Dataset Information

TNFRSF11A and TNFSF11 are associated with age at menarche and natural menopause in white women.

ABSTRACT: OBJECTIVE:Menarche and menopause mark the lower and upper limits of the female reproductive period. The timing of these events influences women's health in later life. The onsets of menarche and menopause have a strong genetic basis. We tested two genes, TNFRSF11A (RANK) and TNFSF11 (RANKL), for their association with age at menarche (AM) and age at natural menopause (ANM). METHODS:Nineteen single nucleotide polymorphisms (SNPs) of TNFRSF11A and 12 SNPs of TNFSF11 were genotyped in a random sample of 306 unrelated white women. This sample was analyzed for the association of the SNPs and common haplotypes with AM. Then, a subsample of 211 women with natural menopause was analyzed for the association of both genes with ANM. Smoking, alcohol intake, and duration of lactation were applied as covariates in the association analyses. RESULTS:Three polymorphisms of TNFSF11 were associated with AM: rs2200287 (P = 0.005), rs9525641 (P = 0.039), and rs1054016 (P = 0.047). Two SNPs of this gene, rs346578 and rs9525641, showed an association with ANM (P = 0.007 and P = 0.011, respectively). Two SNPs of TNFRSF11A were associated with AM (rs3826620; P = 0.022) and ANM (rs8086340; P = 0.015). Multiple SNP-SNP and SNP-environment interaction effects on AM and ANM were detected for both genes. One polymorphism of TNFRSF11A, rs4436867, was not directly associated with either trait but indicated significant interactions with four TNFSF11 polymorphisms on ANM. Two other TNFRSF11A polymorphisms, rs4941125 and rs7235803, showed interaction effects with several TNFSF11 polymorphisms on AM. Both genes manifested significant interaction with the duration of breast-feeding in their effect on ANM. CONCLUSIONS:The TNFRSF11A and TNFSF11 genes are associated with the onset of AM and ANM in white women.

SUBMITTER: Lu Y

PROVIDER: S-EPMC2939156 | biostudies-literature | 2010 Sep-Oct

REPOSITORIES: biostudies-literature

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TNFRSF11A and TNFSF11 are associated with age at menarche and natural menopause in white women.

Lu Yan Y Liu Pengyuan P Recker Robert R RR Deng Hong-Wen HW Dvornyk Volodymyr V

Menopause (New York, N.Y.) 20100901 5

<h4>Objective</h4>Menarche and menopause mark the lower and upper limits of the female reproductive period. The timing of these events influences women's health in later life. The onsets of menarche and menopause have a strong genetic basis. We tested two genes, TNFRSF11A (RANK) and TNFSF11 (RANKL), for their association with age at menarche (AM) and age at natural menopause (ANM).<h4>Methods</h4>Nineteen single nucleotide polymorphisms (SNPs) of TNFRSF11A and 12 SNPs of TNFSF11 were genotyped i ...[more]

PMID: 20531232

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Project description:STUDY QUESTION:Is age at menarche associated with age at menopause or with duration of the reproductive period (interval between menarche and menopause)? SUMMARY ANSWER:The association of age at menarche with age at menopause was weak and non-linear, and the duration of the reproductive period decreased by increasing age at menarche. WHAT IS KNOWN ALREADY:It remains uncertain whether age at menarche is associated with age at menopause. Some studies report that women with early menarche also have early menopause. Other studies report that women with early menarche have late menopause, or they report no association. The duration of the reproductive period may be an indicator of the cumulative endogenous exposure to estrogens and progestogens during life course and is associated with risk of breast cancer and endometrial cancer. STUDY DESIGN, SIZE, DURATION:A retrospective cohort study of 336 788 women, aged 48-71 years, in the BreastScreen Norway during the years 2006-2014 was performed. PARTICIPANTS/MATERIALS, SETTING, METHODS:Information about age at menarche and menopausal status was obtained by self-administered questionnaires. We used time to event approaches to estimate the associations. MAIN RESULTS AND THE ROLE OF CHANCE:Median age at menopause was 51 years in most menarche groups. Women with menarche at age 16 years or age ? 17 years had menopause 1 year later [median: 52 years, interquartile range (IQR): 49-54 years] than women with menarche at age 13 years (median: 51 years, IQR: 49-54 years, reference) (crude hazard ratio (HR) = 0.95; 95% CI: 0.93-0.97 and 0.95; 95% CI: 0.92-0.99, Pnon-linearity < 0.001). The reproductive period decreased with increasing age at menarche (Pnon-linearity < 0.001), and women with menarche at age ? 9 years had 9 years longer median reproductive period than women with menarche at age ? 17 years (median: 43 versus 34 years). Adjustment for year of birth did not change the HR estimates notably. LARGE SCALE DATA:Not applicable. LIMITATIONS, REASONS FOR CAUTION:Information about age at menarche and age at menopause was based on self-reports. Particularly for age at menarche, the long time interval between the event and data collection may have caused imprecise reporting. WIDER IMPLICATIONS OF THE FINDINGS:Our study suggests that age at menarche is a strong indicator for the duration of women's reproductive period. Our findings should encourage studies of the independent role of duration of the reproductive period on the risk of breast cancer and endometrial cancer, since these cancers have been associated with exposure to estrogens and progestogens. STUDY FUNDING/COMPETING INTEREST(S):The present study was funded by the Norwegian Cancer Society [Grant number 6863294-2015]. The authors declare no conflicts of interest.

Project description:BackgroundHormonal reproductive factors have been suggested to play an important role in the etiology of rheumatoid arthritis (RA), an autoimmune inflammatory disorder affecting primarily women. We conducted a two-sample Mendelian randomization (MR) study examining three relevant exposures, age at menarche (AAM), age at natural menopause (ANM), and age at first birth (AFB) with the risk of RA.MethodsWe collected summary statistics from the hitherto largest GWAS conducted in AAM (N = 329,345), ANM (N = 69,360), AFB (N = 251,151), and RA (Ncase = 14,361, Ncontrol = 43,923), all of European ancestry. We constructed strong instruments using hundreds of exposure-associated genetic variants and estimated causal relationship through different MR approaches including an inverse-variance weighted method, an MR-Egger regression and a weighted median method. We conducted a multivariable MR to control for pleiotropic effect acting in particular through obesity and socioeconomic status. We also performed important sensitivity analyses to verify model assumptions.ResultsWe did not find any evidence in support for a causal association between genetically predicted reproductive factors and risk of RA (ORper-SD increment in AAM = 1.06 [0.98-1.15]; ORper-SD increment in ANM = 1.05 [0.98-1.11], OR per-SD increment in AFB = 0.85 [0.65-1.10]). Results remained consistent after removing palindromic SNPs (ORper-SD increment in AAM = 1.06 [0.97-1.15], ORper-SD increment in ANM = 1.05 [0.98-1.13], ORper-SD increment in AFB = 0.81 [0.61-1.07]) or excluding SNPs associated with potential confounding traits (ORper-SD increment in AAM = 1.03 [0.94-1.12], ORper-SD increment in ANM = 1.04 [0.95-1.14]). No outlying instrument was identified through the leave-one-out analysis.ConclusionsOur MR study does not convincingly support a casual effect of reproductive factors, as reflected by age at menarche, age at menopause, and age at first birth, on the development of RA. Despite the largely augmented set of instruments we used, these instruments only explained a modest proportion of phenotypic variance of exposures. Our knowledge regarding this topic is still insufficient and future studies with larger sample size should be designed to replicate or dispute our findings.

Dataset Information

TNFRSF11A and TNFSF11 are associated with age at menarche and natural menopause in white women.

Publications

TNFRSF11A and TNFSF11 are associated with age at menarche and natural menopause in white women.

Similar Datasets

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