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1.
Cell ; 179(3): 736-749.e15, 2019 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-31626772

RESUMO

Underrepresentation of Asian genomes has hindered population and medical genetics research on Asians, leading to population disparities in precision medicine. By whole-genome sequencing of 4,810 Singapore Chinese, Malays, and Indians, we found 98.3 million SNPs and small insertions or deletions, over half of which are novel. Population structure analysis demonstrated great representation of Asian genetic diversity by three ethnicities in Singapore and revealed a Malay-related novel ancestry component. Furthermore, demographic inference suggested that Malays split from Chinese ∼24,800 years ago and experienced significant admixture with East Asians ∼1,700 years ago, coinciding with the Austronesian expansion. Additionally, we identified 20 candidate loci for natural selection, 14 of which harbored robust associations with complex traits and diseases. Finally, we show that our data can substantially improve genotype imputation in diverse Asian and Oceanian populations. These results highlight the value of our data as a resource to empower human genetics discovery across broad geographic regions.

2.
Artigo em Inglês | MEDLINE | ID: mdl-31628846

RESUMO

CONTEXT: Kallmann Syndrome (KS), is a rare, genetically heterogeneous Mendelian disorder in which structural defects in KS patients have helped define the genetic architecture of GnRH neuronal development in this condition. OBJECTIVE: Examine the functional role a novel structural defect affecting a long noncoding RNA (lncRNA), RMST, found in a KS patient. DESIGN: Whole genome sequencing (WGS), induced pluripotent stem cells (IPSC) and derived neural crest cells (NCC) from the KS patient were contrasted with controls. Setting: The Harvard Reproductive Sciences Center, MGH Center for Genomic Medicine and Singapore Genome Institute. PATIENT: A KS patient with a unique translocation, t(7;12)(q22;q24). INTERVENTIONS/MAIN OUTCOME MEASURE/ RESULTS: A novel translocation was detected affecting the lncRNA, RMST, on chromosome 12 in the absence of any other KS mutations. Compared to controls, the patient's iPSC and NCC provided functional information regarding RMST. Whereas RMST expression increased during NCC differentiation in controls, it was substantially reduced in the KS patient's NCC co-incident with abrogated NCC morphological development and abnormal expression of several 'downstream' genes essential for GnRH ontogeny (SOX2, PAX3, CHD7, TUBB3 & MKRN3). Additionally, an intronic SNP in RMST was significantly implicated in a GWAS associated with age of menarche. CONCLUSIONS: A novel deletion in RMST implicates the loss of function of a lncRNA as a unique cause of KS and suggests it plays a critical role in the ontogeny of GnRH neurons and puberty.

3.
Sci Rep ; 9(1): 14570, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31601979

RESUMO

Strong evidence suggests that genetic variations in DNA methyltransferases (DNMTs) may alter the downstream expression and DNA methylation patterns of neuronal genes and influence cognition. This study investigates the association between a DNMT1 polymorphism, rs2162560, and chemotherapy-associated cognitive impairment (CACI) in a cohort of breast cancer patients. This is a prospective, longitudinal cohort study. From 2011 to 2017, 351 early-stage breast cancer patients receiving chemotherapy were assessed at baseline, the midpoint, and the end of chemotherapy. DNA was extracted from whole blood, and genotyping was performed using Sanger sequencing. Patients' self-perceived cognitive function and cognitive performance were assessed at three different time points using FACT-Cog (v.3) and a neuropsychological battery, respectively. The association between DNMT1 rs2162560 and cognitive function was evaluated using logistic regression analyses. Overall, 33.3% of the patients reported impairment relative to baseline in one or more cognitive domains. Cognitive impairment was observed in various objective cognitive domains, with incidences ranging from 7.2% to 36.9%. The DNMT1 rs2162560 A allele was observed in 21.8% of patients and this was associated with lower odds of self-reported cognitive decline in the concentration (OR = 0.45, 95% CI: 0.25-0.82, P = 0.01) and functional interference (OR = 0.48, 95% CI: 0.24-0.95, P = 0.03) domains. No significant association was observed between DNMT1 rs2162560 and objective cognitive impairment. This is the first study to show a significant association between the DNMT1 rs2162560 polymorphism and CACI. Our data suggest that epigenetic processes could contribute to CACI, and further studies are needed to validate these findings.

4.
Exp Eye Res ; 189: 107835, 2019 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-31634478

RESUMO

Glaucoma, the leading cause of irreversible blindness worldwide, can be divided into two major types: primary open angle glaucoma (POAG) and primary angle closure glaucoma (PACG). PACG could lead to severe vision loss and has a high prevalence among Asian populations. The worldwide population affected by PACG is estimated to exceed 20 million by 2020. Recent studies have shown that there are at least eight genetic loci significantly associated with risk of PACG, possibly contributing to the phenotype by interacting with environmental factors. This review presents the progress that has been achieved in the genetics of PACG and its future perspectives. This article should be considered as a memorial article to honor Dr. R. Rand Allingham's remarkable contribution to genetic association studies in glaucoma. We are deeply saddened by the loss of Dr. Allingham, not only a huge loss for ophthalmology, but also loss of a dear friend. Looking back to his extraordinary career, Dr. Allingham devoted his whole life and passion into establishing the genetic basis of different forms of glaucoma such as open angle, angle closure, and exfoliation glaucoma. He had a special interest in analyses of populations from African ancestry, which greatly boosted the understanding of glaucoma genetics.

5.
J Rheumatol ; 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31523044

RESUMO

OBJECTIVE: We aimed to present a systematic evaluation of 47 non Major Histocompatibility Complex (MHC) Ankylosing Spondylitis (AS) susceptibility loci which have been initially discovered through Caucasian Genome-wide association studies (GWASs) in Han Chinese. METHODS: Totally 10,743 samples representing north and south Chinese in four datasets were obtained. After data quality control and imputation, meta-analysis results of 94,621 variants within 47 loci were extracted. Four ERAP1 single-nucleotide polymorphisms (SNPs) and HLA-B27 tag SNP rs13202464 were used for interaction analysis. Population-attributable risk percentages (PARPs) of AS-associated variants were compared. Functional annotation of AS-associated variants were conducted using HaploReg, RegulomeDB and rVarBase Database. RESULTS: We revealed 16 AS-associated variants with nominal evidence in Han Chinese, including rs10865331 (P=6.30×10-10), rs10050860 (P=4.09×10-5) and rs8070463 (P=1.03×10-4). Potential susceptible SNPs within these 47 loci were also identified, such as rs13024541 (2p15), rs17401719 (5q15) and rs62074054 (17q21). Epistatic ineractions between three ERAP1 SNPs (rs17401719, rs30187 and rs10050860) and HLA-B27 were confirmed. Among the 16 AS-associated variants, rs30187 showed weaker risk effect while rs10050860 and rs12504282 seemed to attribute more risk in Han Chinese than Caucasians. Further genomic annotation pinpointed 35 candidate functional SNPs, especially in 2p15, ERAP1 and NPEPPS-TBKBP1 region. CONCLUSION: Our results provided a detailed spectrum of all the reported non-MHC AS susceptibility loci in Han Chinese, which comprehensively exhibited the ethnic heterogeneity of AS susceptibility and highlighted that 2p15, ERAP1 and NPEPPS-TBKBP1 region may play a critical role in AS pathogenesis across diverse populations.

6.
JAMA Netw Open ; 2(9): e1910915, 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31539074

RESUMO

Importance: Observational studies have shown associations of birth weight with type 2 diabetes (T2D) and glycemic traits, but it remains unclear whether these associations represent causal associations. Objective: To test the association of birth weight with T2D and glycemic traits using a mendelian randomization analysis. Design, Setting, and Participants: This mendelian randomization study used a genetic risk score for birth weight that was constructed with 7 genome-wide significant single-nucleotide polymorphisms. The associations of this score with birth weight and T2D were tested in a mendelian randomization analysis using study-level data. The association of birth weight with T2D was tested using both study-level data (7 single-nucleotide polymorphisms were used as an instrumental variable) and summary-level data from the consortia (43 single-nucleotide polymorphisms were used as an instrumental variable). Data from 180 056 participants from 49 studies were included. Main Outcomes and Measures: Type 2 diabetes and glycemic traits. Results: This mendelian randomization analysis included 49 studies with 41 155 patients with T2D and 80 008 control participants from study-level data and 34 840 patients with T2D and 114 981 control participants from summary-level data. Study-level data showed that a 1-SD decrease in birth weight due to the genetic risk score was associated with higher risk of T2D among all participants (odds ratio [OR], 2.10; 95% CI, 1.69-2.61; P = 4.03 × 10-5), among European participants (OR, 1.96; 95% CI, 1.42-2.71; P = .04), and among East Asian participants (OR, 1.39; 95% CI, 1.18-1.62; P = .04). Similar results were observed from summary-level analyses. In addition, each 1-SD lower birth weight was associated with 0.189 SD higher fasting glucose concentration (ß = 0.189; SE = 0.060; P = .002), but not with fasting insulin, 2-hour glucose, or hemoglobin A1c concentration. Conclusions and Relevance: In this study, a genetic predisposition to lower birth weight was associated with increased risk of T2D and higher fasting glucose concentration, suggesting genetic effects on retarded fetal growth and increased diabetes risk that either are independent of each other or operate through alterations of integrated biological mechanisms.

7.
Am J Ophthalmol ; 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31377279

RESUMO

PURPOSE: The purpose of this study was to investigate whether the addition of primary angle closure glaucoma (PACG) associated genetic loci allows improved detection of PACG, compared to anterior segment parameters measured by imaging. DESIGN: Case-control study METHODS: Genotype data of the 8 PACG SNPs (rs11024102 at PLEKHA7, rs3753841 at COL11A1, rs1015213 located between PCMTD1 and ST18 on Chromosome 8q, rs3816415 at EPDR1, rs1258267 at CHAT, rs736893 at GLIS3, rs7494379 at FERMT2, and rs3739821 mapping in between DPM2 and FAM102A) were available. Customized software was used to measure anterior segment optical coherence tomography (ASOCT) parameters, namely anterior chamber depth, width, and area (ACD, ACW, ACA) and lens vault (LV). Statistical analysis for positive predictive values was modelled using the Receiver operating characteristic curve (AUC). Statistical significance comparing predictive power of the different parameters was calculated using permutation. RESULTS: A total of 388 PACG subjects and 751 controls with both ASOCT and genetic data were available for analysis. Anterior segment parameters including ACD, ACA, and LV had excellent predictive value (AUC) >0.94), except ACW (AUC=0.65) for identifying PACG. The inclusion of genetic risk alleles (either singly or as a composite genetic risk score for 8 GWAS SNPs) to ACD only provided a +0.50% improvement in re-classifying PACG cases and controls over and above the discriminatory value of ACD. This +0.50% improvement was not statistically significant (P>0.05). CONCLUSIONS: Although significant on their own, the incorporation of genetic data in the context of anterior segment imaging parameters like ACD provided only a marginal improvement of PACG detection.

8.
BMJ Open ; 9(7): e022877, 2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31371282

RESUMO

OBJECTIVE: We tested whether genetic variants near fatty acid desaturases gene (FADS) cluster, which were recently identified to be signatures of adaptation to fish-rich and n-3 polyunsaturated fatty acids (PUFAs)-rich diet, interacted with these dietary factors on change in body mass index (BMI). DESIGN: Three FADS variants were examined for gene-diet interactions on long-term (~10 years) changes in BMI and body weight in four prospective cohort studies. SETTING: Population based study. PARTICIPANTS: 11 323 women from the Nurses' Health Study (NHS), 6833 men from the Health Professionals Follow-up Study (HPFS) and replicated in 6254 women from the Women's Health Initiative (WHI) and 5 264 Chinese from the Singapore Chinese Health Study (SCHS). MAIN OUTCOMES: Long-term (~10 years) changes in BMI and body weight. RESULTS: In the NHS and HPFS cohorts, food-sourced n-3 PUFAs intake showed interactions with the FADS rs174570 on changes of BMI (P for interaction=0.02 in NHS, 0.05 in HPFS and 0.007 in combined). Such interactions were replicated in two independent cohorts WHI and SCHS (P for interaction=0.04 in WHI, 0.02 in SCHS and 0.001 in combined). The genetic associations of the FADS rs174570 with changes in BMI increased across the tertiles of n-3 PUFAs in all the cohorts. Fish intake also accentuated the genetic associations of the FADS rs174570 with long-term changes in BMI (pooled P for interaction=0.006). Viewed differently, long chain n-3 PUFAs intake showed stronger association with long-term changes in BMI among the rs174570 T carriers (beta=0.79 kg/m2 per g, p=3×10-5) than the rs174570 non-T carriers (beta=0.16 kg/m2 per g, p=0.08). Similar results were observed for fish intake. CONCLUSIONS: Our hypothesis-driven analyses provide replicable evidence that long chain n-3 PUFAs and fish intakes may interact with the FADS variant on long-term weight gain. Further investigation is needed to confirm our findings in other cohorts.

9.
J Gene Med ; 21(9): e3113, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31310406

RESUMO

BACKGROUND: Hypohidrotic ectodermal dysplasia (HED) is a rare congenital disorder arising from the abnormal development of ectoderm derived structures, including skin, hair, nails, teeth and glands. These patients have sparse hair on the whole body, including the scalp, as well as hypoplastic teeth. They have no resistance to heat as a result of abnormal sweat glands. In total, four genes, namely ectodysplasin A (EDA), ectodysplasin A receptor (EDAR), EDAR-associated death domain protein (EDARADD) and Wnt family member 10A (WNT10A), are known to be involved in the etiology of HED. METHODS: In the present study, we investigated two consanguineous Kashmiri families (A &B) with an autosomal recessive form of HED. Using whole exome sequencing and different bioinformatics tools, we detected a recurrent mutation causing severe HED. RESULTS: We identified an already known rare homozygous missense (NM_022336 c.1300 T>C; p.W434R; minor allele frequency 0.00007) variant in exon 12 of the EDAR gene. This variant segregated with a homozygous form in all patients and their obligate carriers were heterozygous. A panel of > 100 unrelated ethnically matched controls was screened, and the mutation was not identified outside the families. Furthermore, the candidate variant is predicted to be damaging by in silico software giving a CADD (Combined Annotation Dependent Depletion) score of 25.5, which indicates that the variant is among the top 1% of the deleterious variants in the human genome. CONCLUSIONS: The identification of the same homozygous mutation segregating with disease in two different families supports the important role of the gene in the development of the disorder and this may contribute to novel approaches, prenatal diagnosis and genetic counseling of families with EDAR related disorders.

10.
Cell Stem Cell ; 25(3): 373-387.e9, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31303547

RESUMO

Human pluripotent stem cell-derived kidney organoids recapitulate developmental processes and tissue architecture, but intrinsic limitations, such as lack of vasculature and functionality, have greatly hampered their application. Here we establish a versatile protocol for generating vascularized three-dimensional (3D) kidney organoids. We employ dynamic modulation of WNT signaling to control the relative proportion of proximal versus distal nephron segments, producing a correlative level of vascular endothelial growth factor A (VEGFA) to define a resident vascular network. Single-cell RNA sequencing identifies a subset of nephron progenitor cells as a potential source of renal vasculature. These kidney organoids undergo further structural and functional maturation upon implantation. Using this kidney organoid platform, we establish an in vitro model of autosomal recessive polycystic kidney disease (ARPKD), the cystic phenotype of which can be effectively prevented by gene correction or drug treatment. Our studies provide new avenues for studying human kidney development, modeling disease pathogenesis, and performing patient-specific drug validation.

11.
Ophthalmol Retina ; 3(11): 985-992, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31331787

RESUMO

PURPOSE: To investigate potential genetic prognostic factors associated with spontaneous resolution of serous retinal detachment (SRD) and development of choroidal neovascularization (CNV) in central serous chorioretinopathy (CSC). DESIGN: Retrospective analysis of a case series. PARTICIPANTS: One hundred ninety-six eyes from 196 patients with active CSC. METHODS: We retrospectively reviewed medical records and determined the presence or absence of SRD using OCT imaging. The duration until the spontaneous SRD resolution was analyzed using the Kaplan-Meier method, and associations between the duration to spontaneous resolution and Complement factor H (CFH) I62V, Age-Related Maculopathy Susceptibility 2 (ARMS2) A69S, or Vasoactive Intestinal Peptide Receptor 2 (VIPR2) rs3793217 genotypes were evaluated, followed by the assessment of their associations with CNV that developed secondary to CSC. MAIN OUTCOME MEASURES: Genetic associations of CFH rs800292, ARMS2 rs10490924, and VIPR2 rs3793217 genotypes with the duration to spontaneous resolution of SRD and development of CNV during follow-up of CSC. RESULTS: In 105 of the 196 study participants, we revealed spontaneous SRD resolution in their eyes during follow-up evaluation. Sixty-eight eyes received treatment, and 23 eyes dropped out before spontaneous SRD resolution. Among the 3 genetic polymorphisms assessed herein, only the CFH I62V genotype was predictive of spontaneous SRD resolution among its genotypes (P = 0.017); the average durations for the spontaneous SRD resolution for the individuals with AA, AG, and GG genotype were 126.6±115.5 days, 157.7±243.1 days, and 242.7±198.0 days, respectively, indicating that the G allele was associated with significantly longer persistent SRD (P = 0.035). Among the total number of eyes of all participants, 14 demonstrated CNV during follow-up evaluation. The CFH I62V G and ARMS2 A69S T alleles were associated significantly with CNV development (P = 0.0023 and P = 0.019, respectively), whereas the VIPR2 rs3793217 genotype was not. CONCLUSIONS: The CFH I62V and ARMS2 A69S genotypes can predict the prognosis of CSC. Knowledge of the genetic status may help physicians determine the need for early treatment and possibly prevent subsequent CNV development. Further prospective studies are needed to confirm the observed genotype-phenotype relationship.

12.
Ophthalmic Genet ; 40(4): 323-328, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31322012

RESUMO

Purpose: The aim of this study was to evaluate the frequency of single nucleotide polymorphisms (SNP) of estrogen receptor genes (ESR1: rs12154178, rs1884054 and ESR2: rs1268656, rs7159462) and to assess their possible influence on the clinical phenotype of primary open angle glaucoma (POAG). Methods: The study included 235 patients with POAG (143 patients with normal-tension glaucoma [NTG] and 92 patients with high-tension glaucoma [HTG]), and 165 healthy controls. DNA was isolated from peripheral blood, and SNP genotyping was performed using the Real-Time Polymerase Chain Reaction method to analyze the frequency of selected polymorphic variants of estrogen receptor genes. The clinical phenotype (best-corrected visual acuity, intraocular pressure [IOP], mean deviation [MD], cup to disc ratio, disc hemorrhages, notches, peripapillary atrophy, cold extremities) of participants were examined for association with the polymorphisms. Results: A similar frequency of the polymorphic variants of the studied genes was observed in patients with NTG, HTG and control group. Initial intraocular pressure was the lowest in NTG patients with GG variant of rs1268656 (p = 0.044). The lowest maximal IOP in HTG patients was observed in CC variant of rs12154178 (p = 0.039). Patients with HTG and CC variant of ESR1 polymorphism rs1884054 had the best visual acuity (p = 0.009), similar tendency was also observed in the NTG group. This polymorphic variant of ESR1 gene in HTG was also related to earlier damage in visual field assessed according to MD values and higher percentage of notches. For rs12154178, homozygotic variant CC was related to earlier glaucoma damage according to MD in HTG patients (p = 0.006). For polymorphism rs12154178, disc hemorrhages were found only for those with the AC variant. Cold extremities were most frequent in NTG patients with TT variant of rs1268656 comparing to other variants (p = 0.021). Notches on optic disc were less frequent in patients with CC variant of rs12154178 of ERS-1 gene (p = 0.022). Conclusions: The studied polymorphic variants of ESR1 and ESR2 genes may have an influence on the clinical phenotype of patients with POAG.

13.
Cell Rep ; 27(11): 3241-3253.e4, 2019 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-31189108

RESUMO

Vaccines have revolutionized public health, preventing millions of deaths each year, particularly in childhood. Yet, there is considerable variability in the magnitude and persistence of vaccine-induced immunity. Maintenance of specific antibody is essential for continuity of vaccine-induced serological protection. We conducted a genome-wide association study into the persistence of immunity to three childhood vaccines: capsular group C meningococcal (MenC), Haemophilus influenzae type b, and tetanus toxoid (TT) vaccines. We detail associations between variants in a locus containing a family of signal-regulatory proteins and the persistence MenC immunity. We postulate a regulatory role for the lead SNP, with supporting epigenetic and expression quantitative trait loci data. Furthermore, we define associations between SNPs in the human leukocyte antigen (HLA) locus and the persistence of TT-specific immunity. Moreover, we describe four classical HLA alleles, HLA DRB1∗0301, HLA DQB1∗0201, HLA DQB1∗0602, and HLA DRB1∗1501, associated with TT-specific immunity, independent of the lead SNP association.

14.
Nat Commun ; 10(1): 2491, 2019 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-31171785

RESUMO

Genetic factors underlying leukocyte telomere length (LTL) may provide insights into telomere homeostasis, with direct links to disease susceptibility. Genetic evaluation of 23,096 Singaporean Chinese samples identifies 10 genome-wide loci (P < 5 × 10-8). Several of these contain candidate genes (TINF2, PARP1, TERF1, ATM and POT1) with potential roles in telomere biology and DNA repair mechanisms. Meta-analyses with additional 37,505 European individuals reveals six more genome-wide loci, including associations at MPHOSPH6, NKX2-3 and TYMS. We demonstrate that longer LTL associates with protection against respiratory disease mortality [HR = 0.854(0.804-0.906), P = 1.88 × 10-7] in the Singaporean Chinese samples. We further show that the LTL reducing SNP rs7253490 associates with respiratory infections (P = 7.44 × 10-4) although this effect may not be strongly mediated through LTL. Our data expands on the genetic basis of LTL and may indicate on a potential role of LTL in immune competence.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Reparo do DNA/genética , Leucócitos/metabolismo , Homeostase do Telômero/genética , Telômero/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Infecções Respiratórias/genética , Singapura , Adulto Jovem
15.
Hum Mol Genet ; 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30986821

RESUMO

LOXL1 (lysyl oxidase-like 1) has been identified as the major effect locus in pseudoexfoliation (PEX) syndrome, a fibrotic disorder of the extracellular matrix and frequent cause of chronic open-angle glaucoma. However, all known PEX-associated common variants show allele effect reversal in populations of different ancestry, casting doubt on their biological significance. Based on extensive LOXL1 deep sequencing, we report here the identification of a common noncoding sequence variant, rs7173049A>G, located downstream of LOXL1, consistently associated with a decrease in PEX risk (OR=0.63, p=6.33x10-31) in nine different ethnic populations. We provide experimental evidence for a functional enhancer-like regulatory activity of the genomic region surrounding rs7173049 influencing expression levels of ISLR2 (immunoglobulin superfamily containing leucine-rich repeat protein 2) and STRA6 (stimulated by retinoic acid receptor 6), apparently mediated by allele-specific binding of the transcription factor THRß (thyroid hormone receptor beta). We further show that the protective rs7173049-G allele correlates with increased tissue expression levels of ISLR2 and STRA6 and that both genes are significantly downregulated in tissues of PEX patients together with other key components of the STRA6 receptor-driven retinoic acid signaling pathway. siRNA-mediated downregulation of retinoic acid signaling induces upregulation of LOXL1 and PEX-associated matrix genes in PEX-relevant cell types. These data indicate that dysregulation of STRA6 and impaired retinoid metabolismare involved in the pathophysiology of PEX syndrome and that the variant rs7173049-G, which represents the first common variant at the broad LOXL1 locus without allele effect reversal, mediates a protective effect through upregulation of STRA6 in ocular tissues.

16.
J Biomed Sci ; 26(1): 31, 2019 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-31030663

RESUMO

In the original publication of this article [1], there are two errors in the article which the cDNA position of the pathogenic variant WNT1 p.Gly324Cys should be c.970G>T instead of c.1168G>T.

18.
Mol Neurobiol ; 2018 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-30382534

RESUMO

Cancer-related cognitive impairment (CRCI) adversely affects cancer patients. We had previously demonstrated that the BDNF Val66Met genetic polymorphism is associated with lower odds of subjective CRCI in the multitasking and verbal ability domains among breast cancer patients receiving chemotherapy. To further assess our previous findings, we evaluated the association of BDNF Val66Met polymorphism with subjective and objective CRCI in a temporally separate cohort of patients and pooled findings from both the original (n = 145) and current (n = 193) cohorts in a meta-analysis. Subjective CRCI was assessed using FACT-Cog. Objective CRCI was evaluated using computerized neuropsychological tests. Genotyping was carried out using Sanger sequencing. The association of BDNF Val66Met genotypes and CRCI was examined with logistic regression. A fixed-effect meta-analysis was conducted using the inverse variance method. In the meta-analysis (n = 338), significantly lower odds of CRCI were associated with Met allele carriers based on the global FACT-Cog score (OR = 0.52, 95% CI 0.29-0.94). Furthermore, Met allele carriers were at lower odds of developing impairment in the domains of memory (OR = 0.34, 95% CI: 0.17-0.70), multitasking (OR = 0.33, 95% CI: 0.18-0.59), and verbal ability (OR = 0.46, 95% CI: 0.24-0.88). Consistent with the previous study, lower odds of subjective CRCI among patients with the BDNF Met allele was observed after adjusting for potential confounders in the multitasking (OR = 0.30, 95% CI: 0.14-0.67) domain. In conclusion, carriers of the BDNF Met allele were protected against global subjective CRCI, particularly in the domains of memory, multitasking, and verbal ability. Our findings further contribute to the understanding of CRCI pathophysiology.

19.
J Biomed Sci ; 25(1): 82, 2018 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-30447692

RESUMO

INTRODUCTION: Osteogenesis imperfecta (OI) is a clinically and genetically heterogeneous disease with skeletal fragility and variable extra-skeletal manifestations. To date several point mutations in 18 different genes causing different types of OI have been identified. Mutations in WNT1 compromise activity of the osteoblasts leading to disturbed bone mass accrual, fragility fractures and progressive skeletal abnormalities. The present study was conducted to determine the underlying genetic cause of an autosomal recessive skeletal dysplasia in a large consanguineous family from Chinute, Pakistan. MATERIALS AND METHODS: Blood was collected from 24 individuals of affected family along with clinical data. Homozygosity mapping was performed to confirm consanguinity. SNPs were identified, followed by whole exome and Sanger sequencing. In silico characterization of WNT1 mutation was performed using multiple platforms. RESULTS: Nine affected family members exhibited severe bone deformities, recurrent fractures, short stature and low bone mineral density. SNP array data revealed homozygous segments > 1 Mb in length accounting for 2.1-12.7% of the genome in affected individuals and their siblings and a single 6,344,821 bp homozygous region in all affected individuals on chromosome 12q12-q13. This region includes two potential OI candidate genes WNT1 and VDR. We did whole-exome sequencing for both genes in two patients and identified a novel damaging missense mutation in exon 4 of WNT1: c.1168G > T (NM_005430) resulting in p.G324C. Sanger sequencing confirmed segregation of mutation with the disease in family. CONCLUSION: We report a novel mutation responsible for OI and our investigation expands the spectrum of disease-causing WNT1 mutations and the resulting OI phenotypes.

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