Irina Ponomarenko1, Evgeny Reshetnikov2, Oksana Altuchova3, Alexey Polonikov4, Inna Sorokina1, Anna Yermachenko5, Volodymyr Dvornyk6, Oleg Golovchenko1, Mikhail Churnosov1. 1. Department of Medical Biological Disciplines, Belgorod State University, 308015 Belgorod, Russia. 2. Department of Medical Biological Disciplines, Belgorod State University, 308015 Belgorod, Russia. Electronic address: reshetnikov@bsu.edu.ru. 3. Department of Obstetrics and Gynecology, Belgorod State University, 308015 Belgorod, Russia. 4. Department of Biology, Medical Genetics and Ecology, Kursk State Medical University, 305041 Kursk, Russia. 5. Department of Social Epidemiology, Pierre Louis Institute of Epidemiology and Public Health, 75571 Paris, France; Sorbonne Universités, 75320 Paris, France. 6. Department of Life Sciences, College of Science and General Studies, Alfaisal University, 11533 Riyadh, Saudi Arabia.
Abstract
OBJECTIVES: Examine the association of genetic polymorphisms with age at menarche (AAM) in Russian women. STUDY DESIGN: A total of 1613 Russian females were recruited for the study. Fifty two polymorphisms were analyzed for their association with AAM, height, and BMI. The associations were analyzed assuming the additive, dominant, and recessive models and using the log-linear regression as implemented in PLINK v. 2.050. The 2-, 3-, and 4-loci models of gene-gene interactions were analyzed using the MB-MDR method and validated by the permutation test. MAIN OUTCOME MEASURES: Genetic polymorphism rs6438424 3q13.32 was independently associated with AAM in Russian women. In addition, 14 SNPs were determined as possible contributors to this trait through gene-gene interactions. RESULTS: The obtained results suggest that 14 out of 52 studied polymorphisms may contribute to AAM in Russian women. The rs6438424 3q13.32 polymorphism was associated with AAM according to both additive and dominant models (рperm = 0.005). In total 12 two-, three-, and four-locus models of gene-gene interactions were determined as contributing to AAM (pperm ≤ 0.006). Nine of the 14 AAM-associated SNPs are also associated with height and BMI (pperm ≤ 0.003). Among 14 AAM-associated SNPs (a priori all having regulatory significance), the highest regulatory potential was determined for rs4633 COMT, rs2164808 POMC, rs2252673INSR, rs6438424 3q13.32, and rs10769908 STK33. Eleven loci are cis-eQTL and affect expression of 14 genes in various tissues and organs (FDR < 0.05). The neuropeptide-encoding genes were overrepresented among the AAM-associated genes (pbonf = 0.039). CONCLUSIONS: The rs6438424 polymorphism is independently associated with AAM in Russian females in this study. The other 14 SNPs manifest this association through gene-gene interactions.
OBJECTIVES: Examine the association of genetic polymorphisms with age at menarche (AAM) in Russian women. STUDY DESIGN: A total of 1613 Russian females were recruited for the study. Fifty two polymorphisms were analyzed for their association with AAM, height, and BMI. The associations were analyzed assuming the additive, dominant, and recessive models and using the log-linear regression as implemented in PLINK v. 2.050. The 2-, 3-, and 4-loci models of gene-gene interactions were analyzed using the MB-MDR method and validated by the permutation test. MAIN OUTCOME MEASURES: Genetic polymorphism rs6438424 3q13.32 was independently associated with AAM in Russian women. In addition, 14 SNPs were determined as possible contributors to this trait through gene-gene interactions. RESULTS: The obtained results suggest that 14 out of 52 studied polymorphisms may contribute to AAM in Russian women. The rs6438424 3q13.32 polymorphism was associated with AAM according to both additive and dominant models (рperm = 0.005). In total 12 two-, three-, and four-locus models of gene-gene interactions were determined as contributing to AAM (pperm ≤ 0.006). Nine of the 14 AAM-associated SNPs are also associated with height and BMI (pperm ≤ 0.003). Among 14 AAM-associated SNPs (a priori all having regulatory significance), the highest regulatory potential was determined for rs4633COMT, rs2164808 POMC, rs2252673INSR, rs6438424 3q13.32, and rs10769908STK33. Eleven loci are cis-eQTL and affect expression of 14 genes in various tissues and organs (FDR < 0.05). The neuropeptide-encoding genes were overrepresented among the AAM-associated genes (pbonf = 0.039). CONCLUSIONS: The rs6438424 polymorphism is independently associated with AAM in Russian females in this study. The other 14 SNPs manifest this association through gene-gene interactions.