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1.
JAMA ; 322(7): 632-641, 2019 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-31429897

RESUMO

Importance: Maternal hypothyroidism and hyperthyroidism are risk factors for preterm birth. Milder thyroid function test abnormalities and thyroid autoimmunity are more prevalent, but it remains controversial if these are associated with preterm birth. Objective: To study if maternal thyroid function test abnormalities and thyroid autoimmunity are risk factors for preterm birth. Data Sources and Study Selection: Studies were identified through a search of the Ovid MEDLINE, EMBASE, Web of Science, the Cochrane Central Register of Controlled Trials, and Google Scholar databases from inception to March 18, 2018, and by publishing open invitations in relevant journals. Data sets from published and unpublished prospective cohort studies with data on thyroid function tests (thyrotropin [often referred to as thyroid-stimulating hormone or TSH] and free thyroxine [FT4] concentrations) or thyroid peroxidase (TPO) antibody measurements and gestational age at birth were screened for eligibility by 2 independent reviewers. Studies in which participants received treatment based on abnormal thyroid function tests were excluded. Data Extraction and Synthesis: The primary authors provided individual participant data that were analyzed using mixed-effects models. Main Outcomes and Measures: The primary outcome was preterm birth (<37 weeks' gestational age). Results: From 2526 published reports, 35 cohorts were invited to participate. After the addition of 5 unpublished data sets, a total of 19 cohorts were included. The study population included 47 045 pregnant women (mean age, 29 years; median gestational age at blood sampling, 12.9 weeks), of whom 1234 (3.1%) had subclinical hypothyroidism (increased thyrotropin concentration with normal FT4 concentration), 904 (2.2%) had isolated hypothyroxinemia (decreased FT4 concentration with normal thyrotropin concentration), and 3043 (7.5%) were TPO antibody positive; 2357 (5.0%) had a preterm birth. The risk of preterm birth was higher for women with subclinical hypothyroidism than euthyroid women (6.1% vs 5.0%, respectively; absolute risk difference, 1.4% [95% CI, 0%-3.2%]; odds ratio [OR], 1.29 [95% CI, 1.01-1.64]). Among women with isolated hypothyroxinemia, the risk of preterm birth was 7.1% vs 5.0% in euthyroid women (absolute risk difference, 2.3% [95% CI, 0.6%-4.5%]; OR, 1.46 [95% CI, 1.12-1.90]). In continuous analyses, each 1-SD higher maternal thyrotropin concentration was associated with a higher risk of preterm birth (absolute risk difference, 0.2% [95% CI, 0%-0.4%] per 1 SD; OR, 1.04 [95% CI, 1.00-1.09] per 1 SD). Thyroid peroxidase antibody-positive women had a higher risk of preterm birth vs TPO antibody-negative women (6.6% vs 4.9%, respectively; absolute risk difference, 1.6% [95% CI, 0.7%-2.8%]; OR, 1.33 [95% CI, 1.15-1.56]). Conclusions and Relevance: Among pregnant women without overt thyroid disease, subclinical hypothyroidism, isolated hypothyroxinemia, and TPO antibody positivity were significantly associated with higher risk of preterm birth. These results provide insights toward optimizing clinical decision-making strategies that should consider the potential harms and benefits of screening programs and levothyroxine treatment during pregnancy.


Assuntos
Doenças Autoimunes/diagnóstico , Iodeto Peroxidase/imunologia , Complicações na Gravidez/diagnóstico , Nascimento Prematuro/etiologia , Doenças da Glândula Tireoide/diagnóstico , Testes de Função Tireóidea , Adulto , Autoanticorpos/sangue , Doenças Autoimunes/sangue , Doenças Autoimunes/complicações , Feminino , Idade Gestacional , Humanos , Hipotireoidismo/complicações , Hipotireoidismo/diagnóstico , Recém-Nascido , Gravidez , Complicações na Gravidez/sangue , Doenças da Glândula Tireoide/sangue , Doenças da Glândula Tireoide/complicações , Tireotropina/sangue , Tiroxina/sangue
2.
J Bone Miner Res ; 34(7): 1284-1296, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30888730

RESUMO

Hip geometry is an important predictor of fracture. We performed a meta-analysis of GWAS studies in adults to identify genetic variants that are associated with proximal femur geometry phenotypes. We analyzed four phenotypes: (i) femoral neck length; (ii) neck-shaft angle; (iii) femoral neck width, and (iv) femoral neck section modulus, estimated from DXA scans using algorithms of hip structure analysis. In the Discovery stage, 10 cohort studies were included in the fixed-effect meta-analysis, with up to 18,719 men and women ages 16 to 93 years. Association analyses were performed with ∼2.5 million polymorphisms under an additive model adjusted for age, body mass index, and height. Replication analyses of meta-GWAS significant loci (at adjusted genomewide significance [GWS], threshold p ≤ 2.6 × 10-8 ) were performed in seven additional cohorts in silico. We looked up SNPs associated in our analysis, for association with height, bone mineral density (BMD), and fracture. In meta-analysis (combined Discovery and Replication stages), GWS associations were found at 5p15 (IRX1 and ADAMTS16); 5q35 near FGFR4; at 12p11 (in CCDC91); 11q13 (near LRP5 and PPP6R3 (rs7102273)). Several hip geometry signals overlapped with BMD, including LRP5 (chr. 11). Chr. 11 SNP rs7102273 was associated with any-type fracture (p = 7.5 × 10-5 ). We used bone transcriptome data and discovered several significant eQTLs, including rs7102273 and PPP6R3 expression (p = 0.0007), and rs6556301 (intergenic, chr.5 near FGFR4) and PDLIM7 expression (p = 0.005). In conclusion, we found associations between several genes and hip geometry measures that explained 12% to 22% of heritability at different sites. The results provide a defined set of genes related to biological pathways relevant to BMD and etiology of bone fragility. © 2019 American Society for Bone and Mineral Research.

3.
Sci Rep ; 9(1): 1052, 2019 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-30705363

RESUMO

Paget's disease of bone (PDB) is characterised by focal abnormalities of bone remodelling, with increased osteoclastic resorption the primary feature of the disease. Genetic factors have been shown to play an important role in PDB, and genome-wide association studies (GWAS) have identified 7 genetic loci as associated with PDB at the genome-wide level. Expression quantitative trait locus (eQTL) studies using cell types that are directly relevant to the disease of interest are increasingly being used to identify putative effector genes for GWAS loci. We have recently constructed a unique osteoclast-specific eQTL resource using cells differentiated in vitro from 158 subjects for study of the genetics of bone disease. Considering the major role osteoclasts have in PDB, we used this resource to investigate potential genetic regulatory effects for the 7 PDB genome-wide significant loci on genes located within 500 kb of each locus. After correction for multiple testing, we observed statistically significant associations for rs4294134 with expression of the gene STMP1, and rs2458413 with expression of the genes DPYS and DCSTAMP. The eQTL associations observed for rs4294134 with STMP1, and rs2458413 with DCSTAMP were further supported by eQTL data from other tissue types. The product of the STMP1 gene has not been extensively studied, however the DCSTAMP gene has an established role in osteoclast differentiation and the associations seen between rs2458413 and PDB are likely mediated through regulatory effects on this gene. This study highlights the value of eQTL data in determining which genes are relevant to GWAS loci.

4.
Nat Commun ; 9(1): 4455, 2018 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-30367059

RESUMO

Thyroid dysfunction is an important public health problem, which affects 10% of the general population and increases the risk of cardiovascular morbidity and mortality. Many aspects of thyroid hormone regulation have only partly been elucidated, including its transport, metabolism, and genetic determinants. Here we report a large meta-analysis of genome-wide association studies for thyroid function and dysfunction, testing 8 million genetic variants in up to 72,167 individuals. One-hundred-and-nine independent genetic variants are associated with these traits. A genetic risk score, calculated to assess their combined effects on clinical end points, shows significant associations with increased risk of both overt (Graves' disease) and subclinical thyroid disease, as well as clinical complications. By functional follow-up on selected signals, we identify a novel thyroid hormone transporter (SLC17A4) and a metabolizing enzyme (AADAT). Together, these results provide new knowledge about thyroid hormone physiology and disease, opening new possibilities for therapeutic targets.

5.
PLoS One ; 13(4): e0196631, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29709030

RESUMO

OBJECTIVE: Guidelines for thyroid function evaluation recommend testing TSH first, then assessing fT4 only if TSH is out of the reference range (two-step), but many clinicians initially request both TSH and fT4 (one-step). Given limitations of previous studies, we aimed to compare the two-step with the one-step approach in an unselected community-dwelling study population, and develop a prediction score based on clinical parameters that could identify at-risk patients for thyroid dysfunction. DESIGN: Cross-sectional analysis of the population-based Busselton Health Study. METHODS: We compared the two-step with the one-step approach, focusing on cases that would be missed by the two-step approach, i.e. those with normal TSH, but out-of-range fT4. We used likelihood ratio tests to identify demographic and clinical parameters associated with thyroid dysfunction and developed a clinical prediction score by using a beta-coefficient based scoring method. RESULTS: Following the two-step approach, 93.0% of all 4471 participants had normal TSH and would not need further testing. The two-step approach would have missed 3.8% of all participants (169 of 4471) with a normal TSH, but a fT4 outside the reference range. In 85% (144 of 169) of these cases, fT4 fell within 2 pmol/l of fT4 reference range limits, consistent with healthy outliers. The clinical prediction score that performed best excluded only 22.5% of participants from TSH testing. CONCLUSION: The two-step approach may avoid measuring fT4 in as many as 93% of individuals with a very small risk of missing thyroid dysfunction. Our findings do not support the simultaneous initial measurement of both TSH and fT4.


Assuntos
Doenças da Glândula Tireoide/sangue , Doenças da Glândula Tireoide/diagnóstico , Tireotropina/sangue , Tiroxina/sangue , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Feminino , Humanos , Hipertireoidismo/sangue , Hipotireoidismo/sangue , Funções Verossimilhança , Masculino , Pessoa de Meia-Idade , Valores de Referência , Estudos Retrospectivos , Sensibilidade e Especificidade , Austrália Ocidental , Adulto Jovem
6.
J Bone Miner Res ; 33(6): 1044-1051, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29473973

RESUMO

Osteoporosis is a complex disease with a strong genetic component. Genomewide association studies (GWAS) have been very successful at identifying common genetic variants associated with bone parameters. A recently published study documented the results of the largest GWAS for bone mineral density (BMD) performed to date (n = 142,487), identifying 307 conditionally independent single-nucleotide polymorphisms (SNPs) as associated with estimated BMD (eBMD) at the genomewide significance level. The vast majority of these variants are non-coding SNPs. Expression quantitative trait locus (eQTL) studies using disease-specific cell types have increasingly been integrated with the results from GWAS to identify genes through which the observed GWAS associations are likely mediated. We generated a unique human osteoclast-specific eQTL data set using cells differentiated in vitro from 158 participants. We then used this resource to characterize the 307 recently identified BMD GWAS SNPs for association with nearby genes (±500 kb). After correction for multiple testing, 24 variants were found to be significantly associated with the expression of 32 genes in the osteoclast-like cells. Bioinformatics analysis suggested that these variants and those in strong linkage disequilibrium with them are enriched in regulatory regions. Several of the eQTL associations identified are relevant to genes that present strongly as having a role in bone, particularly IQGAP1, CYP19A1, CTNNB1, and COL6A3. Supporting evidence for many of the associations was obtained from publicly available eQTL data sets. We have also generated strong evidence for the presence of a regulatory region on chromosome 15q21.2 relevant to both the GLDN and CYP19A1 genes. In conclusion, we have generated a unique osteoclast-specific eQTL resource and have used this to identify 32 eQTL associations for recently identified BMD GWAS loci, which should inform functional studies of osteoclast biology. © 2018 American Society for Bone and Mineral Research.

7.
J Cell Physiol ; 233(1): 38-56, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28419469

RESUMO

The mechanisms responsible for the processing and quality control of the calcium-sensing receptor (CaSR) in the endoplasmic reticulum (ER) are largely unknown. In a yeast two-hybrid screen of the CaSR C-terminal tail (residues 865-1078), we identified osteosarcoma-9 (OS-9) protein as a binding partner. OS-9 is an ER-resident lectin that targets misfolded glycoproteins to the ER-associated degradation (ERAD) pathway through recognition of specific N-glycans by its mannose-6-phosphate receptor homology (MRH) domain. We show by confocal microscopy that the CaSR and OS-9 co-localize in the ER in COS-1 cells. In immunoprecipitation studies with co-expressed OS-9 and CaSR, OS-9 specifically bound the immature form of wild-type CaSR in the ER. OS-9 also bound the immature forms of a CaSR C-terminal deletion mutant and a C677A mutant that remains trapped in the ER, although binding to neither mutant was favored over wild-type receptor. OS-9 binding to immature CaSR required the MRH domain of OS-9 indicating that OS-9 acts as a lectin most likely to target misfolded CaSR to ERAD. Our results also identify two distinct binding interactions between OS-9 and the CaSR, one involving both C-terminal domains of the two proteins and the other involving both N-terminal domains. This suggests the possibility of more than one functional interaction between OS-9 and the CaSR. When we investigated the functional consequences of altered OS-9 expression, neither knockdown nor overexpression of OS-9 was found to have a significant effect on CaSR cell surface expression or CaSR-mediated ERK1/2 phosphorylation.


Assuntos
Retículo Endoplasmático/metabolismo , Lectinas/metabolismo , Proteínas de Neoplasias/metabolismo , Receptores de Detecção de Cálcio/metabolismo , Animais , Células COS , Cercopithecus aethiops , Degradação Associada com o Retículo Endoplasmático , Glicosilação , Células HEK293 , Humanos , Imunoprecipitação , Lectinas/genética , Microscopia Confocal , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Mutação , Proteínas de Neoplasias/genética , Fosforilação , Ligação Proteica , Dobramento de Proteína , Domínios e Motivos de Interação entre Proteínas , Proteólise , Interferência de RNA , Receptores de Detecção de Cálcio/genética , Transfecção , Técnicas do Sistema de Duplo-Híbrido
8.
Ann Hum Genet ; 82(2): 109-113, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29058319

RESUMO

The ability to perform whole-exome and, increasingly, whole-genome sequencing on large numbers of individuals has led to increased efforts to identify rare genetic variants that affect the risk of both common and rare diseases. In such applications, it is important to identify families that are segregating the rare variants of interest. For rare diseases or rare familial forms of common diseases, pedigrees with multiple affected members are clearly harbouring risk variants. For more common diseases, however, it may be unclear whether a family with a few affected members is segregating a familial disease, is the result of multiple sporadic cases, or is a mixture of familial cases and phenocopies. We provide calculations for the probability that a family is harbouring familial disease, presented in general terms that admit working guidelines for selecting families for current sequencing studies. Using examples motivated by our own studies of thyroid cancer and published studies of colorectal cancer, we show that for common diseases, families with exactly two affected first-degree relatives have only a moderate probability of segregating familial disease, but this probability is higher for families with three or more affected relatives, and those families should therefore be prioritised in sequencing studies.

9.
J Clin Endocrinol Metab ; 102(11): 4235-4241, 2017 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-28938415

RESUMO

Context: Thyroid function testing often uses thyrotropin (TSH) measurement first, followed by reflex testing for free thyroxine (T4) if TSH is outside the reference range. The utility of different TSH cutoffs for reflex testing is unknown. Objective: To examine different TSH cutoffs for reflex free T4 testing. Design, Setting, and Patients: We analyzed concurrent TSH and free T4 results from 120,403 individuals from a single laboratory in Western Australia (clinical cohort) and 4568 Busselton Health Study participants (community cohort). Results: In the clinical cohort, restricting free T4 measurement to individuals with TSH <0.3 or >5.0 mU/L resulted in a 22% reduction in free T4 testing compared with a TSH reference range of 0.4 to 4.0 mU/L; using TSH cutoffs of 0.2 and 6.0 mU/L resulted in a 34% reduction in free T4 testing. In the community cohort, the corresponding effect was less: 3.3% and 4.8% reduction in free T4 testing. In the clinical cohort, using TSH cutoffs of 0.2 and 6.0 mU/L, elevated free T4 would go undetected in 4.2% of individuals with TSH levels of 0.2 to 0.4 mU/L. In most, free T4 was marginally elevated and unlikely to indicate clinically relevant hyperthyroidism. Low free T4 would go undetected in 2.5% of individuals with TSH levels of 4 to 6 mU/L; in 94%, free T4 was marginally reduced and unlikely to indicate clinically relevant hypothyroidism. Conclusions: Setting TSH cutoffs at 0.1 to 0.2 mU/L less than and 1 to 2 mU/L greater than the reference range for reflex testing of free T4 would reduce the need for free T4 testing, with minimal effect on case finding.


Assuntos
Testes de Função Tireóidea/estatística & dados numéricos , Testes de Função Tireóidea/normas , Tireotropina/sangue , Tiroxina/análise , Tiroxina/sangue , Adulto , Idoso , Feminino , Humanos , Hipertireoidismo/sangue , Hipertireoidismo/diagnóstico , Hipotireoidismo/sangue , Hipotireoidismo/diagnóstico , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Curva ROC , Racionalização , Valores de Referência , Sensibilidade e Especificidade , Glândula Tireoide/fisiologia
10.
Eur J Endocrinol ; 177(4): 297-308, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28684452

RESUMO

CONTEXT: Thyroid hormones modulate proliferative, metabolic and angiogenic pathways. However few studies have examined associations of thyroid hormones with cancer risk. OBJECTIVES: To explore associations of thyrotropin (TSH), free thyroxine (FT4) and anti-thyroperoxidase antibodies (TPOAb) with the incidence of all (non-skin) cancers and specific common cancers. DESIGN AND SETTING: A prospective cohort study of a community-dwelling population aged 25-84 years in Western Australia. MAIN OUTCOME MEASURES: Archived sera from 3649 participants in the 1994/1995 Busselton Health Survey were assayed for TSH, FT4 and TPOAb. Cancer outcomes until 30 June 2014 were ascertained using data linkage. Longitudinal analyses were performed using Cox proportional hazards regression. RESULTS: During 20-year follow-up, 600 participants were diagnosed with non-skin cancer, including 126, 100, 103 and 41 prostate, breast, colorectal and lung cancers respectively. Higher TSH was associated with a lower risk of prostate cancer after adjusting for potential confounders, with a 30% lower risk for every 1 IU/L increase in TSH (adjusted hazard ratio (HR): 0.70, 95% confidence interval (CI): 0.55-0.90, P = 0.005). Similarly, higher FT4 was associated with an increased risk of prostate cancer (adjusted HR: 1.11 per 1 pmol/L increase, 95% CI: 1.03-1.19, P = 0.009). There were no associations of TSH, FT4 or TPOAb with all non-skin cancer events combined, or with breast, colorectal or lung cancer. CONCLUSION: In a community-dwelling population, lower TSH and higher FT4 were associated with an increased risk of prostate cancer. Further studies are required to assess if thyroid function is a biomarker or risk factor for prostate cancer.


Assuntos
Neoplasias da Mama/sangue , Neoplasias Colorretais/sangue , Neoplasias Pulmonares/sangue , Neoplasias da Próstata/sangue , Tireotropina/sangue , Tiroxina/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/sangue , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/epidemiologia , Estudos de Coortes , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/epidemiologia , Feminino , Seguimentos , Humanos , Incidência , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/epidemiologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/epidemiologia , Características de Residência , Fatores de Risco , Austrália Ocidental/epidemiologia
11.
Hum Mol Genet ; 26(14): 2791-2802, 2017 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-28472463

RESUMO

Osteoporosis is a common and debilitating bone disease that is characterised by low bone mineral density, typically assessed using dual-energy X-ray absorptiometry. Quantitative ultrasound (QUS), commonly utilising the two parameters velocity of sound (VOS) and broadband ultrasound attenuation (BUA), is an alternative technology used to assess bone properties at peripheral skeletal sites. The genetic influence on the bone qualities assessed by QUS remains an under-studied area. We performed a comprehensive genome-wide association study (GWAS) including low-frequency variants (minor allele frequency ≥0.005) for BUA and VOS using a discovery population of individuals with whole-genome sequence (WGS) data from the UK10K project (n = 1268). These results were then meta-analysed with those from two deeply imputed GWAS replication cohorts (n = 1610 and 13 749). In the gender-combined analysis, we identified eight loci associated with BUA and five with VOS at the genome-wide significance level, including three novel loci for BUA at 8p23.1 (PPP1R3B), 11q23.1 (LOC387810) and 22q11.21 (SEPT5) (P = 2.4 × 10-8 to 1.6 × 10-9). Gene-based association testing in the gender-combined dataset revealed eight loci associated with BUA and seven with VOS after correction for multiple testing, with one novel locus for BUA at FAM167A (8p23.1) (P = 1.4 × 10-6). An additional novel locus for BUA was seen in the male-specific analysis at DEFB103B (8p23.1) (P = 1.8 × 10-6). Fracture analysis revealed significant associations between variation at the WNT16 and RSPO3 loci and fracture risk (P = 0.004 and 4.0 × 10-4, respectively). In conclusion, by performing a large GWAS meta-analysis for QUS parameters of bone using a combination of WGS and deeply imputed genotype data, we have identified five novel genetic loci associated with BUA.


Assuntos
Osteoporose/diagnóstico por imagem , Ultrassonografia/métodos , Absorciometria de Fóton , Adulto , Idoso , Idoso de 80 Anos ou mais , Densidade Óssea , Calcâneo/diagnóstico por imagem , Feminino , Fraturas Ósseas/diagnóstico por imagem , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade
12.
Fertil Steril ; 106(5): 1258-1263, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27456547

RESUMO

OBJECTIVE: To examine the prevalence of a history of polycystic ovary syndrome (PCOS) in women with type 2 diabetes (DM2) and to compare metabolic and reproductive outcomes between women with and without PCOS. DESIGN: Cross-sectional study. SETTING: Tertiary hospital. PATIENT(S): Female inpatients age 18-75 years with DM2. INTERVENTION(S): A face-to-face questionnaire was administered. MAIN OUTCOME MEASURE(S): Age at diagnosis of diabetes, history of gestational diabetes, family history of diabetes, and reproductive history, fertility history, number of miscarriages, and morbidity in pregnancy. RESULT(S): One hundred seventy-one inpatients with DM2 participated. The prevalence of a history of PCOS was 37%. Women with PCOS had an earlier mean age of diagnosis of DM2 (44.2 vs. 48.8 years), higher recalled peak body mass index (BMI; 43.1 kg/m2 vs. 36.8 kg/m2), higher rate of gestational diabetes (28% vs. 18%), and higher rate of hypertension in pregnancy (40% vs. 22%). Women with PCOS were less likely to have a family history of DM2 than those without PCOS (45% vs. 67%). CONCLUSION(S): A history of PCOS in women with DM2 is associated with earlier onset of DM2, higher BMI, and a more severe phenotype. Since PCOS subjects were less likely to have a family history of DM2, lack of a family history of DM2 in women with PCOS is not reassuring for DM2 risk. We recommend identifying PCOS in early life and intervening to reduce the risk of diabetes and its comorbidities and suboptimal reproductive outcomes.


Assuntos
Diabetes Mellitus Tipo 2/epidemiologia , Síndrome do Ovário Policístico/epidemiologia , Adulto , Idade de Início , Idoso , Índice de Massa Corporal , Comorbidade , Estudos Transversais , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/genética , Feminino , Fertilidade , Predisposição Genética para Doença , Humanos , Pessoa de Meia-Idade , Paridade , Fenótipo , Síndrome do Ovário Policístico/sangue , Síndrome do Ovário Policístico/diagnóstico , Gravidez , Prevalência , Fatores de Risco , Índice de Gravidade de Doença , Inquéritos e Questionários , Centros de Atenção Terciária , Fatores de Tempo , Austrália Ocidental/epidemiologia , Adulto Jovem
13.
Fertil Steril ; 106(5): 1230-1237, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27351446

RESUMO

OBJECTIVE: To quantify intraindividual variability of antimüllerian hormone (AMH) as analytical and biological coefficients of variation and assess the effects of variation on clinical classification. DESIGN: Retrospective cohort study. SETTING: Not applicable. PATIENT(S): Thirty-eight women referred by general practitioners. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Total intraindividual variability (CVW), analytical (CVA) and biological variability (CVI) for each woman and for AMH ranges: low (<5 pmol/L), reduced (5-10), moderate (>10-30) and high (>30 pmol/L), with calculation of proportion of women crossing clinical cutoffs and expected variability around each cutoff. RESULT(S): Cycling women (n = 38) contributed 238 blood samples (average 6 samples each). The average total intraindividual AMH variability was 20% (range: 2.1% to 73%). Biological variation was 19% (range: 0 to 71%) and at least twice the analytical variation of 6.9% (range: 4.5% to 16%). Reclassification rates were highest in women with low (33%) or reduced AMH (67%) levels. Expected variations around the 5, 10, and 30 pmol/L cutoffs were 3-7, 7-13, and 20-40 pmol/L, respectively. In a woman with mean AMH in the 10-30 pmol/L range, the span of results that could occur was 7-40 pmol/L. CONCLUSION(S): Total variation in AMH was 20%, and the majority of this was biological. Changes in AMH resulted in reclassification in 29% of women and occurred most frequently in those with low and reduced AMH. In cycling women, the variability in AMH should be considered by clinicians, especially if a result is close to a clinical cutoff.


Assuntos
Hormônio Antimülleriano/sangue , Ciclo Menstrual/sangue , Adulto , Biomarcadores/sangue , Feminino , Humanos , Estudos Retrospectivos , Fatores de Tempo , Adulto Jovem
15.
Clin Endocrinol (Oxf) ; 85(5): 789-796, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27197788

RESUMO

BACKGROUND: The TSH-T4 relationship was thought to be inverse log-linear, but recent cross-sectional studies of selected populations report a complex, nonlinear relationship. The TSH-T4 relationship has not been evaluated in an unselected, community-based cohort, and there are limited data regarding clinical factors which affect it. OBJECTIVE: To analyse the TSH-free T4 relationship in a community-based cohort. DESIGN, PARTICIPANTS AND METHODS: In a cross-sectional, retrospective study, we analysed serum TSH and free T4 concentrations from 4427 participants (55% female) in the 1994 Busselton Health Study who were not taking thyroxine. Simple linear, segmented-linear and nonlinear regression models of log10 TSH on free T4 were compared for goodness of fit. RESULTS: All 5 log TSH-free T4 models tested (separate lines, segmented conterminal line, quartic, error function, double-sigmoid curve) fitted significantly better than a simple linear model (each P < 0·01 by Vuong test). Ranking by Akaike information criterion indicated that the segmented conterminal line and double-sigmoid models provided best fit, followed by the error function, quartic and separate lines models. From multiple regression analysis, age tertile, current smoking and TPOAb status each significantly influenced the TSH-free T4 relationship, whereas BMI category and diabetes did not. A sex difference in the TSH-free T4 relationship was apparent only in the lower part of the free T4 reference range. CONCLUSION: In a community-based setting, the relationship between log TSH and free T4 is complex, nonlinear and influenced by age, smoking and TPOAb status.


Assuntos
Tireotropina/sangue , Tiroxina/sangue , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Autoanticorpos , Estudos de Coortes , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Regressão , Estudos Retrospectivos , Fumar , Adulto Jovem
17.
BMC Genomics ; 17: 136, 2016 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-26911590

RESUMO

BACKGROUND: Osteoporosis is a common and debilitating bone disease that is characterised by a low bone mineral density (BMD), a highly heritable trait. Genome-wide association studies (GWAS) have proven to be very successful in identifying common genetic variants associated with BMD adjusted for age, gender and weight, however a large portion of the genetic variance for this trait remains unexplained. There is evidence to suggest significant genetic correlation between body size traits and BMD. It has also recently been suggested that unintended bias can be introduced as a result of adjusting a phenotype for a correlated trait. We performed a GWAS meta-analysis in two populations (total n = 6,696) using BMD data adjusted for only age and gender, in an attempt to identify genetic variants associated with BMD including those that may have potential pleiotropic effects on BMD and body size traits. RESULTS: We observed a single variant, rs2566752, associated with spine BMD at the genome-wide significance level in the meta-analysis (P = 3.36 × 10(-09)). Logistic regression analysis also revealed an association between rs2566752 and fracture rate in one of our study cohorts (P = 0.017, n = 5,654). This is an intronic variant located in the wntless Wnt ligand secretion mediator (WLS) gene (1p31.3), a known BMD locus which encodes an integral component of the Wnt ligand secretion pathway. Bioinformatics analyses of variants in moderate LD with rs2566752 produced strong evidence for a regulatory role for the variants rs72670452, rs17130567 and rs1430738. Expression quantitative trait locus (eQTL) analysis suggested that the variants rs12568456 and rs17130567 are associated with expression of the WLS gene in whole blood, cerebellum and temporal cortex brain tissue (P = 0.034-1.19 × 10(-23)). Gene-wide association testing using the VErsatile Gene-based Association Study 2 (VEGAS2) software revealed associations between the coiled-coil domain containing 170 (CCDC170) gene, located adjacent to the oestrogen receptor 1 (ESR1) gene, and BMD at the spine, femoral neck and total hip sites (P = 1.0 × 10(-06), 2.0 × 10(-06) and 2.0 × 10(-06) respectively). CONCLUSIONS: Genetic variation at the WLS and CCDC170/ESR1 loci were found to be significantly associated with BMD adjusted for only age and gender at the genome-wide level in this meta-analysis.


Assuntos
Densidade Óssea/genética , Proteínas de Transporte/genética , Receptor alfa de Estrogênio/genética , Estudo de Associação Genômica Ampla , Peptídeos e Proteínas de Sinalização Intracelular/genética , Receptores Acoplados a Proteínas-G/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Colo do Fêmur/patologia , Fraturas Ósseas/genética , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Osteoporose/genética , Fenótipo , Polimorfismo de Nucleotídeo Único , Coluna Vertebral/patologia , Adulto Jovem
18.
J Clin Endocrinol Metab ; 101(3): 1151-8, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26735261

RESUMO

CONTEXT: The TSH-T4 relationship was thought to be inverse log-linear, but recent cross-sectional studies report a complex, nonlinear relationship; large, intra-individual studies are lacking. OBJECTIVE: Our objective was to analyze the TSH-free T4 relationship within individuals. METHODS: We analyzed data from 13 379 patients, each with six or more TSH/free T4 measurements and at least a 5-fold difference between individual median TSH and minimum or maximum TSH. Linear and nonlinear regression models of log TSH on free T4 were fitted to data from individuals and goodness of fit compared by likelihood ratio testing. RESULTS: Comparing all models, the linear model achieved best fit in 31% of individuals, followed by quartic (27%), cubic (15%), null (12%), and quadratic (11%) models. After eliminating least favored models (with individuals reassigned to best fitting, available models), the linear model fit best in 42% of participants, quartic in 43%, and null model in 15%. As the number of observations per individual increased, so did the proportion of individuals in whom the linear model achieved best fit, to 66% in those with more than 20 observations. When linear models were applied to all individuals and averaged according to individual median free T4 values, variations in slope and intercept indicated a nonlinear log TSH-free T4 relationship across the population. CONCLUSIONS: The log TSH-free T4 relationship appears linear in some individuals and nonlinear in others, but is predominantly linear in those with the largest number of observations. A log-linear relationship within individuals can be reconciled with a non-log-linear relationship in a population.


Assuntos
Dinâmica não Linear , Testes de Função Tireóidea/estatística & dados numéricos , Tireotropina/sangue , Tiroxina/sangue , Adulto , Idoso , Estudos Transversais , Feminino , Humanos , Individualidade , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Variações Dependentes do Observador , Densidade Demográfica , Tireotropina/análise , Tiroxina/análise
19.
Eur J Hum Genet ; 24(2): 284-90, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26014426

RESUMO

Genetic factors contribute strongly to sex hormone levels, yet knowledge of the regulatory mechanisms remains incomplete. Genome-wide association studies (GWAS) have identified only a small number of loci associated with sex hormone levels, with several reproductive hormones yet to be assessed. The aim of the study was to identify novel genetic variants contributing to the regulation of sex hormones. We performed GWAS using genotypes imputed from the 1000 Genomes reference panel. The study used genotype and phenotype data from a UK twin register. We included 2913 individuals (up to 294 males) from the Twins UK study, excluding individuals receiving hormone treatment. Phenotypes were standardised for age, sex, BMI, stage of menstrual cycle and menopausal status. We tested 7,879,351 autosomal SNPs for association with levels of dehydroepiandrosterone sulphate (DHEAS), oestradiol, free androgen index (FAI), follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin, progesterone, sex hormone-binding globulin and testosterone. Eight independent genetic variants reached genome-wide significance (P<5 × 10(-8)), with minor allele frequencies of 1.3-23.9%. Novel signals included variants for progesterone (P=7.68 × 10(-12)), oestradiol (P=1.63 × 10(-8)) and FAI (P=1.50 × 10(-8)). A genetic variant near the FSHB gene was identified which influenced both FSH (P=1.74 × 10(-8)) and LH (P=3.94 × 10(-9)) levels. A separate locus on chromosome 7 was associated with both DHEAS (P=1.82 × 10(-14)) and progesterone (P=6.09 × 10(-14)). This study highlights loci that are relevant to reproductive function and suggests overlap in the genetic basis of hormone regulation.


Assuntos
Sulfato de Desidroepiandrosterona , Hormônio Foliculoestimulante/genética , Hormônios Esteroides Gonadais/genética , Hormônio Luteinizante/genética , Progesterona/genética , Sulfato de Desidroepiandrosterona/metabolismo , Estradiol/genética , Feminino , Hormônio Foliculoestimulante/metabolismo , Genoma Humano , Estudo de Associação Genômica Ampla , Genótipo , Hormônios Esteroides Gonadais/metabolismo , Humanos , Hormônio Luteinizante/metabolismo , Masculino , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Prolactina/genética , Prolactina/metabolismo , Globulina de Ligação a Hormônio Sexual/genética , Globulina de Ligação a Hormônio Sexual/metabolismo , Testosterona/genética
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