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1.
Hum Hered ; : 1-9, 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31480066

RESUMO

BACKGROUND: Heritability estimates (including twin and single nucleotide polymorphism [SNP]-based heritability studies) for fibroids have been inconsistent across prior studies ranging between 9 and 69%. These inconsistencies are due to variations in study design and included populations. A major design issue has been lack of imaging confirmation to identify controls, where asymptomatic women without imaging confirmation may be misclassified as controls leading to an attenuation of heritability estimates. To reconcile the differences in prior heritability estimates and the impact of misclassification of controls on heritability, we determined SNP-based heritability and characterized the genetic architecture of pelvic image-confirmed fibroid cases and controls. METHODS: Analyses were performed among women of European American descent using genome-wide SNP data from BioVU, a clinical database composed of DNA linked to de-identified electronic health records. We estimated the genetic variance explained by all SNPs using Genome-Wide Complex Trait Analysis on imputed data. Fibroid cases and controls were identified using a previously reported phenotyping algorithm that required pelvic imaging confirmation. RESULTS: In total, we used 1,067 image-confirmed fibroid cases and 1,042 image-confirmed fibroid controls. The SNP-based heritability estimate for fibroid risk was h2 = 0.33 ± 0.18 (p = 0.040). We investigated the relationship between heritability per chromosome and chromosome length (r2 < 1%), with chromosome 8 explaining the highest proportion of variance for fibroid risk. There was no enrichment for intergenic or genic SNPs for the fibroid SNP-based heritability. Excluding loci previously associated with fibroid risk from genome-wide association study did not attenuate fibroid heritability suggesting that loci associating with fibroid risk are yet to be discovered. CONCLUSIONS: We observed that fibroid SNP-based heritability was higher than the previous estimate using genome-wide SNP data that relied on self-reported outcomes, but within the range of prior twin pair studies. Furthermore, these data support that imprecise phenotyping can significantly affect the ability to estimate heritability using genotype data.

2.
Nat Commun ; 10(1): 3842, 2019 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-31451708

RESUMO

Chronic kidney disease (CKD), defined by low estimated glomerular filtration rate (eGFR), contributes to global morbidity and mortality. Here we conduct a transethnic Genome-Wide Association Study of eGFR in 280,722 participants of the Million Veteran Program (MVP), with replication in 765,289 participants from the Chronic Kidney Disease Genetics (CKDGen) Consortium. We identify 82 previously unreported variants, confirm 54 loci, and report interesting findings including association of the sickle cell allele of betaglobin among non-Hispanic blacks. Our transcriptome-wide association study of kidney function in healthy kidney tissue identifies 36 previously unreported and nine known genes, and maps gene expression to renal cell types. In a Phenome-Wide Association Study in 192,868 MVP participants using a weighted genetic score we detect associations with CKD stages and complications and kidney stones. This investigation reinterprets the genetic architecture of kidney function to identify the gene, tissue, and anatomical context of renal homeostasis and the clinical consequences of dysregulation.

3.
Pharmacotherapy ; 39(9): 889-898, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31278762

RESUMO

STUDY OBJECTIVE: The potential for maternal antidepressant use to influence the risk of spontaneous abortion, one of the most important adverse pregnancy outcomes, is not clear. We aimed to assess whether first trimester antidepressant exposure was associated with an increased risk of spontaneous abortion. DESIGN: Community-based prospective cohort study (Right from the Start). SETTING: Eight metropolitan areas in North Carolina, Tennessee, and Texas. PARTICIPANTS: A total of 5451 women (18 years of age or older) who were planning to conceive or were pregnant (before 12 weeks of completed gestation) and were enrolled in the study between 2000 and 2012; of those women, 223 used antidepressants (selective serotonin reuptake inhibitors [SSRIs] only [170], SSRIs and non-SSRIs [9], and non-SSRIs only [44]) during their first trimester, and 5228 did not (never users). Measurements and Main Results First trimester antidepressant use was determined during a first trimester telephone interview. Spontaneous abortion was self-reported and verified by medical records. The association of first trimester antidepressant use and spontaneous abortion was assessed by using Cox proportional hazard regression. Among the 5451 women enrolled, 223 (4%) reported first trimester antidepressant use, and 659 (12%) experienced a spontaneous abortion. SSRIs were the most common class of antidepressants used (179 [80%]). Compared with women who never used antidepressants during the first trimester of pregnancy, women who reported antidepressant use were 34% (adjusted hazard ratio [aHR] 1.34, 95% confidence interval [CI] 0.97-1.85) more likely to experience a spontaneous abortion after adjusting for covariates. Women who reported ever using SSRIs were 45% (aHR 1.45, 95% CI 1.02-2.06) more likely to experience a spontaneous abortion compared with never users. When time of loss relative to the time of interview was taken into consideration, the association between first trimester SSRI use and spontaneous abortion was significant only among those with losses before the interview (aHR 1.49, 95% CI 1.04-2.13) but was not significant among those with losses after the interview (aHR 0.43, 95% CI 0.06-3.15). CONCLUSION: The association between use of first trimester antidepressants, particularly SSRI use, and spontaneous abortion was significant only among women whose exposure status was assessed after loss. In this instance, reporting bias may create a spurious association. Future studies should take the timing of data collection relative to the timing of loss into consideration.

4.
Alcohol Clin Exp Res ; 43(8): 1606-1616, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31194258

RESUMO

To systematically review and critically evaluate studies reporting alcohol exposure during pregnancy and miscarriage. We searched PubMed, EMBASE, PsycINFO, and ProQuest Theses for publications from January 1970 to January 2019. We identified studies about alcohol exposure during pregnancy and miscarriage. Information about study population, alcohol exposure assessment, outcome definition, covariates, and measures of association was collected. We assessed study quality using an adapted Newcastle-Ottawa Scale. Data were abstracted by 2 investigators independently. We conducted a random-effects meta-analysis to calculate the association between alcohol exposure and miscarriage risk and performed subgroup analyses to determine robustness of results to study differences. For studies reporting dose-specific effects, a pooled dose-response association was estimated using generalized least squares regression with and without restricted cubic spline terms for number of drinks consumed per week. Of 2,164 articles identified, 24 were eligible for inclusion. Meta-analysis of data from 231,808 pregnant women finds those exposed to alcohol during pregnancy have a greater risk of miscarriage compared to those who abstained (odds ratio [OR] 1.19, 95% confidence intervals [CI] 1.12, 1.28). Estimates did not vary by study design, study country, or method of alcohol ascertainment. For alcohol use of 5 or fewer drinks per week, each additional drink per week was associated with a 6% increase in miscarriage risk (OR 1.06, 95% CI 1.01, 1.10). Common study limitations reflect challenges inherent to this research, including difficulty recruiting participants early enough in pregnancy to observe miscarriage and collecting and quantifying information about alcohol consumption during pregnancy that accurately reflects use. This review provides evidence that alcohol consumption during pregnancy is associated with a dose-mediated increase in miscarriage risk. Future studies evaluating change in alcohol use in pregnancy are needed to provide insight into how alcohol consumption prior to pregnancy recognition impacts risk.

5.
Mol Metab ; 25: 73-82, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31036449

RESUMO

OBJECTIVE: In humans, offspring of women who are overweight or obese are more likely to develop metabolic disease later in life. Studies in lower animal species reveal that a calorically-dense maternal diet is associated with alterations in islet cell mass and function. The long-term effects of maternal diet on the structure and function of offspring islets with characteristics similar to humans are unknown. We used a well-established non-human primate (NHP) model to determine the consequences of exposure to Western-Style Diet (WSD) in utero and during lactation on islet cell mass and function in the offspring. METHODS: Female Japanese Macaques (Macaca fuscata) were fed either control (CTR) or WSD before and throughout pregnancy and lactation. Offspring were weaned onto CTR or WSD to generate four different groups based on maternal/offspring diets: CTR/CTR, WSD/CTR, CTR/WSD, and WSD/WSD. Offspring were analyzed at three years of age. Pancreatic tissue sections were immunolabelled to measure α- and ß-cell mass and proliferation as well as islet vascularization. Live islets were also isolated to test the effects of WSD-exposure on islet function ex vivo. Offspring glucose tolerance was correlated with various maternal characteristics. RESULTS: α-cell mass was reduced as a result of maternal WSD exposure. α-cell proliferation was reduced in response to offspring WSD. Islet vasculature did not differ among the diet groups. Islets from WSD/CTR offspring secreted a greater amount of insulin in response to glucose ex vivo. We also found that maternal glucose tolerance and parity correlated with offspring glucose tolerance. CONCLUSIONS: Maternal WSD exposure results in persistently decreased α-cell mass in the three-year old offspring. WSD/CTR islets secreted greater amounts of insulin ex vivo, suggesting that these islets are primed to hyper-secrete insulin under certain metabolic stressors. Although WSD did not induce overt impaired glucose tolerance in dams or offspring, offspring born to mothers with higher glucose excursions during a glucose tolerance test were more likely to also show higher glucose excursions.

6.
Sci Rep ; 9(1): 6077, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30988330

RESUMO

Benign prostatic hyperplasia (BPH) results in a significant public health burden due to the morbidity caused by the disease and many of the available remedies. As much as 70% of men over 70 will develop BPH. Few studies have been conducted to discover the genetic determinants of BPH risk. Understanding the biological basis for this condition may provide necessary insight for development of novel pharmaceutical therapies or risk prediction. We have evaluated SNP-based heritability of BPH in two cohorts and conducted a genome-wide association study (GWAS) of BPH risk using 2,656 cases and 7,763 controls identified from the Electronic Medical Records and Genomics (eMERGE) network. SNP-based heritability estimates suggest that roughly 60% of the phenotypic variation in BPH is accounted for by genetic factors. We used logistic regression to model BPH risk as a function of principal components of ancestry, age, and imputed genotype data, with meta-analysis performed using METAL. The top result was on chromosome 22 in SYN3 at rs2710383 (p-value = 4.6 × 10-7; Odds Ratio = 0.69, 95% confidence interval = 0.55-0.83). Other suggestive signals were near genes GLGC, UNCA13, SORCS1 and between BTBD3 and SPTLC3. We also evaluated genetically-predicted gene expression in prostate tissue. The most significant result was with increasing predicted expression of ETV4 (chr17; p-value = 0.0015). Overexpression of this gene has been associated with poor prognosis in prostate cancer. In conclusion, although there were no genome-wide significant variants identified for BPH susceptibility, we present evidence supporting the heritability of this phenotype, have identified suggestive signals, and evaluated the association between BPH and genetically-predicted gene expression in prostate.

7.
Cancer Med ; 8(5): 2503-2513, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31001917

RESUMO

An association between genetic variants in the vitamin D receptor (VDR) gene and epithelial ovarian cancer (EOC) was previously reported in women of African ancestry (AA). We sought to examine associations between genetic variants in VDR and additional genes from vitamin D biosynthesis and pathway targets (EGFR, UGT1A, UGT2A1/2, UGT2B, CYP3A4/5, CYP2R1, CYP27B1, CYP24A1, CYP11A1, and GC). Genotyping was performed using the custom-designed 533,631 SNP Illumina OncoArray with imputation to the 1,000 Genomes Phase 3 v5 reference set in 755 EOC cases, including 537 high-grade serous (HGSOC), and 1,235 controls. All subjects are of African ancestry (AA). Logistic regression was performed to estimate odds ratios (OR) and 95% confidence intervals (CI). We further evaluated statistical significance of selected SNPs using the Bayesian False Discovery Probability (BFDP). A significant association with EOC was identified in the UGT2A1/2 region for the SNP rs10017134 (per allele OR = 1.4, 95% CI = 1.2-1.7, P = 1.2 × 10-6 , BFDP = 0.02); and an association with HGSOC was identified in the EGFR region for the SNP rs114972508 (per allele OR = 2.3, 95% CI = 1.6-3.4, P = 1.6 × 10-5 , BFDP = 0.29) and in the UGT2A1/2 region again for rs1017134 (per allele OR = 1.4, 95% CI = 1.2-1.7, P = 2.3 × 10-5 , BFDP = 0.23). Genetic variants in the EGFR and UGT2A1/2 may increase susceptibility of EOC in AA women. Future studies to validate these findings are warranted. Alterations in EGFR and UGT2A1/2 could perturb enzyme efficacy, proliferation in ovaries, impact and mark susceptibility to EOC.

8.
JAMA Cardiol ; 4(2): 136-143, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30673079

RESUMO

Importance: Thyroid hormone levels are tightly regulated through feedback inhibition by thyrotropin, produced by the pituitary gland. Hyperthyroidism is overwhelmingly due to thyroid disorders and is well recognized to contribute to a wide spectrum of cardiovascular morbidity, particularly the increasingly common arrhythmia atrial fibrillation (AF). Objective: To determine the association between genetically determined thyrotropin levels and AF. Design, Setting, and Participants: This phenome-wide association study scanned 1318 phenotypes associated with a polygenic predictor of thyrotropin levels identified by a previously published genome-wide association study that included participants of European ancestry. North American individuals of European ancestry with longitudinal electronic health records were analyzed from May 2008 to November 2016. Analysis began March 2018. Main Outcomes and Measures: Clinical diagnoses associated with a polygenic predictor of thyrotropin levels. Exposures: Genetically determined thyrotropin levels. Results: Of 37 154 individuals, 19 330 (52%) were men. The thyrotropin polygenic predictor was positively associated with hypothyroidism (odds ratio [OR], 1.10; 95% CI, 1.07-1.14; P = 5 × 10-11) and inversely associated with diagnoses related to hyperthyroidism (OR, 0.64; 95% CI, 0.54-0.74; P = 2 × 10-8 for toxic multinodular goiter). Among nonthyroid associations, the top association was AF/flutter (OR, 0.93; 95% CI, 0.9-0.95; P = 9 × 10-7). When the analyses were repeated excluding 9801 individuals with any diagnoses of a thyroid-related disease, the AF association persisted (OR, 0.91; 95% CI, 0.88-0.95; P = 2.9 × 10-6). To replicate this association, we conducted an inverse-variance weighted average meta-analysis using AF single-nucleotide variant weights from a genome-wide association study of 17 931 AF cases and 115 142 controls. As in the discovery analyses, each SD increase in predicted thyrotropin was associated with a decreased risk of AF (OR, 0.86; 95% CI, 0.79-0.93; P = 4.7 × 10-4). In a set of AF cases (n = 745) and controls (n = 1680) older than 55 years, directly measured thyrotropin levels that fell within the normal range were inversely associated with AF risk (OR, 0.91; 95% CI, 0.83-0.99; P = .04). Conclusions and Relevance: This study suggests a role for genetically determined variation in thyroid function within a physiologically accepted normal range as a risk factor for AF. The clinical decision to treat subclinical thyroid disease should incorporate the risk for AF as antithyroid medications to treat hyperthyroidism may reduce AF risk and thyroid hormone replacement for hypothyroidism may increase AF risk.

9.
Am J Epidemiol ; 2018 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-30521025

RESUMO

Time between arrest of pregnancy development and miscarriage represents a window in which pregnancy is nonviable and not developing. In effect, the loss has happened and exposures cannot influence its fate. However, epidemiologic studies of miscarriage traditionally use gestational age at miscarriage to assign time in survival analyses, which overestimates duration of exposure and time at risk. In the Right from the Start pregnancy cohort (2000-2012), we characterized the gap between estimated gestational age at arrest of development (GAAD) and miscarriage using transvaginal ultrasound in 500 women recruited from 3 states (North Carolina, Tennessee, and Texas). We compare effect estimates from models using GAAD versus gestational age at miscarriage to assign time at risk through a simulation study of 4 exposure patterns with varying effect sizes. The median gap between GAAD and miscarriage was 23 days (inter-quartile range 15-32 days). Use of GAAD decreased bias and variance of the estimated association for time-varying exposures, whereas half the time using gestational age at miscarriage led to estimates that differed from the true effect by more than 20%. Using GAAD to assign time at risk should result in more accurate and consistent characterization of miscarriage risk associated with time-varying exposures.

11.
Nat Genet ; 50(10): 1412-1425, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30224653

RESUMO

High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.

12.
Fertil Steril ; 110(4): 737-745.e34, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30196971

RESUMO

OBJECTIVE: To identify, through genome-wide association studies, genetic loci that associate with differences in fibroid size and number in a population of African American and European American women. DESIGN: Cross-sectional study. SETTING: Not applicable. PATIENT(S): Using BioVU, a clinical population from the Vanderbilt University Medical Center, and the Coronary Artery Risk Development in Young Adults cohort, a prospective cohort, we identified 1520 women (609 African American and 911 European American) with documented fibroid characteristics. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Outcome measurements include volume of largest fibroid, largest fibroid dimension, and number of fibroids (single vs. multiple). RESULT(S): In race-stratified analyses we achieved genome-wide significance at a variant located between MAT2B and TENM2 (rs57542984, ß = 0.13; 95% confidence interval 0.09, 0.17) for analyses of largest fibroid dimension in African Americans. The strongest signal for transethnic analyses was at a variant on 1q31.1 located between PLA2G4A and BRINP3 (rs6605005, ß = 0.24; 95% confidence interval 0.15, 0.33) for fibroid volume. Results from MetaXcan identified an association between predicted expression of the gene ER degradation enhancing alpha-mannosidase like protein 2 (EDEM2) in the thyroid and number of fibroids (Z score = -4.51). CONCLUSION(S): This study identified many novel associations between genetic loci and fibroid size and number in both race-stratified and transethnic analyses. Future studies are necessary to further validate our study findings and to better understand the mechanisms underlying these associations.

13.
Am J Reprod Immunol ; 80(4): e13020, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29984475

RESUMO

PROBLEM: GDM has been associated with disturbances in iron homeostasis and exaggerated immune activation. We sought to investigate the extent to which placental iron storage and macrophage accumulations were altered in GDM. METHOD OF STUDY: We conducted a retrospective, case-control study of archived placental tissues obtained from 22 pregnancies complicated by GDM and 22 unaffected controls. Controls were matched to cases based on maternal age, gestational age at birth, and method of delivery. Placental tissues were assessed for altered histology and CD68 and CD163 staining. Tissue iron was assessed using Prussian blue staining. RESULTS: Maternal hematocrit levels were higher in GDM participants compared to controls (P = 0.02). The presence of meconium-laden macrophages was significantly greater within the amnion of GDM cases (adjusted odds ratio (OR) 12.51). Although the total abundance of CD68-expressing macrophages was not significantly different between groups, we detected a significantly greater abundance of CD163 expression within the chorion and decidua of cases. The total area staining positive for iron was 24% (95% confidence intervals of 2%-46%) greater in GDM placentae versus controls. CONCLUSION: GDM is associated with altered placental histology and increases in meconium-laden macrophages. Greater iron stores within the placentae of women with GDM is consistent with reports that iron excess is associated with an increased risk for GDM. The higher level of expression of CD163 on macrophage-like cells of the chorion and decidua in GDM suggests an increase in M2-like macrophages. Overall, our results add to growing evidence that GDM has direct effects on placental structure.

14.
Maturitas ; 114: 9-13, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29907250

RESUMO

OBJECTIVE: To evaluate individual characteristics of women with fibroids in relation to fibroid size and number. METHODS: This cross-sectional study involved 2302 women (black and white, age range 18-87) with image- or surgery-confirmed fibroids from the Synthetic Derivative, a database of de-identified demographic and clinical information from patient electronic health records (EHRs) from the Vanderbilt University Medical Center. We performed multivariate regression analyses on the following outcomes: volume of largest fibroid, largest dimension of all fibroids, and number of fibroids (single vs multiple). Candidate risk factors included age at diagnosis, body mass index (BMI), race, type 2 diabetes status, and number of living children (a proxy for parity). We assessed potential effect measure modification by race and both age and BMI using a likelihood ratio test. RESULTS: Black race was strongly associated with having multiple fibroids (adjusted odds ratio [aOR]: 1.83, 95% confidence interval [CI]: 1.49, 2.24) and larger fibroid volume (adjusted beta: 1.77, 95% CI: 1.38, 2.27) and greater largest dimension (adjusted beta: 1.28, 95% CI: 1.18, 1.38). Having multiple fibroids was most strongly associated with ages 43-47 (aOR = 3.37, 95% CI: 2.55, 4.46) compared with the youngest age group (ages 18-36). Having a larger number of living children was associated with having single a fibroid (aOR: 0.88, 95% CI: 0.78, 0.99). CONCLUSIONS: Our findings suggest that different underlying etiologies are involved for women developing single versus multiple fibroids and small versus large fibroids. Studies are needed of the mechanisms by which these characteristics influence fibroid formation and growth.


Assuntos
Índice de Massa Corporal , Diabetes Mellitus Tipo 2/complicações , Leiomioma/patologia , Neoplasias Uterinas/patologia , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Diabetes Mellitus Tipo 2/patologia , Registros Eletrônicos de Saúde , Feminino , Humanos , Leiomioma/etiologia , Pessoa de Meia-Idade , Fatores de Risco , Neoplasias Uterinas/etiologia , Adulto Jovem
16.
Science ; 359(6381): 1233-1239, 2018 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-29590070

RESUMO

Genetic association studies often examine features independently, potentially missing subpopulations with multiple phenotypes that share a single cause. We describe an approach that aggregates phenotypes on the basis of patterns described by Mendelian diseases. We mapped the clinical features of 1204 Mendelian diseases into phenotypes captured from the electronic health record (EHR) and summarized this evidence as phenotype risk scores (PheRSs). In an initial validation, PheRS distinguished cases and controls of five Mendelian diseases. Applying PheRS to 21,701 genotyped individuals uncovered 18 associations between rare variants and phenotypes consistent with Mendelian diseases. In 16 patients, the rare genetic variants were associated with severe outcomes such as organ transplants. PheRS can augment rare-variant interpretation and may identify subsets of patients with distinct genetic causes for common diseases.


Assuntos
Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Predisposição Genética para Doença , Análise Mutacional de DNA , Bases de Dados Genéticas , Registros Eletrônicos de Saúde , Exoma , Estudos de Associação Genética , Variação Genética , Humanos , Fenótipo , Fatores de Risco
18.
Ann Hum Genet ; 82(4): 206-215, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29484647

RESUMO

Keloids are benign dermal tumors occurring approximately 20 times more often in individuals of African descent as compared to individuals of European descent. While most keloids occur sporadically, a genetic predisposition is supported by both familial aggregation of some keloids and large differences in risk among populations. Despite Africans and African Americans being at increased risk over lighter-skinned individuals, little genetic research exists into this phenotype. Using a combination of admixture mapping and exome analysis, we reported multiple common variants within chr15q21.2-22.3 associated with risk of keloid formation in African Americans. Here we describe a gene-based association analysis using 478 African American samples with exome genotyping data to identify genes containing low-frequency variants associated with keloids, with evaluation of genetically-predicted gene expression in skin tissues using association summary statistics. The strongest signal from gene-based association was located in C15orf63 (P-value = 6.6 × 10-6 ) located at 15q15.3. The top result from gene expression was increased predicted DCAF4 expression (P-value = 5.5 × 10-4 ) in non-sun-exposed skin, followed by increased predicted OR10A3 expression in sun-exposed skin (P-value = 6.9 × 10-4 ). Our findings identify variation with putative roles in keloid formation, enhanced by the use of predicted gene expression to support the biological roles of variation identified only though genetic association studies.

19.
Fertil Steril ; 108(6): 1034-1042.e26, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29202956

RESUMO

OBJECTIVE: To evaluate the relationship between genetic ancestry and uterine fibroid characteristics. DESIGN: Cross-sectional study. SETTING: Not applicable. PATIENT(S): A total of 609 African American participants with image- or surgery-confirmed fibroids in a biorepository at Vanderbilt University electronic health record biorepository and the Coronary Artery Risk Development in Young Adults studies were included. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Outcome measures include fibroid number (single vs. multiple), volume of largest fibroid, and largest fibroid dimension of all fibroid measurements. RESULT(S): Global ancestry meta-analyses revealed a significant inverse association between percentage of European ancestry and risk of multiple fibroids (odds ratio: 0.78; 95% confidence interval 0.66, 0.93; P=6.05 × 10-3). Local ancestry meta-analyses revealed five suggestive (P<4.80 × 10-3) admixture mapping peaks in 2q14.3-2q21.1, 3p14.2-3p14.1, 7q32.2-7q33, 10q21.1, 14q24.2-14q24.3, for number of fibroids and one suggestive admixture mapping peak (P<1.97 × 10-3) in 10q24.1-10q24.32 for volume of largest fibroid. Single variant association meta-analyses of the strongest associated region from admixture mapping of fibroid number (10q21.1) revealed a strong association at single nucleotide polymorphism variant rs12219990 (odds ratio: 0.41; 95% confidence interval 0.28, 0.60; P=3.82 × 10-6) that was significant after correction for multiple testing. CONCLUSION(S): Increasing African ancestry is associated with multiple fibroids but not with fibroid size. Local ancestry analyses identified several novel genomic regions not previously associated with fibroid number and increasing volume. Future studies are needed to explore the genetic impact that ancestry plays into the development of fibroid characteristics.


Assuntos
Afro-Americanos/genética , Biomarcadores Tumorais/genética , Leiomioma/genética , Leiomioma/patologia , Leiomiomatose/genética , Leiomiomatose/patologia , Carga Tumoral/genética , Neoplasias Uterinas/genética , Neoplasias Uterinas/patologia , Adulto , Bancos de Espécimes Biológicos , Estudos Transversais , Bases de Dados Factuais , Registros Eletrônicos de Saúde , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Hereditariedade , Humanos , Leiomioma/etnologia , Leiomiomatose/etnologia , Modelos Lineares , Modelos Logísticos , Pessoa de Meia-Idade , Razão de Chances , Fenótipo , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Estados Unidos/epidemiologia , Neoplasias Uterinas/etnologia
20.
Obstet Gynecol ; 130(6): 1312-1318, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29112656

RESUMO

OBJECTIVE: To assess whether interpregnancy interval length after a pregnancy loss is associated with risk of repeat miscarriage. METHODS: This analysis includes pregnant women participating in the Right From the Start (2000-2012) community-based prospective cohort study whose most recent pregnancy before enrollment ended in miscarriage. Interpregnancy interval was defined as the time between a prior miscarriage and the last menstrual period of the study pregnancy. Miscarriage was defined as pregnancy loss before 20 weeks of gestation. Cox proportional hazard models were used to estimate crude and adjusted hazard ratios and 95% CIs for the association between different interpregnancy interval lengths and miscarriage in the study pregnancy. Adjusted models included maternal age, race, parity, body mass index, and education. RESULTS: Among the 514 study participants who reported miscarriage as their most recent pregnancy outcome, 15.7% had a repeat miscarriage in the study pregnancy (n=81). Median maternal age was 30 years (interquartile range 27-34) and 55.6% of participants had at least one previous livebirth (n=286). When compared with women with interpregnancy intervals of 6-18 months (n=136), women with intervals of less than 3 months (n=124) had the lowest risk of repeat miscarriage (7.3% compared with 22.1%; adjusted hazard ratio 0.33, 95% CI 0.16-0.71). Neither maternal race nor parity modified the association. Attempting to conceive immediately was not associated with increased risk of miscarriage in the next pregnancy. CONCLUSION: An interpregnancy interval after pregnancy loss of less than 3 months is associated with the lowest risk of subsequent miscarriage. This implies counseling women to delay conception to reduce risk of miscarriage may not be warranted.


Assuntos
Aborto Espontâneo , Complicações na Gravidez , Medição de Risco , Aborto Espontâneo/diagnóstico , Aborto Espontâneo/epidemiologia , Aborto Espontâneo/prevenção & controle , Adulto , Intervalo entre Nascimentos/estatística & dados numéricos , Estudos de Coortes , Feminino , Humanos , Idade Materna , Paridade , Gravidez , Complicações na Gravidez/diagnóstico , Complicações na Gravidez/epidemiologia , Resultado da Gravidez/epidemiologia , Modelos de Riscos Proporcionais , Estudos Prospectivos , Medição de Risco/métodos , Medição de Risco/estatística & dados numéricos , Fatores de Risco , Tennessee/epidemiologia
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