Abstract
Aim. To determine the frequency of the polymorphisms within the genes encoding estrogen metabolism enzymes: CYP1A1 (rs4646903), CYP1A2 (rs762551), CYP19 (rs700519) and SULT1A1 (rs9282861) in women with early miscarriage.Materials and Methods. We recruited 103 consecutive women who experienced early miscarriage (< 12 weeks of pregnancy, n = 103) and 257 women without past medical history of adverse pregnancy outcomes. Following DNA extraction, we genotyped all samples by means of restriction fragment length polymorphism analysis. We analyzed the polymorphisms within the CYP1A1 gene (T264 → C, rs4646903), CYP1A2 gene (C734 → A, rs762551), CYP19 gene (C → T, rs700519), and SULT1A1 gene (G638 → A, rs9282861).Results. We found a significantly increased prevalence of the mutant allele C as well as T/C and C/C genotypes of the rs4646903 polymorphism within the CYP1A1 gene and mutant T allele along with the T/C genotype of the rs700519 polymorphism within the CYP19 gene in women with early miscarriage as compared with those having a normal pregnancy course. Concurrently, we detected a reduced frequency of the C/A genotype of the rs762551 polymorphism within the CYP1A2 gene in patients who suffered from early miscarriage. The risk of miscarriage was significantly increased in carriers of CYP1A2 (rs762551 C/C) + CYP1A1 (rs4646903 T/C + C/C) + CYP19 (rs700519 C/T), CYP1A2 (rs762551 C/C) + CYP1A1 (rs4646903 T/C + C/C) + SULT1A1 (rs9282861 G/G) + CYP19 (rs700519 C/T), CYP19 (rs700519 C/T) + SULT1A1 (rs9282861 G/G), (CYP1A2 (rs762551 C/C) + CYP1A1 (rs4646903 T/C + C/C); CYP1A2 (rs762551 C/C) + CYP19 (rs700519 C/T), CYP19 (rs700519 C/T) + CYP1A1 (rs4646903 T/C + C/C), and SULT1A1 (rs9282861 G/G) + CYP1A1 (rs4646903 T/C + C/C) haplotypes. Investigation of the possible gene-environment interactions found a considerable increase in CYP1A1 (rs4646903 T/C) + CYP1A2 (rs762551 A/A) and CYP1A1 (rs4646903 T/C) + SULT1A1 (rs9282861 A/A) haplotypes in conjunction with a CYP1A2 (rs762551 A/A) + SULT1A1 (rs9282861 G/A) haplotype.Conclusion. Patients with early miscarriage more frequently have the mutant allele C as well as C/T or C/C genotypes of the rs4646903 polymorphism within the CYP1A1 gene and mutant allele T (in particular within the C/T genotype) of the rs700519 polymorphism within the CYP19 gene; in contrast, C/A genotype of the rs762551 polymorphism within the CYP1A2 gene was less common in these patients. Specific risk haplotypes revealed in our study may indicate a combination of estrogen-dependent and chemically induced process caused by the bioactivation of exogenous xenobiotics in patients with early miscarriage.
Highlights
Investigation of the possible gene-environment interactions found a considerable increase in CYP1A1 + CYP1A2 and CYP1A1 + SULT1A1 haplotypes in conjunction with a CYP1A2 + SULT1A1 haplotype
Patients with early miscarriage more frequently have the mutant allele C as well as C/T or C/C genotypes of the rs4646903 polymorphism within the CYP1A1 gene and mutant allele T of the rs700519 polymorphism within the CYP19 gene; in contrast, C/A genotype of the rs762551 polymorphism within the CYP1A2 gene was less common in these patients
Specific risk haplotypes revealed in our study may indicate a combination of estrogen-dependent and chemically induced process caused by the bioactivation of exogenous xenobiotics in patients with early miscarriage
Summary
ПОЛИМОРФИЗМ ГЕНОВ CYP1A1, CYP1A2, CYP19 и SULT1A1 У ЖЕНЩИН С НЕВЫНАШИВАНИЕМ БЕРЕМЕННОСТИ В РАННИЕ СРОКИ. Определить частоту встречаемости аллельных вариантов генов, кодирующих ферменты метаболизма эстрогенов: CYP1A1 (rs4646903), CYP1A2 (rs762551), CYP19 (rs700519) и SULT1A1 (rs9282861) у женщин со спорадической потерей беременности в ранние сроки. У пациенток с выкидышем в анамнезе наблюдалось статистически значимое увеличение частоты мутантного аллеля C, гетерозиготного генотипа Т/С и гомозиготного генотипа С/С гена CYP1A1, снижение частоты гетерозиготного генотипа С/А гена CYP1A2, статистически значимые различия в частоте встречаемости мутантного аллеля Т и генотипа Т/С гена CYP19 по сравнению с контролем. Не имевших неблагоприятных исходов беременности в анамнезе, характерен гетерозиготный генотипС/A гена CYP1A2. Результаты, полученные для комбинаций генотипов, могут свидетельствовать о совокупности эстрогензависимого и химически индуцированного процесса, обусловленного биоактивацией экзогенных ксенобиотиков у пациенток с репродуктивными потерями. Ключевые слова: невынашивание беременности, полиморфизм генов CYP1A1, CYP1A2, CYP19, SULT1A1. Полиморфизм генов CYP1A1, CYP1A2, CYP19 и SULT1A1 у женщин с невынашиванием беременности в ранние сроки.
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