Candidate genes for age at menarche are associated with endometriosis.

RESEARCH QUESTION: Are the candidate genes for age at menarche associated with a risk of endometriosis? DESIGN: Fifty-two candidate single nucleotide polymorphisms (SNP) for age at menarche, their gene-gene and gene-environment interactions were analysed for possible association with endometriosis in a sample of 395 patients and 981 controls. Association of the polymorphisms was analysed using logistic regression according to three main genetic models (additive, recessive and dominant). The gene-gene and gene-environment interactions were analysed for the second-, third- and fourth-order models with adjustment for covariates and multiple comparisons with subsequent cross-validation. RESULTS: Sixteen SNP for age at menarche out of the 52 studied were associated with endometriosis. Polymorphism rs6589964 BSX was associated with endometriosis according to the additive and recessive models (OR 1.27-1.47, Pperm ≤ 0.006). Fourteen SNP were associated with the disease within 12 most significant models of gene-gene interactions (Pperm ≤ 0.008). Twelve SNP involved in 10 most significant models of SNP-induced abortion interactions are associated with endometriosis. Fourteen of the 16 polymorphisms associated with endometriosis demonstrated pleiotropic effects: they were also associated with either age at menarche (7 SNP) or height and/or body mass index (10 SNP) in the studied sample. The 16 SNP associated with endometriosis and 316 SNP linked to them have regulatory and expression quantitative trait locus significance for 28 genes contributing to the G alpha signal pathway (fold enrichment 31.09, PFDR = 0.001) and responses to endogenous stimuli (fold enrichment 16.01, PFDR = 0.027). CONCLUSIONS: Sixteen SNP for age at menarche out of the 52 studied were associated with endometriosis.

Candidate genes for age at menarche are associated with endometrial hyperplasia.

OBJECTIVES: To study associations candidate genes for age at menarche with a risk of endometrial hyperplasia (EH). METHODS: 52 candidate loci for age at menarche were analyzed for possible association with EH in a sample of 520 patients and 981 controls. Association of the polymorphisms was analyzed using the method of logistic regression. The gene-gene and gene-environment interactions were analyzed using MB-MDR. 21 polymorphisms, which were associated with EH, and 397 polymorphisms linked to them (r2 ≥ 0.8) were analyzed in silico for their functional significance. RESULTS: 21 out of the 52 studied polymorphisms had association with EH. Locus rs11031010 FSHB was individually associated with the disease according to the dominant (OR = 0.62, pperm = 0.001) and additive (OR = 0.67, pperm = 0.002) models. Haplotype GAA of loci rs555621-rs11031010-rs1782507 FSHB were associated with the EH (OR = 0.66, pperm = 0.007). Seventeen loci were associated with EH within 12 most significant models of intergenic interactions (pperm ≤ 0.001). Locus rs4374421 of the LHCGR gene appeared in the largest number of models (four models). Nine loci involved in 14 most significant models of interactions between SNP, induced abortions, and chronic endometritis were associated with EH. The polymorphisms of genes FTO (rs12324955) and FSHB (rs11031010) appeared in the largest number of the models (9 and 6, respectively). Among the 21 loci associated with EH, 16 manifested association also with either age at menarche (7 SNPs) or height and/or BMI (13 SNPs). The above 21 SNPs and 397 SNPs linked to them have non-synonymous, regulatory and eQTL significance for 25 genes, which play roles in the pathways related to development of the female reproductive organs and hormone-mediated signaling (FDR ≤ 0.05). CONCLUSIONS: Candidate genes for age at menarche are associated with endometrial hyperplasia.

Unintended pregnancy prevention in women using psychoactive substances: A systematic review.

This systematic review seeks to evaluate the efficacy of interventions aimed at preventing unintended pregnancies in women using psychoactive substances. Seven electronic databases (Medline, EMBASE, CINAHL, Web of Science Core Collection, PsycINFO, Cochrane CENTRAL database) were searched in October 2017. Twenty-two articles met our inclusion criteria. Interventions based on behavior change theory yielded an increase in the initiation of effective contraception as compared with provision of written information materials. The effect was more pronounced when the intervention provided on-site contraceptive counseling and free access to birth control. Financial incentives also seemed to effectively increase women's contraception intake. Case management interventions including pregnant and postpartum women with heavy levels of substance use showed promising results in terms of initiation of contraception, but rates of unintended pregnancy over long-term follow-up were nevertheless elevated. Finally, some interventions integrated family planning services into specialized centers taking care of pregnant and postpartum women with substance abuse. However, most studies aimed at postpartum and post-abortion contraception used a non-comparative design and had a number of methodological flaws. The risk of bias in most studies is high. All interventions with a primary or secondary focus on the prevention of unintended pregnancy in women using psychoactive substances short-term improvements in contraception intake, but it is unclear if these effects last or have any impact on unintended pregnancy rates in the long-term.

Dataset of allele and genotype frequencies of five polymorphisms candidate genes analyzed for association with body mass index in Russian women.

Data on the allele and genotype frequencies of the five single nucleotide polymorphisms (SNPs) 5 genes - rs1514175 TNNI3K, rs713586 RBJ, rs887912 FANCL, rs2241423 MAP2K5, rs12444979 GPRC5B in Russian women are presented. Several genome-wide association studies identified these SNPs could be significant genetic markers associated with body mass index (BMI). Standard methods were used for collecting of the anthropometric characteristics (height and weight). We calculated the frequencies of alleles and genotypes of five SNPs in 5 groups: all samples, underweight (BMI<18.50), normal weight (18.50-24.99), overweight (25.00-29.99), obese (>30.00).

Candidate Genes for Age at Menarche Are Associated With Uterine Leiomyoma.

Age at menarche (AAM) is an important marker of the pubertal development and function of the hypothalamic-pituitary-ovarian system. It was reported as a possible factor for a risk of uterine leiomyoma (UL). However, while more than 350 loci for AAM have been determined by genome-wide association studies (GWASs) to date, no studies of these loci for their association with UL have been conducted so far. In this study, we analyzed 52 candidate loci for AAM for possible association with UL in a sample of 569 patients and 981 controls. The results of the study suggested that 23 out of the 52 studied polymorphisms had association with UL. Locus rs7759938 LIN28B was individually associated with the disease according to the dominant model. Twenty loci were associated with UL within 11 most significant models of intergenic interactions. Nine loci involved in 16 most significant models of interactions between single-nucleotide polymorphism (SNP), induced abortions, and chronic endometritis were associated with UL. Among the 23 loci associated with UL, 16 manifested association also with either AAM (7 SNPs) or height and/or body mass index (BMI) (13 SNPs). The above 23 SNPs and 514 SNPs linked to them have non-synonymous, regulatory, and expression quantitative trait locus (eQTL) significance for 35 genes, which play roles in the pathways related to development of the female reproductive organs and hormone-mediated signaling [false discovery rate (FDR) ≤ 0.05]. This is the first study reporting associations of candidate genes for AAM with UL.

Dataset of allele, genotype and haplotype frequencies of four LIN28B gene polymorphisms analyzed for association with age at menarche in Russian women.

In this paper, we present the allele, genotype and haplotype frequencies of 4 single nucleotide polymorphisms (SNPs) in LIN28B gene (rs4946651, rs7759938, rs314280, rs314276) in a sample of Russian women. These SNPs had been previously identified to be associated with age at menarche in genome-wide association studies (GWAS). The information about age at menarche was obtained using the questionnaire. The frequencies of alleles, genotypes and haplotypes of four SNPs were classified in 3 groups: the whole sample, individuals with the early age at menarche (<12 years), and those with the average age at menarche (12-14 years).

Maternal immigrant status and signs of neurodevelopmental problems in early childhood: The French representative ELFE birth cohort.

A growing body of evidence suggests that children of immigrants may have increased risks of neurodevelopmental disorders. However, evidence based on parent report and on very young children is lacking. We therefore investigated the association between maternal immigrant status and early signs of neurodevelopmental problems in a population-based sample of 2-year-old children using standardized parent-report instruments. We used data from the French representative Étude Longitudinale Française depuis l'Enfance birth cohort, initiated in 2011. The study sample included 9,900 children of nonimmigrant French, 1,403 children of second, and 1,171 children of first generation immigrant women followed-up to age 2 years. Neurodevelopment was assessed using the Modified Checklist for Autism in Toddlers (M-CHAT) and an adaptation of the MacArthur-Bates Communicative Development Inventories (MB-CDI). In fully adjusted linear regression models, maternal immigrant status was associated with M-CHAT scores, with stronger associations in children of first (ß-coefficient: 0.19; 95% CI 0.08-0.29) than second generation immigrants (0.09; 0.01-0.17). This association was especially strong among children of first generation immigrant mothers native of North Africa (vs. nonimmigrant French: 0.33; 0.16-0.49) and French-speaking Sub-Saharan Africa (0.26; 0.07-0.45). MB-CDI scores were lowest among children of first generation immigrant mothers, particularly from mostly non-francophone regions. Children of first generation immigrant mothers were most likely to have simultaneously low MB-CDI and high M-CHAT scores. Our findings suggest that maternal immigrant status is associated with early signs of neurodevelopmental difficulties, with strong variations according to maternal region of origin. Further research is necessary to test whether these associations persist and to determine the underlying mechanisms. Autism Res 2019, 12: 1845-1859. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: We asked immigrant and nonimmigrant mothers in France about early signs of neurodevelopmental problems in their 2-year-old children. Overall, we found that children of immigrants may be at higher risk of showing these early warning signs, as compared to children of nonimmigrants. This is in line with previous studies, which were based on doctors' diagnoses at later ages. However, our results differed depending on the mothers' regions of origin. We found the highest risks in children of first generation immigrants from North and French-speaking Sub-Saharan Africa, who also seemed especially at risk of neurodevelopmental problems combined with low language development.

Association of genetic polymorphisms with age at menarche in Russian women.

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.

Non-genetic risk factors for early and late age at menarche in Eastern Ukrainian females.

ABSTRACT: BACKGROUND: Age at menarche is a reproductive trait, which is largely influenced by environmental factors. Each population has a set of lifestyle factors that may shift age at menarche in different direction. Populations of Eastern Slavs, particularly Ukrainians, are underrepresented in studies of reproductive health. The objective of the present research was to determine important non-genetic risk factors, which may contribute to menarcheal onset in Eastern Ukrainians. METHODS: In total 620 females aged 17-25 years participated in the cross-sectional survey. The questionnaire included lifestyle factors previously reported in other populations as those, which might affect age at menarche. The risk factors for early and late age at menarche were determined using logistic regression models. The models were validated by receiver operating curves. RESULTS: Body composition in the prepubertal stage as presented by responders seems to have the strongest association with age at menarche. Those who were shorter and thinner as compared to their peers at age six had significantly more chance to start menstruating later (OR = 1.66, 95% CI [1.01-2.73]) and reduced chance to have menarche before 12 years old (OR = 0.32, 95% CI [0.14-0.73]). Maternal smoking during pregnancy and low protein intake reported during childhood may decrease a probability of late age at menarche. CONCLUSIONS: Although overall body composition at age of six was a main trait, which was associated with menarcheal timing, more information on body measurements (e.g. waist-hip ratio) in prepubertal stage would help to establish a greater degree of accuracy on this matter.

UGT2B4 previously implicated in the risk of breast cancer is associated with menarche timing in Ukrainian females.

Age at menarche (AAM) is a multifactorial trait that is regulated by dozens environmental and genetic factors. Recent meta-analysis of GWAS showed significant association of 106 loci with AAM. These polymorphisms need replicating in different ethnic populations in order to confirm their association with menarche timing. This study was aimed to replicate 53 polymorphisms that were previously associated with AAM. DNA samples were collected from 416 Ukrainian young females for further genotyping. After data quality control 47 polymorphisms remained for the association analysis using the linear regression model. SNP rs13111134 located in UGT2B4 showed the most significant association with AAM (0.431years per allele A, padj=0.044 after the Bonferroni correction). Polymorphisms rs7589318 in POMC, rs11724758 in FABP2, rs7753051 in IGF2R, rs2288696 in FGFR1 and rs12444979 in GPRC5B may also contribute to menarche timing. However, none of these associations remained significant after the Bonferroni correction for multiple testing. The obtained results provide evidence that UGT2B4, which was previously associated with predisposition to breast cancer, may play a role in the onset of menarche.

A meta-analysis provides evidence that prenatal smoking exposure decreases age at menarche.

Since studies of association between prenatal tobacco exposure and age at menarche have reported inconsistent results so far, we conducted a meta-analysis to examine this association. In total 36 relevant articles (1995-2014) were identified, 17 of which satisfied the inclusion criteria and were used in the analysis. Nearly one month decrease (-0.092 [95%CI:-0.160, -0.024] year) in age at menarche was found in women who were exposed to tobacco in utero. The meta-regression analysis showed that average year of birth in the cohorts might significantly influence association between maternal smoking and daughter's age at menarche. Based on results obtained from 5 studies where age at menarche was treated as a categorical variable, maternal smoking status during pregnancy increased a risk for daughters to have menarche earlier than at 11 years old by 15%.

Nongenetic determinants of age at menarche: a systematic review.

BACKGROUND: The acceleration of pubertal development is an important medical and social problem, as it may result in increased morbidity and mortality in later life. This systematic review summarizes relevant data about nongenetic factors, which contribute to age at menarche (AAM), and suggests those which may be the most important. METHODS: The available literature from 1980 till July 2013 was searched using PubMed and Google Scholar databases. Finally, 154 papers were selected for the analysis. RESULTS: Environmental factors, which may affect AAM, vary in populations of different ethnicity. The prenatal, infancy, and early childhood periods are the most susceptible to these factors. Body weight, high animal protein intake, family stressors (e.g., single parenting), and physical activity seem to influence AAM in most populations. CONCLUSIONS: The data about influence of nongenetic factors on AAM are still inconsistent. The factors affecting prenatal and early childhood growth seem to have a larger effect on further sexual maturation. Further studies are needed in order to validate the association between other environmental determinants and AAM in different ethnical groups.