%. CONCLUSION(S): G homozygote and G allele for TNF-alpha promoter are related to a higher risk of leiomyomas. The p53 codon 72 gene polymorphism is not associated with the susceptibility of leiomyomas.

T allele for VEGF gene-460 polymorphism at the 5'-untranslated region: association with a higher susceptibility to endometriosis.

OBJECTIVE: To investigate whether vascular endothelial growth factor (VEGF) gene 5'-UTR-460 polymorphism could be used as a marker of susceptibility to endometriosis. STUDY DESIGN: Women were divided into 2 groups, endometriosis (n = 122) and nonendometriosis (n = 131). Polymorphisms for VEGF were detected by polymerase chain reaction and BstUI (New England Biolabs, Beverly, Massachusetts) restriction enzyme analysis. Genotypes and allelic frequencies between the groups were compared. RESULTS: Proportions of different VEGF polymorphisms in the groups were significantly different. Proportions of cuttable (C) homozygote/heterozygote/ uncuttable (T) homozygotefor VEGF in the groups were 0/44.3/55.7% and 0/63.4/36.6%, respectively. A higher percentage of T/F homozygote and T allele was present in the endometriosis population. The proportions of C/T alleles in the groups were 22.1/77.9% and 31.7/68.3%, respectively. CONCLUSION: T/T homozygotes and the T allele of the VEGF-460 gene are associated with a higher risk of endometriosis. Heterozygotes and C allele are related to the lower risk of endometriosis formation. VEGF polymorphism likely contributes to the pathogenesis of endometriosis and may become a useful markerfor predicting endometriosis susceptibility.

Androgen receptor trinucleotide polymorphism in leiomyoma.

OBJECTIVE: Androgen receptor (AR) was detected in leiomyoma. AR gene has a polymorphic microsatellite encoding cytosine, adenine, and guanine (CAG) repeats. We aimed to investigate the association between the AR gene CAG repeats and leiomyoma. METHODS: Women were divided into two groups: (1) leiomyoma (n = 159); (2) non- leiomyoma groups (n = 129). Their CAG repeats were detected by polymerase chain reaction. The CAG repeats ranged in length from 168 bp (9 CAG repeats, genotype A) to 234 bp (31 CAG repeats, genotype W). Distributions of CAG repeats in both groups were compared. RESULTS: Genotype proportions of different CAG repeats for AR gene in both groups were significantly different. The genotype S (27 CAG repeats) is associated with higher susceptibility of leiomyoma. Distribution of CAG repeats in both groups appeared mono-peak distributions. Percentages of genotypes K-S (19-27 CAG repeats) in leiomyoma and non-leiomyoma groups were: (1) 5,11,19.5, 10.4, 12.9, 8.8, 7.5, 5.7, 4.4%; (2) 5.4, 14.3,16.7, 12.8, 12.4, 5.8, 9.3, 7,1.2%. CONCLUSIONS: AR trinucleotide polymorphism is associated with leiomyoma susceptibility. The 27 CAG repeats is related with higher risk of leiomyoma.

Insulin-like growth factor II gene Apa I polymorphism is not associated with endometriosis susceptibility

Insulin-like growth factor II (IGF2) has been shown to play a role in abnormal cell growth and carcinogenesis. We investigated if the IGF2 gene Apa I polymorphism at exon 9 was associated with the susceptibility to endometriosis, analyzing 120 women with moderate/severe endometriosis and 103 controls. The genotype frequencies did not differ statistically between the endometriosis (aa = 25.4, ab = 57.4, bb = 17.2 percent) and control (aa = 20.8 ab = 52.8, bb = 26.4 percent) groups. The allele frequencies did not differ either: a = 54.1, b = 45.9 percent among women with endometriosis and a = 47.2, b = 52.8 percent in the control group. Therefore, no indication was found for an association of this polymorphism with endometriosis susceptibility.

Estrogen receptor thymine-adenine dinucleotide repeat polymorphism is associated with susceptibility to leiomyoma.

OBJECTIVE: To evaluate the association between leiomyomas and estrogen receptor gene polymorphism. DESIGN: Prospective study. SETTING: Department of gynecology and genetics. PATIENT(S): Women with (n = 159) or without leiomyomas (n = 131). MAIN OUTCOME MEASURE(S): Polymerase chain reaction was used to detect dinucleotide (thymine-adenine [TA]) repeat polymorphisms upstream of the estrogen receptor gene. Genotypes were classified as A through P according to the number of the TA repeats from 12 to 27. Distributions of TA repeat for estrogen receptor in both groups were compared. RESULT(S): Genotypes A to E were detected in 10.7%, 18.9%, 15.7%, 16.4%, and 4.4%, respectively, of women with leiomyomas and 4.2%, 9.5%, 20.6%, 19.1%, and 10.3% of women without leiomyomas. Women with genotypes A and B (12 or 13 TA repeats) have a higher risk for leiomyomas, and those with genotype E (16 TA repeats) have a lower risk. CONCLUSION(S): Estrogen receptor gene polymorphism probably contributes to the pathogenesis of leiomyoma and may predict the susceptibility to leiomyoma. The 12 and 13 TA repeats are associated with a higher risk of leiomyoma.