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1.
Wishal D. Ramdas Leonieke M. E. van Koolwijk M. Kamran Ikram Nomdo M. Jansonius Paulus T. V. M. de Jong Arthur A. B. Bergen Aaron Isaacs Najaf Amin Yurii S. Aulchenko Roger C. W. Wolfs Albert Hofman Fernando Rivadeneira Ben A. Oostra Andre G. Uitterlinden Pirro Hysi Christopher J. Hammond Hans G. Lemij Johannes R. Vingerling Caroline C. W. Klaver Cornelia M. van Duijn 《PLoS genetics》2010,6(6)
The optic nerve head is involved in many ophthalmic disorders, including common diseases such as myopia and open-angle glaucoma. Two of the most important parameters are the size of the optic disc area and the vertical cup-disc ratio (VCDR). Both are highly heritable but genetically largely undetermined. We performed a meta-analysis of genome-wide association (GWA) data to identify genetic variants associated with optic disc area and VCDR. The gene discovery included 7,360 unrelated individuals from the population-based Rotterdam Study I and Rotterdam Study II cohorts. These cohorts revealed two genome-wide significant loci for optic disc area, rs1192415 on chromosome 1p22 (p = 6.72×10−19) within 117 kb of the CDC7 gene and rs1900004 on chromosome 10q21.3-q22.1 (p = 2.67×10−33) within 10 kb of the ATOH7 gene. They revealed two genome-wide significant loci for VCDR, rs1063192 on chromosome 9p21 (p = 6.15×10−11) in the CDKN2B gene and rs10483727 on chromosome 14q22.3-q23 (p = 2.93×10−10) within 40 kbp of the SIX1 gene. Findings were replicated in two independent Dutch cohorts (Rotterdam Study III and Erasmus Rucphen Family study; N = 3,612), and the TwinsUK cohort (N = 843). Meta-analysis with the replication cohorts confirmed the four loci and revealed a third locus at 16q12.1 associated with optic disc area, and four other loci at 11q13, 13q13, 17q23 (borderline significant), and 22q12.1 for VCDR. ATOH7 was also associated with VCDR independent of optic disc area. Three of the loci were marginally associated with open-angle glaucoma. The protein pathways in which the loci of optic disc area are involved overlap with those identified for VCDR, suggesting a common genetic origin. 相似文献
2.
The purpose of this study was to confirm previously reported associations of common variants in or near CDC7/TGFBR3, ZP4, SRBD1, ELOVL5, CAV1/CAV2, TLR4, CDKN2B, CDKN2B-AS1, ATOH7, PLXDC2, TMTC2, SIX1, and CARD10, with primary open angle glaucoma (POAG) in the Afro-Caribbean population of Barbados, West Indies. A total of 437 unrelated subjects from the Barbados Family Study of Open Angle Glaucoma (BFSG), including 272 with POAG and 165 unaffected individuals were included in this study. Eighteen SNPs were genotyped by using the multiplex SNaPshot method. Allelic, genotypic and model-based (dominant, recessive, and additive) associations of the SNPs with POAG were analyzed using Chi-squared tests and logistic regression. SNP rs1063192 (near CDKN2B) was found to be significantly associated with POAG (allelic P = 0.0008, genotypic P = 0.0029), and the minor allele C of rs1063192 was protective against POAG (OR = 0.39; 95%CI = 0.22-0.69). Suggestive association was also noted for rs7916697 (near ATHO7, allelic P = 0.0096, genotypic P = 0.01) with the minor allele being protective (OR = 0.67; 95% CI = 0.50-0.91), although this finding did not withstand correction for multiple testing. However, a significant interactive effect on POAG risk was identified between rs1063192 and rs7916697 (P-interaction = 2.80 × 10(-5)). Individuals with the rs1063192 protective genotype CC or CT and also rs7916697 genotypes GG or GA show a significantly decreased risk of POAG (OR = 0.17, 95%CI: 0.07-0.41). Our study confirms the significant association between SNP rs1063192 (CDKN2B, previously shown to influence vertical cup-to-disc ratio and POAG at 9p21) and POAG in the Afro-Caribbean population of Barbados. The minor allele of rs1063192 interacts with that of rs7916697 (ATOH7)) to reduce POAG risk. Our results also suggest that rs1063912 is a common protective variant for POAG in populations of African as well as European descent. 相似文献
3.
A. Bilge Ozel Sayoko E. Moroi David M. Reed Melisa Nika Caroline M. Schmidt Sara Akbari Kathleen Scott Frank Rozsa Hemant Pawar David C. Musch Paul R. Lichter Doug Gaasterland Kari Branham Jesse Gilbert Sarah J. Garnai Wei Chen Mohammad Othman John Heckenlively Anand Swaroop Gonçalo Abecasis David S. Friedman Don Zack Allison Ashley-Koch Megan Ulmer Jae H. Kang Yutao Liu Brian L. Yaspan Jonathan Haines R. Rand Allingham Michael A. Hauser Louis Pasquale Janey Wiggs Julia E. Richards Jun Z. Li 《Human genetics》2014,133(1):41-57
Elevated intraocular pressure (IOP) is a major risk factor for glaucoma and is influenced by genetic and environmental factors. Recent genome-wide association studies (GWAS) reported associations with IOP at TMCO1 and GAS7, and with primary open-angle glaucoma (POAG) at CDKN2B-AS1, CAV1/CAV2, and SIX1/SIX6. To identify novel genetic variants and replicate the published findings, we performed GWAS and meta-analysis of IOP in >6,000 subjects of European ancestry collected in three datasets: the NEI Glaucoma Human genetics collaBORation, GLAUcoma Genes and ENvironment study, and a subset of the Age-related Macular Degeneration-Michigan, Mayo, AREDS and Pennsylvania study. While no signal achieved genome-wide significance in individual datasets, a meta-analysis identified significant associations with IOP at TMCO1 (rs7518099-G, p = 8.0 × 10?8). Focused analyses of five loci previously reported for IOP and/or POAG, i.e., TMCO1, CDKN2B-AS1, GAS7, CAV1/CAV2, and SIX1/SIX6, revealed associations with IOP that were largely consistent across our three datasets, and replicated the previously reported associations in both effect size and direction. These results confirm the involvement of common variants in multiple genomic regions in regulating IOP and/or glaucoma risk. 相似文献
4.
Megan Ulmer Carnes Yangfan P. Liu R. Rand Allingham Benjamin T. Whigham Shane Havens Melanie E. Garrett Chunyan Qiao NEIGHBORHOOD Consortium Investigators Nicholas Katsanis Janey L. Wiggs Louis R. Pasquale Allison Ashley-Koch Edwin C. Oh Michael A. Hauser 《PLoS genetics》2014,10(5)
Glaucoma is a leading cause of blindness worldwide. Primary open-angle glaucoma (POAG) is the most common subtype and is a complex trait with multigenic inheritance. Genome-wide association studies have previously identified a significant association between POAG and the SIX6 locus (rs10483727, odds ratio (OR) = 1.32, p = 3.87×10−11). SIX6 plays a role in ocular development and has been associated with the morphology of the optic nerve. We sequenced the SIX6 coding and regulatory regions in 262 POAG cases and 256 controls and identified six nonsynonymous coding variants, including five rare and one common variant, Asn141His (rs33912345), which was associated significantly with POAG (OR = 1.27, p = 4.2×10−10) in the NEIGHBOR/GLAUGEN datasets. These variants were tested in an in vivo Danio rerio (zebrafish) complementation assay to evaluate ocular metrics such as eye size and optic nerve structure. Five variants, found primarily in POAG cases, were hypomorphic or null, while the sixth variant, found only in controls, was benign. One variant in the SIX6 enhancer increased expression of SIX6 and disrupted its regulation. Finally, to our knowledge for the first time, we have identified a clinical feature in POAG patients that appears to be dependent upon SIX6 genotype: patients who are homozygous for the SIX6 risk allele (His141) have a statistically thinner retinal nerve fiber layer than patients homozygous for the SIX6 non-risk allele (Asn141). Our results, in combination with previous SIX6 work, lead us to hypothesize that SIX6 risk variants disrupt the development of the neural retina, leading to a reduced number of retinal ganglion cells, thereby increasing the risk of glaucoma-associated vision loss. 相似文献
5.
Jinghong Sang Liyun Jia Bowen Zhao Huaizhou Wang Nihong Zhang Ningli Wang 《中国科学:生命科学英文版》2016,59(7):694-699
This study investigated the genetic association of three single nucleotide polymorphisms(SNPs; rs10483727, rs33912345, and rs146737847) at the SIX1-SIX6 locus with primary open angle glaucoma(POAG) in the Chinese population. A total of 866 subjects with POAG(685 high-tension glaucoma(HTG) and 181 normal-tension glaucoma(NTG)) and 266 control individuals were included. Significant genetic association was identified for rs10483727 in HTG(P=0.02; odds ratio(OR)=1.31), NTG(P=7.41×10~(-6); OR=2.71), and POAG(i.e., HTG and NTG combined; P=0.001; OR=1.44). rs33912345 was also significantly associated with HTG(P=0.008; OR=1.36), NTG(P=2.72×10~(-6); OR=2.27), and POAG(P=3.84×10~(-4); OR=1.49). The rare SIX6 mutation, rs146737847, was not found in the subjects enrolled in this study. Stratification by patient age identified that both rs10483727 and rs33912345 were significantly associated with NTG in patients aged above 40 years(P=2.08×10~(-5); OR=2.28), whereas in patients aged between 20–40 years, rs33912345 was significantly associated with NTG(P=0.017; OR=2.06). In HTG, the genetic associations for both rs10483727 and rs33912345 were significant in patients aged between 20–40 years(P=0.006; OR=1.56) but not in those aged above 40 years(P=0.118, OR=1.21 and P=0.042, OR=1.29, respectively). This study replicated the association of POAG with two SNPs at the SIX1-SIX6 locus and demonstrated that SNPs, rs10483727 and rs33912345, are significantly associated with POAG, especially with NTG in patients aged above 40 years. 相似文献
6.
Wiggs JL Yaspan BL Hauser MA Kang JH Allingham RR Olson LM Abdrabou W Fan BJ Wang DY Brodeur W Budenz DL Caprioli J Crenshaw A Crooks K Delbono E Doheny KF Friedman DS Gaasterland D Gaasterland T Laurie C Lee RK Lichter PR Loomis S Liu Y Medeiros FA McCarty C Mirel D Moroi SE Musch DC Realini A Rozsa FW Schuman JS Scott K Singh K Stein JD Trager EH Vanveldhuisen P Vollrath D Wollstein G Yoneyama S Zhang K Weinreb RN Ernst J Kellis M Masuda T Zack D Richards JE Pericak-Vance M Pasquale LR 《PLoS genetics》2012,8(4):e1002654
Optic nerve degeneration caused by glaucoma is a leading cause of blindness worldwide. Patients affected by the normal-pressure form of glaucoma are more likely to harbor risk alleles for glaucoma-related optic nerve disease. We have performed a meta-analysis of two independent genome-wide association studies for primary open angle glaucoma (POAG) followed by a normal-pressure glaucoma (NPG, defined by intraocular pressure (IOP) less than 22 mmHg) subgroup analysis. The single-nucleotide polymorphisms that showed the most significant associations were tested for association with a second form of glaucoma, exfoliation-syndrome glaucoma. The overall meta-analysis of the GLAUGEN and NEIGHBOR dataset results (3,146 cases and 3,487 controls) identified significant associations between two loci and POAG: the CDKN2BAS region on 9p21 (rs2157719 [G], OR = 0.69 [95%CI 0.63–0.75], p = 1.86×10−18), and the SIX1/SIX6 region on chromosome 14q23 (rs10483727 [A], OR = 1.32 [95%CI 1.21–1.43], p = 3.87×10−11). In sub-group analysis two loci were significantly associated with NPG: 9p21 containing the CDKN2BAS gene (rs2157719 [G], OR = 0.58 [95% CI 0.50–0.67], p = 1.17×10−12) and a probable regulatory region on 8q22 (rs284489 [G], OR = 0.62 [95% CI 0.53–0.72], p = 8.88×10−10). Both NPG loci were also nominally associated with a second type of glaucoma, exfoliation syndrome glaucoma (rs2157719 [G], OR = 0.59 [95% CI 0.41–0.87], p = 0.004 and rs284489 [G], OR = 0.76 [95% CI 0.54–1.06], p = 0.021), suggesting that these loci might contribute more generally to optic nerve degeneration in glaucoma. Because both loci influence transforming growth factor beta (TGF-beta) signaling, we performed a genomic pathway analysis that showed an association between the TGF-beta pathway and NPG (permuted p = 0.009). These results suggest that neuro-protective therapies targeting TGF-beta signaling could be effective for multiple forms of glaucoma. 相似文献
7.
Ryo Asaoka Shunsuke Nakakura Hitoshi Tabuchi Hiroshi Murata Yoshitaka Nakao Noriko Ihara Ulfah Rimayanti Makoto Aihara Yoshiaki Kiuchi 《PloS one》2015,10(10)
The purpose of the study was to investigate the correlation between Corneal Visualization Scheimpflug Technology (Corvis ST tonometry: CST) parameters and various other ocular parameters, including intraocular pressure (IOP) with Goldmann applanation tonometry. IOP with Goldmann applanation tonometry (IOP-G), central corneal thickness (CCT), axial length (AL), corneal curvature, and CST parameters were measured in 94 eyes of 94 normal subjects. The relationship between ten CST parameters against age, gender, IOP-G, AL, CST-determined CCT and average corneal curvature was investigated using linear modeling. In addition, the relationship between IOP-G versus CST-determined CCT, AL, and other CST parameters was also investigated using linear modeling. Linear modeling showed that the CST measurement ‘A time-1’ is dependent on IOP-G, age, AL, and average corneal curvature; ‘A length-1’ depends on age and average corneal curvature; ‘A velocity-1’ depends on IOP-G and AL; ‘A time-2’ depends on IOP-G, age, and AL; ‘A length-2’ depends on CCT; ‘A velocity-2’ depends on IOP-G, age, AL, CCT, and average corneal curvature; ‘peak distance’ depends on gender; ‘maximum deformation amplitude’ depends on IOP-G, age, and AL. In the optimal model for IOP-G, A time-1, A velocity-1, and highest concavity curvature, but not CCT, were selected as the most important explanatory variables. In conclusion, many CST parameters were not significantly related to CCT, but IOP usually was a significant predictor, suggesting that an adjustment should be made to improve their usefulness for clinical investigations. It was also suggested CST parameters were more influential for IOP-G than CCT and average corneal curvature. 相似文献
8.
Mee Hyun Song Tae-Jun Kwon Hui Ram Kim Ju Hyun Jeon Jeong-In Baek Won-Sang Lee Un-Kyung Kim Jae Young Choi 《PloS one》2013,8(6)
Background
Branchio-oto-renal (BOR) or branchio-otic (BO) syndrome is one of the most common forms of autosomal dominant syndromic hearing loss. Mutations in EYA1, SIX1 and SIX5 genes have been associated with BOR syndrome. In this study, clinical and genetic analyses were performed in patients with BOR/BO syndrome focusing on auditory manifestations and rehabilitation.Methods
The audiologic manifestations were reviewed in 10 patients with BOR/BO syndrome. The operative findings and hearing outcome were analyzed in patients who underwent middle ear surgeries. The modality and outcome of auditory rehabilitation were evaluated. Genetic analysis was performed for EYA1, SIX1, and SIX5 genes.Results
All patients presented with mixed hearing loss. Five patients underwent middle ear surgeries without successful hearing gain. Cochlear implantation performed in two patients resulted in significant hearing improvement. Genetic analysis revealed four novel EYA1 mutations and a large deletion encompassing the EYA1 gene.Conclusions
Auditory rehabilitation in BOR/BO syndrome should be individually tailored keeping in mind the high failure rate after middle ear surgeries. Successful outcome can be expected with cochlear implantations in patients with BOR/BO syndrome who cannot benefit from hearing aids. The novel EYA1 mutations may add to the genotypic and phenotypic spectrum of BOR syndrome in the East Asian population. 相似文献9.
M Takamoto T Kaburaki A Mabuchi M Araie S Amano M Aihara A Tomidokoro A Iwase F Mabuchi K Kashiwagi S Shirato N Yasuda H Kawashima F Nakajima J Numaga Y Kawamura T Sasaki K Tokunaga 《PloS one》2012,7(7):e40107
Although intraocular pressure (IOP) is the most definitive cause of glaucoma, a subtype of open angle glaucoma (OAG) termed normal tension glaucoma (NTG), which occurs in spite of normal IOP, accounts for a large part of glaucoma cases, especially in Japan. To find common genetic variants contributing to NTG in Japanese patients, we conducted a genome-wide association study (GWAS). We performed the first screening for 531,009 autosomal SNPs with a discovery cohort of 286 cases and 557 controls, and then a second screening for the top 30 suggestive loci in an independent cohort of 183 cases and 514 controls. Our findings identified a significantly associated SNP; rs523096 [combined p-value = 7.40× 10−8, odds ratio (OR) = 2.00 with 95% confidence interval (CI) 1.55–2.58] located 10 kbp upstream of CDKN2B on chromosome 9p21. Moreover, analysis of another independent case-control set successfully replicated the results of the screening studies (combined values of all 3 stages p = 4.96 × 10−11, OR = 2.13 with 95% CI 1.69–2.68). The SNPs near rs523096 were recently reported to be associated with OAG associated with elevated IOP in primary open-angle glaucoma (POAG), the predominant subtype of glaucoma in Caucasian populations. Our results revealed that the 9p21 locus is also associated with NTG in Japanese. In addition, we identified SNPs more strongly associated with NTG. 相似文献
10.
Nakano M Ikeda Y Tokuda Y Fuwa M Omi N Ueno M Imai K Adachi H Kageyama M Mori K Kinoshita S Tashiro K 《PloS one》2012,7(3):e33389
Background
To date, only a small portion of the genetic variation for primary open-angle glaucoma (POAG), the major type of glaucoma, has been elucidated.Methods and Principal Findings
We examined our two data sets of the genome-wide association studies (GWAS) derived from a total of 2,219 Japanese subjects. First, we performed a GWAS by analyzing 653,519 autosomal common single-nucleotide polymorphisms (SNPs) in 833 POAG patients and 686 controls. As a result, five variants that passed the Bonferroni correction were identified in CDKN2B-AS1 on chromosome 9p21.3, which was already reported to be a significant locus in the Caucasian population. Moreover, we combined the data set with our previous GWAS data set derived from 411 POAG patients and 289 controls by the Mantel-Haenszel test, and all of the combined variants showed stronger association with POAG (P<5.8×10−10). We then subdivided the case groups into two subtypes based on the value of intraocular pressure (IOP)—POAG with high IOP (high pressure glaucoma, HPG) and that with normal IOP (normal pressure glaucoma, NPG)—and performed the GWAS using the two data sets, as the prevalence of NPG in Japanese is much higher than in Caucasians. The results suggested that the variants from the same CDKN2B-AS1 locus were likely to be significant for NPG patients.Conclusions and Significance
In this study, we successfully identified POAG-associated variants in the CDKN2B-AS1 locus using a Japanese population, i.e., variants originally reported as being associated with the Caucasian population. Although we cannot rule out that the significance could be due to the differences in sample size between HPG and NPG, the variants could be associated specifically with the vulnerability of the optic nerve to IOP, which is useful for investigating the etiology of glaucoma. 相似文献11.
12.
Wallax Augusto Silva Ferreira Mariana Diniz Araújo Nilson Praia Anselmo Edivaldo Herculano Correa de Oliveira José Reginaldo Nascimento Brito Rommel Rodriguez Burbano Maria Lúcia Harada Bárbara do Nascimento Borges 《PloS one》2015,10(8)
Astrocytic gliomas, which are derived from glial cells, are considered the most common primary neoplasias of the central nervous system (CNS) and are histologically classified as low grade (I and II) or high grade (III and IV). Recent studies have shown that astrocytoma formation is the result of the deregulation of several pathways, including the RB/E2F pathway, which is commonly deregulated in various human cancers via genetic or epigenetic mechanisms. On the basis of the assumption that the study of the mechanisms controlling the INK4/ARF locus can help elucidate the molecular pathogenesis of astrocytic tumors, identify diagnostic and prognostic markers, and help select appropriate clinical treatments, the present study aimed to evaluate and compare methylation patterns using bisulfite sequencing PCR and evaluate the gene expression profile using real-time PCR in the genes CDKN2A, CDKN2B, CDC6, Bmi-1, CCND1, and RB1 in astrocytic tumors. Our results indicate that all the evaluated genes are not methylated independent of the tumor grade. However, the real-time PCR results indicate that these genes undergo progressive deregulation as a function of the tumor grade. In addition, the genes CDKN2A, CDKN2B, and RB1 were underexpressed, whereas CDC6, Bmi-1, and CCND1 were overexpressed; the increase in gene expression was significantly associated with decreased patient survival. Therefore, we propose that the evaluation of the expression levels of the genes involved in the RB/E2F pathway can be used in the monitoring of patients with astrocytomas in clinical practice and for the prognostic indication of disease progression. 相似文献
13.
Humaira Ayub Shazia Micheal Farah Akhtar Muhammad Imran Khan Shaheena Bashir Nadia K. Waheed Mahmood Ali Frederieke E. Schoenmaker-Koller Sobia Shafique Raheel Qamar Anneke I. den Hollander 《PloS one》2014,9(8)
Recently an association was observed between alleles in genes of the unfolded protein response pathway and primary open angle glaucoma (POAG). The goal of the current study is to investigate the role of these two genes, protein disulphide isomerase A member 5 (PDIA5) and baculoviral IAP repeat containing 6 (BIRC6), in different forms of glaucoma. 278 patients with POAG, 132 patients with primary angle closure glaucoma (PACG) and 135 patients with pseudoexfoliative glaucoma (PEXG) were genotyped for single nucleotide polymorphisms (SNPs) rs11720822 in PDIA5 and 471 POAG, 184 PACG and 218 PEXG patients were genotyped for rs2754511 in BIRC6. Genotyping was done by allelic discrimination PCR, and genotype and allele frequencies were calculated. Logistic regression analyses were performed using R software to determine the association of these SNPs with glaucoma. The allele and genotype frequencies of rs11720822 in PDIA5 were not associated with POAG, PACG or PEXG. The TT genotype of rs2754511 in BIRC6 was found to be protective for PEXG (p = 0.05, OR 0.42 [0.22–0.81]) in the Pakistani population, but not for POAG or PACG. This study did not confirm a previously reported association of risk alleles in PDIA5 and BIRC6 with POAG, but did demonstrate a protective role of the T allele of rs2754511 in the BIRC6 gene in PEXG. This supports a role for the unfolded protein response pathway and regulation of apoptotic cell death in the pathogenesis of PEXG. 相似文献
14.
Background
The SIX family homeobox genes have been demonstrated to be involved in the tumor initiation and progression, but their clinicopathological features and prognostic values in non-small cell lung cancer (NSCLC) have not been well defined. We analyzed relevant datasets and performed a systemic review and a meta-analysis to assess the profile of SIX family members in NSCLC and evaluate their importance as biomarkers for diagnosis and prediction of NSCLC.Methods
This meta-analysis included 17 studies with 2358 patients. Hazard ratio (HR) and 95 % confidence interval (CI) were calculated to represent the prognosis of NSCLC with expression of the SIX family genes. Heterogeneity of the ORs and HRs was assessed and quantified using the Cochrane Q and I 2 test. Begg’s rank correlation method and Egger’s weighted regression method were used to screen for potential publication bias. Bar graphs of representative datasets were plotted to show the correlation between the SIX expression and clinicopathological features of NSCLC. Kaplan-Meier survival curves were used to validate our prognostic analysis by pooled HR.Results
The systematic meta-analysis unveiled that the higher expressions of SIX1-5 were associated with the greater possibility of the tumorigenesis. SIX4 and SIX6 were linked to the lymph node metastasis (LNM). SIX2, SIX3, and SIX4 were correlated with higher TNM stages. Furthermore, the elevated expressions of SIX2, SIX4, and SIX6 predicted poor overall survival (OS) in NSCLC (SIX2: HR?=?1.14, 95 % CI, 1.00–1.31; SIX4: HR?=?1.39, 95 % CI, 1.16–1.66; SIX6: HR?=?1.18, 95 % CI, 1.00–1.38) and poor relapse-free survival (RFS) in lung adenocarcinoma (ADC) (SIX2: HR?=?1.42, 95 % CI, 1.14–1.77; SIX4: HR?=?1.52, 95 % CI, 1.09–2.11; SIX6: HR?=?1.25, 95 % CI, 1.01–1.56).Conclusions
Our report demonstrated that the SIX family members play distinct roles in the tumorigenesis of NSCLC and can be potential biomarkers in predicting prognosis of NSCLC patients.15.
In spite of its strong familiality, gene identification for coronary artery disease (CAD) has not yielded a consistent picture.
One major reason for this is that families or cases and controls were not recruited from a homogeneous population. We, therefore,
attempted to map genes underlying 10 quantitative traits (QTs) that are known precursors of CAD in a homogeneous population
(Marwari) of India. The QTs are apolipoprotein B (ApoB), C-reactive protein (CRP), fibrinogen (FBG), homocysteine (HCY), lipoprotein
(a) (LPA), cholesterol – total (CHOL-T), cholesterol – HDL (CHOL-H), cholesterol – LDL (CHOL-L), cholesterol – VLDL (CHOL-V)
and triglyceride (TG). We assayed 209 SNPs in 31 genes among members of Marwari families. After log-transformation and covariate-adjustment
of the QTs, a two-step analysis was performed. In Step-1, data on unrelated individuals were analysed for association with
the SNPs. In Step-2, for validation of Step-1 results, a quantitative transmission-disequilibrium test on parent–offspring
data was performed for each SNP found to be significantly associated with a QT in Step-1 on an independent sample set drawn
from the same population. Statistically significant results found for the various QTs and SNPs were: rs3774933, rs230528,
rs230521, rs1005819 and rs1609798 (intronic, NFKB1) with APOB; rs5361 (Missense, R > S, SELE) and rs4648004 (Intronic, NFKB1) with FBG; rs4220 (Missense, K > R, FGB) with HCY; and rs3025035 (Intronic, VEGFA) with CHOL-H. SNPs in SELE, VEGFA, FGB and NFKB1 genes impact significantly on levels of quantitative precursors of CAD in Marwaris. 相似文献
16.
Jun Zou Kassa Semagn Hua Chen Muhammad Iqbal Mohammad Asif Amidou N’Diaye Alireza Navabi Enid Perez-Lara Curtis Pozniak Rong-Cai Yang Robert J. Graf Harpinder Randhawa Dean Spaner 《Molecular breeding : new strategies in plant improvement》2017,37(12):144
Spring wheat (Triticum aestivum L.) breeding goals in western Canada include good agronomic characteristics and good end-use quality, and also moderate to elevated resistance to diseases of economic importance. In this study, we aimed to identify quantitative trait loci (QTL) associated with resistance to common bunt (Tilletia tritici and Tilletia laevis), tan spot (Pyrenophora tritici-repentis), leaf rust (Puccinia triticina), and stripe rust (Puccinia striiformis f. sp. tritici). A total of 167 recombinant inbred lines (RILs) derived from a cross between two spring wheat cultivars, ‘Attila’ and ‘CDC Go’, were evaluated for reactions to the four diseases in nurseries from three to eight environments, and genotyped with the Wheat 90K SNP array and three gene-specific markers (Ppd-D1, Vrn-A1, and Rht-B1). The RILs exhibited transgressive segregation for all four diseases, and we observed several lines either superior or inferior to the parents. Broad-sense heritability varied from 0.25 for leaf rust to 0.48 for common bunt. Using a subset of 1203 informative markers (1200 SNPs and 3 gene-specific markers) and average disease scores across all environments, we identified two QTLs (QCbt.dms-1B.2 and QCbt.dms-3A) for common bunt, and three QTLs each for tan spot (QTs.dms-2B, QTs.dms-2D, and QTs.dms-6B), leaf rust (QLr.dms-2D.1, QLr.dms-2D.2, and QLr.dms-3A), and stripe rust (QYr.dms-3A, QYr.dms-4A, and QYr.dms-5B). Each QTL individually explained between 5.9 and 18.7% of the phenotypic variation, and altogether explained from 21.5 to 26.5% of phenotypic and from 52.2 to 86.0% of the genetic variation. The resistance alleles for all QTLs except one for stripe rust (QYr.dms-5B) were from CDC Go. Some of the QTLs are novel, while others mapped close to QTLs and/or genes reported in other studies. 相似文献
17.
Jie Wen Tina R?nn Anders Olsson Zhen Yang Bin Lu Yieping Du Leif Groop Charlotte Ling Renming Hu 《PloS one》2010,5(2)
Background
Recent genome-wide association studies (GWASs) have reported several genetic variants to be reproducibly associated with type 2 diabetes. Additional variants have also been detected from a metaanalysis of three GWASs, performed in populations of European ancestry. In the present study, we evaluated the influence of 17 genetic variants from 15 candidate loci, identified in type 2 diabetes GWASs and the metaanalysis, in a Han Chinese cohort.Methodology/Principal Findings
Selected type 2 diabetes–associated genetic variants were genotyped in 1,165 type 2 diabetic patients and 1,136 normoglycemic control individuals of Southern Han Chinese ancestry. The OR for risk of developing type 2 diabetes was calculated using a logistic regression model adjusted for age, sex, and BMI. Genotype-phenotype associations were tested using a multivariate linear regression model. Genetic variants in CDKN2A/B, CDKAL1, TCF7L2, TCF2, MC4R, and PPARG showed a nominal association with type 2 diabetes (P≤0.05), of whom the three first would stand correction for multiple testing: CDKN2A/B rs10811661, OR: 1.26 (1.12–1.43) P = 1.8*10−4; CDKAL1 rs10946398, OR: 1.23 (1.09–1.39); P = 7.1*10−4, and TCF7L2 rs7903146, OR: 1.61 (1.19–2.18) P = 2.3 * 10−3. Only nominal phenotype associations were observed, notably for rs8050136 in FTO and fasting plasma glucose (P = 0.002), postprandial plasma glucose (P = 0.002), and fasting C-peptide levels (P = 0.006) in the diabetic patients, and with BMI in controls (P = 0.033).Conclusions/Significance
We have identified significant association between variants in CDKN2A/B, CDKAL1 and TCF7L2, and type 2 diabetes in a Han Chinese cohort, indicating these genes as strong candidates conferring susceptibility to type 2 diabetes across different ethnicities. 相似文献18.
SIX5 (previously known as myotonic dystrophy associated homeodomain protein-DMAHP) is a member of the SIX [sine oculis homeobox (Drosophila) homologue] gene family which encodes proteins containing a SIX domain adjacent to a homeodomain. To investigate the DNA binding specificities of these two domains in SIX5, they were expressed as GST fusion proteins, both separately and together. Affinity purified recombinant proteins and cell lysates from bacteria expressing the recombinant proteins were used in gel retardation assays with double stranded oligonucleotides representing putative DNA binding sites. The putative sites included two in the promoter region of DMPK (dystrophia myotonica protein kinase) and the previously characterised murine Six4 DNA binding site in the Na+/K+ ATPase α1 subunit gene (ATP1A1) regulatory element (ARE). None of the recombinant proteins showed any affinity for the two putative sites in DMPK. However, the two recombinant proteins containing the homeodomain both formed at least one specific complex with the ARE. The recombinant protein containing both domains formed a second specific complex with the ARE, assumed to be a dimer complex. Finally, a whole genome PCR-based screen was used to identify genomic DNA sequences to which SIX5 binds, as an initial stage in the identification of genes regulated by SIX5. 相似文献
19.
Noriaki Takabatake Sayumi Toriyama Yoshikane Tokairin Tsuneo Konta Shuichi Abe Isao Kubota 《Biochemical and biophysical research communications》2009,381(4):554-559
The effect of smoking cessation on the rate of decline in lung function in patients with advanced stages of chronic obstructive pulmonary disease (COPD) has not been clarified. Saccharomyces cerevisiae cell division cycle 6 homolog (CDC6) protein possesses the pro-apoptotic properties. We tested our hypothesis that the individual susceptibility to rapid decline in lung function despite smoking cessation in patients with advanced stages of COPD is attributed to the genetic variants in the CDC6 gene. We prospectively followed 82 patients (ex-smokers) during 30 months and evaluated the differences among the genotypes in the annual rate of decline in FEV1.0 (%predicted) with ten single nucleotide polymorphisms (SNPs) in and around the CDC6 gene. We found significant differences in SNP5 (National Center for Biotechnology Information SNP reference: rs2077464), SNP6 (rs13706), SNP7 (rs7217852), and SNP8 (rs9904270) with a gene-dosage effect (ANOVA overall-P = 0.029-0.030). The individual allele of SNP5G, SNP6A, SNP7G, and SNP8T were associated with rapid decline in FEV1.0 (%predicted) [odds ratio (95% confidence interval) = 2.35 (1.19-4.65), P = 0.014]. The SNP5G/SNP6A/SNP7G/SNP8T haplotype was associated with an increased risk of deterioration of FEV1.0 (%predicted) (P = 0.017). Importantly, SNP6 caused a change in amino acids in CDC6 protein (Val441Ile), immediately upstream of the caspase-3-dependent cleavage site of CDC6 (Asp442) during apoptosis. These results suggest that CDC6 may be one of the susceptibility genes that contribute to rapid decline in lung function despite smoking cessation in these patients with COPD. 相似文献