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1.  Lack of association between the CHL1 gene and adolescent idiopathic scoliosis susceptibility in Han Chinese: a case-control study 
A previous genome-wide association study (GWAS) suggested a strong association between the single nucleotide polymorphism (SNP) rs10510181 in the proximity of the gene encoding a cell adhesion molecule with homology to L1CAM (CHL1) and adolescent idiopathic scoliosis (AIS) in Caucasians. To clarify the role of CHL1 in the etiopathogenesis of AIS, we performed a case-control replication study in a Han Chinese population.
Five hundred female AIS patients between 10 and 18 years of age, as well as 500 age- and sex-matched controls were included. This study was conducted as a 2-stage case-control analysis: initial screening for the association between AIS and SNPs in and around the CHL1 gene (186 cases and 169 controls) followed by a confirmation test (314 cases and 331 controls). rs10510181 and 4 SNPs (rs2055314, rs331894, rs2272522, and rs2272524) in the CHL1 gene were selected for genotyping.
Putative associations were shown between AIS and rs10510181, rs2055314, and rs2272522 in stage I. However, the associations were not confirmed in stage II. For rs10510181, the genotype frequencies were GG 28.8%, GA 46.2%, and AA 25.0% in AIS patients and GG 29.8%, GA 48.8%, and AA 21.4% in controls. No significant difference was found in genotype distribution between cases and controls (P = 0.39). Similarly, the genotype and allele distribution were comparable between case and control for rs2055314 and rs2272522.
There was no statistical association between polymorphisms of the CHL1 gene and idiopathic scoliosis in a Chinese population.
PMCID: PMC3925962  PMID: 24512353
Adolescent idiopathic scoliosis; CHL1; Chinese; Polymorphism
2.  Association between Common Variants near LBX1 and Adolescent Idiopathic Scoliosis Replicated in the Chinese Han Population 
PLoS ONE  2013;8(1):e53234.
Adolescent idiopathic scoliosis (AIS) is one of the most common spinal deformities found in adolescent populations. Recently, a genome-wide association study (GWAS) in a Japanese population indicated that three single nucleotide polymorphisms (SNPs), rs11190870, rs625039 and rs11598564, all located near the LBX1 gene, may be associated with AIS susceptibility [1]. This study suggests a novel AIS predisposition candidate gene and supports the hypothesis that somatosensory functional disorders could contribute to the pathogenesis of AIS. These findings warrant replication in other populations.
Methodology/Principal Findings
First, we conducted a case-control study consisting of 953 Chinese Han individuals from southern China (513 patients and 440 healthy controls), and the three SNPs were all found to be associated with AIS predisposition. The ORs were observed as 1.49 (95% CI 1.23–1.80, P = 5.09E-5), 1.70 (95% CI 1.42–2.04, P = 1.17E-8) and 1.52 (95% CI 1.27–1.83, P = 5.54E-6) for rs625039, rs11190870 and rs11598564, respectively. Second, a case-only study including a subgroup of AIS patients (N = 234) was performed to determine the effects of these variants on the severity of the condition. However, we did not find any association between these variants and the severity of curvature.
This study shows that the genetic variants near the LBX1 gene are associated with AIS susceptibility in Chinese Han population. It successfully replicates the results of the GWAS, which was performed in a Japanese population.
PMCID: PMC3537668  PMID: 23308168
3.  Identification of a Susceptibility Locus for Severe Adolescent Idiopathic Scoliosis on Chromosome 17q24.3 
PLoS ONE  2013;8(9):e72802.
Adolescent idiopathic scoliosis (AIS) is the most common spinal deformity, affecting around 2% of adolescents worldwide. Genetic factors play an important role in its etiology. Using a genome-wide association study (GWAS), we recently identified novel AIS susceptibility loci on chromosomes 10q24.31 and 6q24.1. To identify more AIS susceptibility loci relating to its severity and progression, we performed GWAS by limiting the case subjects to those with severe AIS. Through a two-stage association study using a total of ∼12,000 Japanese subjects, we identified a common variant, rs12946942 that showed a significant association with severe AIS in the recessive model (P = 4.00×10−8, odds ratio [OR] = 2.05). Its association was replicated in a Chinese population (combined P = 6.43×10−12, OR = 2.21). rs12946942 is on chromosome 17q24.3 near the genes SOX9 and KCNJ2, which when mutated cause scoliosis phenotypes. Our findings will offer new insight into the etiology and progression of AIS.
PMCID: PMC3762929  PMID: 24023777
4.  A single-nucleotide polymorphism rs708567 in the IL-17RC gene is associated with a susceptibility to and the curve severity of adolescent idiopathic scoliosis in a Chinese Han population: a case-control study 
Although the pathogenesis of adolescent idiopathic scoliosis (AIS) remains controversial, genetic factors are thought to play key roles in the development of AIS. In a recent genome-wide association study, a polymorphism in the interleukin-17 receptor C (IL-17RC) gene was reported to be associated with the susceptibility to AIS, implicating IL-17RC as a novel predisposing gene for AIS. However, as this association has not been replicated in other populations, its global applicability remains unclear.
A total of 529 Chinese girls with AIS and 512 healthy age-matched controls were recruited in this case–control study from June 2007 to December 2009. Polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) analysis was performed to detect the genotype of the single-nucleotide polymorphism (SNP) rs708567 in the IL-17RC gene. Case–control and case-only studies were performed to determine the association between the IL-17RC gene polymorphism and the susceptibility to and curve severity of AIS.
The GG genotype and G allele frequencies were significantly higher in the AIS patients than in the controls (χ2 test: P = 0.023 and 0.028, respectively). The risk for the GG genotype is 1.550-fold (95% CI: 1.062 - 2.261) higher than the AG genotype, and the risk for the G allele is 1.507-fold (95% CI: 1.046 - 2.172) higher than the A allele. Additionally, a subgroup of skeletally mature AIS patients (n = 241) who carried the GG genotype showed a significantly higher mean maximum Cobb angle than those carrying the AG genotype (36.01 ± 13.12° vs. 28.92 ± 7.43°, P = 0.007).
This study confirms the significant association between the IL-17RC gene polymorphism and the susceptibility to and curve severity of AIS in a Chinese Han population, suggesting that the IL-17RC gene is an AIS-predisposing gene in Chinese Han population.
PMCID: PMC3517504  PMID: 22999050
Adolescent idiopathic scoliosis; IL-17RC; Single-nucleotide polymorphism
5.  Common polymorphisms in human lysyl oxidase genes are not associated with the adolescent idiopathic scoliosis phenotype 
BMC Medical Genetics  2011;12:92.
Although adolescent idiopathic scoliosis affects approximately 3% of adolescents, the genetic contributions have proven difficult to identify. Work in model organisms, including zebrafish, chickens, and mice, has implicated the lysyl oxidase family of enzymes in the development of scoliosis. We hypothesized that common polymorphisms in the five human lysyl oxidase genes (LOX, LOXL1, LOXL2, LOXL3, and LOXL4) may be associated with the phenotype of adolescent idiopathic scoliosis.
This was a case-control genetic association study. A total of 112 coding and tag SNPs in LOX, LOXL1, LOXL2, LOXL3, and LOXL4 were genotyped in a discovery cohort of 138 cases and 411 controls. Genotypes were tested for association with adolescent idiopathic scoliosis by logistic regression with a two degree of freedom genotypic model and gender as a covariate. Fourteen SNPs with p < 0.1 in the discovery phase were genotyped in an independent replication cohort of 400 cases and 506 controls.
No evidence for significant association was found between coding or tag SNPs in LOX, LOXL1, LOXL2, LOXL3, and LOXL4 and the phenotype of adolescent idiopathic scoliosis.
Despite suggestive evidence in model organisms, common variants and known coding SNPs in the five human lysyl oxidase genes do not confer increased genotypic risk for adolescent idiopathic scoliosis. The above methodology does not address rare variants or individually private mutations in these genes, and future research may focus on this area.
PMCID: PMC3154146  PMID: 21740577
6.  The Association Study of Calmodulin 1 Gene Polymorphisms with Susceptibility to Adolescent Idiopathic Scoliosis 
BioMed Research International  2014;2014:168106.
Objective. Idiopathic scoliosis is the most common pediatric spinal deformity affecting 1% to 3% of the population, and adolescent idiopathic scoliosis (AIS) accounts for approximately 80% of these cases; however, the etiology and pathogenesis of AIS are still uncertain. The current study aims to identify the relationship between calmodulin 1 (CALM1) gene and AIS predisposition, to identify the relationship between the genotypes of the SNPs and the clinical phenotypes of AIS. Methods. 146 AIS patients and 146 healthy controls were enrolled into this case-control study. 12 single nucleotide polymorphisms (SNPs) candidates in CALM1 gene were selected to determine the relationship between CALM1 gene and AIS predisposition. Case-only study was performed to determine the effects of these variants on the severity of the condition. Results. Three SNPs from 12 candidates were found to be associated with AIS predisposition. The ORs were observed as 0.549 (95% CI 0.3519–0.8579, P = 0.0079), 0.549 (95% CI 0.3519–0.8579, P = 0.0079), and 1.6139 (95% CI 1.0576–2.4634, P = 0.0257) for rs2300496, rs2300500, and rs3231718, respectively. There was no statistical difference between main curve, severity, and genotype distributions of all of 12 SNPs. Conclusion. Genetic variants of CALM1 gene are associated with AIS susceptibility.
PMCID: PMC3914287  PMID: 24551838
7.  Identification of a Novel Risk Locus for Multiple Sclerosis at 13q31.3 by a Pooled Genome-Wide Scan of 500,000 Single Nucleotide Polymorphisms 
PLoS ONE  2008;3(10):e3490.
Multiple sclerosis is a chronic inflammatory demyelinating disease of the central nervous system with an important genetic component and strongest association driven by the HLA genes. We performed a pooling-based genome-wide association study of 500,000 SNPs in order to find new loci associated with the disease. After applying several criteria, 320 SNPs were selected from the microarrays and individually genotyped in a first and independent Spanish Caucasian replication cohort. The 8 most significant SNPs validated in this cohort were also genotyped in a second US Caucasian replication cohort for confirmation. The most significant association was obtained for SNP rs3129934, which neighbors the HLA-DRB/DQA loci and validates our pooling-based strategy. The second strongest association signal was found for SNP rs1327328, which resides in an unannotated region of chromosome 13 but is in linkage disequilibrium with nearby functional elements that may play important roles in disease susceptibility. This region of chromosome 13 has not been previously identified in MS linkage genome screens and represents a novel risk locus for the disease.
PMCID: PMC2566815  PMID: 18941528
8.  Replication of the 10q11 and Xp11 Prostate Cancer Risk Variants: Results from a Utah pedigree-based Study 
A recent genome-wide association (GWA) study suggested seven new loci as associated with prostate cancer (PRCA) susceptibility. The strongest associated SNP in each region was identified (rs2660753, rs9364554, rs6465657, rs10993994, rs7931342, rs2735839, rs5945619). We studied these seven SNPs in a replication study consisting of 169 familial PRCA cases selected from Utah high-risk PRCA pedigrees and 805 controls. We performed subset analyses for aggressive and early onset PRCA. At a nominal significance level, two SNPs were found to be associated with PRCA: rs10993994 on chromosome 10q11 (odds ratio (OR) =1.42 [95% confidence interval (CI), 1.05–1.90], p=0.022); and rs5945619 on chromosome Xp11 (OR=1.54 [95% CI, 1.03–2.31], p=0.035). Restricting analysis to familial PRCA cases with aggressive disease yielded very similar risk estimates at both SNPs. However, subset analysis for familial, early onset disease indicated highly significant association evidence and substantially higher risk estimates for rs10993994 (OR=2.20 [95% CI, 1.48–3.27], p<0.0001). This result suggests that the higher risk estimates from the stage 1 cohort in the original study for rs10993994 may have been due to the early-onset and familial nature of the PRCA cases in that cohort. In conclusion, in a small case-control study of PRCA cases from Utah high-risk pedigrees, we have significantly replicated association of PRCA with rs10993994 (10q11) upon study-wide correction for multiple comparisons. We also nominally replicated the association of PRCA with rs5945619 (Xp11). In particular, it appears that the susceptibility locus at 10q11 maybe involved in familial, early onset disease.
PMCID: PMC2697376  PMID: 19336566
Prostate Cancer; Genetic Risk
9.  Promoter polymorphism of matrilin-1 gene predisposes to adolescent idiopathic scoliosis in a Chinese population 
Adolescent idiopathic scoliosis (AIS) is widely recognized as a complex disorder with a strong genetic predisposition. In previous studies, a number of extracellular matrixes (ECMs) related genes have been duplicated as candidate genes for AIS. Matrilin-1 plays an important role in the organization of the ECM, and matrilin-1 gene (MATN1) mutant mice showed similar phenotypes to scoliosis. We hypothesized that MATN1 was a candidate predisposition gene for AIS. A gene-based association study was conducted using seven tagging SNPs identified from the HapMap data. For initial screening, the seven tagSNPs were genotyped in 197 cases and 172 controls. Next, we validated any significant association in an additional sample of 222 cases and 288 controls. In addition, another 290 controls were genotyped to confirm the results. We found that allele G of rs1149048 was a significant predisposition allele of AIS (P=0.0007, odds ratio (OR)=1.35 within 95% confidence interval (CI)=1.14–1.61), and individuals with genotype GG had a higher risk for AIS compared with AA+AG (P=0.0001, OR=1.61 within 95% CI=1.25–2.08). Polymorphism of rs1149048 was also associated with curve severity in AIS patients. Also, a significantly higher maximum Cobb angle was found in patients with GG genotype (P=0.002). We concluded that the tagSNP rs1149048 polymorphism in the MATN1 promoter region was associated with both susceptibility and disease progression in AIS.
PMCID: PMC2986210  PMID: 18985072
scoliosis; tagging SNP; polymorphism; MATN1
10.  Normal Leptin Expression, Lower Adipogenic Ability, Decreased Leptin Receptor and Hyposensitivity to Leptin in Adolescent Idiopathic Scoliosis 
PLoS ONE  2012;7(5):e36648.
Leptin has been suggested to play a role in the etiology of Adolescent Idiopathic Scoliosis (AIS), however, the leptin levels in AIS girls are still a discrepancy, and no in vitro study of leptin in AIS is reported. We took a series of case-control studies, trying to understand whether Leptin gene polymorphisms are involved in the etiology of the AIS or the change in leptin level is a secondary event, to assess the level of leptin receptor, and to evaluate the differences of response to leptin between AIS cases and controls. We screened all exons of Leptin gene in 45 cases and 45 controls and selected six tag SNPs to cover all the observed variations. Association analysis in 446 AIS patients and 550 healthy controls showed no association between the polymorphisms of Leptin gene and susceptibility/severity to AIS. Moreover, adipogenesis assay of bone mesenchymal stem cells (MSCs) suggested that the adipogenic ability of MSCs from AIS girls was lower than controls. After adjusting the differentiation rate, expressions of leptin and leptin receptor were similar between two groups. Meanwhile, osteogenesis assay of MSC showed the leptin level was similar after adjusting the differentiation rate, but the leptin receptor level was decreased in induced AIS osteoblasts. Immunocytochemistry and western blot analysis showed less leptin receptors expressed in AIS group. Furthermore, factorial designed studies with adipogenesis and osteogenesis revealed that the MSCs from patients have no response to leptin treatment. Our results suggested that Leptin gene variations are not associated with AIS and low serum leptin probably is a secondary outcome which may be related to the low capability of adipogenesis in AIS. The decreased leptin receptor levels may lead to the hyposensitivity to leptin. These findings implied that abnormal peripheral leptin signaling plays an important role in the pathological mechanism of AIS.
PMCID: PMC3352937  PMID: 22615788
11.  Association of rs11190870 near LBX1 with adolescent idiopathic scoliosis susceptibility in a Han Chinese population 
European Spine Journal  2012;22(2):282-286.
To investigate whether rs11190870 near LBX1 correlates with the susceptibility or curve progression of adolescent idiopathic scoliosis (AIS) in a Han Chinese population.
A total of 949 AIS patients and 976 age-matched healthy controls were recruited. All the subjects were genotyped using the PCR-based invader assay. Case–control study and case-only study were performed to define the contribution of rs11190870 to predisposition and curve severity of AIS. Additionally, we further conducted a meta-analysis of the study findings together with those of previously reported studies.
A significant association of rs11190870 with AIS was observed in the Han Chinese population (P = 1.8 × 10−9; odd ratio = 1.51; 95 % confidence interval = 1.33–1.71), and AIS patients with TT genotype had a larger Cobb angle than those with TC or CC genotype (P = 0.005). The meta-analysis confirmed that the positive association of this SNP with AIS in the East Asian population.
The SNP rs11190870 near LBX1 is associated with both susceptibility and curve progression of AIS.
PMCID: PMC3555620  PMID: 23096252
Adolescent idiopathic scoliosis; Han Chinese; rs11190870; Genetic; Etiology
12.  Genomic polymorphisms of G-Protein Estrogen Receptor 1 are associated with severity of adolescent idiopathic scoliosis 
International Orthopaedics  2011;36(3):671-677.
Adolescent idiopathic scoliosis (AIS) is reported to be associated with the two traditional estrogen receptor genes, ESR1 and ESR2. Yet, the novel estrogen receptor G protein-coupled estrogen receptor 1 (GPER) has not been studied. To investigate the association of GPER gene polymorphisms with the onset and deterioration of AIS, we performed a case-control study.
Clinical information was recorded, blood samples were taken and genomic DNA was extracted. After resequencing the gene in 45 cases and 45 controls who were randomly selected, 16 tag single nucleotide polymorphisms (SNPs) were selected. Then the association study was extended by an additional 344 patients and 293 controls with direct sequencing and a TaqMan-based genotyping assay. The chi-square test and logistic regression were used to analyse the genotypic and allelic association. One-way analysis of variance was used to compare the mean maximum Cobb angles and ages with different genotypes in the case-only data set.
No association was observed between the polymorphisms of the GPER gene and susceptibility to AIS. However, heterozygotes in three SNPs of the gene (rs3808351, rs10269151 and rs426655s3) were related significantly with the curve severity in AIS patients (P = 0.004, 0.048 and 0.028, respectively).
Our results demonstrate that GPER gene polymorphisms are associated with the severity of curvature in AIS; deficits of GPER may contribute to the deterioration of spine deformity.
PMCID: PMC3291774  PMID: 22002330
13.  Transient long thoracic nerve injury during posterior spinal fusion for adolescent idiopathic scoliosis: A report of two cases 
Indian Journal of Orthopaedics  2013;47(6):621-623.
We present the transient long thoracic nerve (LTN) injury during instrumented posterior spinal arthrodesis for idiopathic scoliosis. The suspected mechanism of injury, postoperative course and final outcome is discussed. The LTN is susceptible to injury due to its long and relatively superficial course across the thoracic wall through direct trauma or tension. Radical mastectomies with resection of axillary lymph nodes, first rib resection to treat thoracic outlet syndrome and cardiac surgery can be complicated with LTN injury. LTN injury producing scapular winging has not been reported in association with spinal deformity surgery. We reviewed the medical notes and spinal radiographs of two adolescent patients with idiopathic scoliosis who underwent posterior spinal arthrodesis and developed LTN neuropraxia. Scoliosis surgery was uneventful and intraoperative spinal cord monitoring was stable throughout the procedure. Postoperative neurological examination was otherwise normal, but both patients developed winging of the scapula at 4 and 6 days after spinal arthrodesis, which did not affect shoulder function. Both patients made a good recovery and the scapular winging resolved spontaneously 8 and 11 months following surgery with no residual morbidity. We believe that this LTN was due to positioning of our patients with their head flexed, tilted and rotated toward the contralateral side while the arm was abducted and extended. The use of heavy retractors may have also applied compression or tension to the nerve in one of our patients contributing to the development of neuropraxia. This is an important consideration during spinal deformity surgery to prevent potentially permanent injury to the nerve, which can produce severe shoulder dysfunction and persistent pain.
PMCID: PMC3868146  PMID: 24379470
Long thoracic nerve; neuropraxia; posterior spinal fusion; scoliosis; spinal deformity; correction; winging
14.  Replication and Fine Mapping for Association of the C2orf43, FOXP4, GPRC6A and RFX6 Genes with Prostate Cancer in the Chinese Population 
PLoS ONE  2012;7(5):e37866.
Prostate cancer represents the leading cause of male death across the world. A recent genome-wide association study (GWAS) identified five novel susceptibility loci for prostate cancer in the Japanese population. This study is to replicate and fine map the potential association of these five loci with prostate cancer in the Chinese Han population.
In Phase I of the study, we tested the five single nucleotide polymorphisms (SNPs) which showed the strongest association evidence in the original GWAS in Japanese. The study sample consists of 1,169 Chinese Hans, comprising 483 patients and 686 healthy controls. Then in phase II, flanking SNPs of the successfully replicated SNPs in Phase I were genotyped and tested for association with prostate cancer to fine map those significant association signals.
We successfully replicated the association of rs13385191 (located in the C2orf43 gene, P = 8.60×10−5), rs12653946 (P = 1.33×10−6), rs1983891 (FOXP4, P = 6.22×10−5), and rs339331 (GPRC6A/RFX6, P = 1.42×10−5) with prostate cancer. The most significant odds ratio (OR) was recorded as 1.41 (95% confidence interval 1.18–1.68) for rs12653946. Rs9600079 did not show significant association (P = 8.07×10−2) with prostate cancer in this study. The Phase II study refined these association signals, and identified several SNPs showing more significant association with prostate cancer than the very SNPs tested in Phase I.
Our results provide further support for association of the C2orf43, FOXP4, GPRC6A and RFX6 genes with prostate cancer in Eastern Asian populations. This study also characterized the novel loci reported in the original GWAS with more details. Further work is still required to determine the functional variations and finally clarify the underlying biological mechanisms.
PMCID: PMC3360662  PMID: 22662242
15.  Mouse Genome-Wide Association Mapping Needs Linkage Analysis to Avoid False-Positive Loci 
PLoS Genetics  2009;5(1):e1000331.
We carried out genome-wide association (GWA) studies in inbred mouse strains characterized for their lung tumor susceptibility phenotypes (spontaneous or urethane-induced) with panels of 12,959 (13K) or 138,793 (140K) single-nucleotide polymorphisms (SNPs). Above the statistical thresholds, we detected only SNP rs3681853 on Chromosome 5, two SNPs in the pulmonary adenoma susceptibility 1 (Pas1) locus, and SNP rs4174648 on Chromosome 16 for spontaneous tumor incidence, urethane-induced tumor incidence, and urethane-induced tumor multiplicity, respectively, with the 13K SNP panel, but only the Pas1 locus with the 140K SNP panel. Haplotype analysis carried out in the latter panel detected four additional loci. Loci reported in previous GWA studies failed to replicate. Genome-wide genetic linkage analysis in urethane-treated (BALB/c×C3H/He)F2, (BALB/c×SWR/J)F2, and (A/J×C3H/He)F2 mice showed that Pas1, but none of the other loci detected previously or herein by GWA, had a significant effect. The Lasc1 gene, identified by GWA as a functional element (Nat. Genet., 38:888–95, 2006), showed no genetic effects in the two independent intercross mouse populations containing both alleles, nor was it expressed in mouse normal lung or lung tumors. Our results indicate that GWA studies in mouse inbred strains can suffer a high rate of false-positive results and that such an approach should be used in conjunction with classical linkage mapping in genetic crosses.
Author Summary
Genome-wide mapping is now popular in both humans and experimental animals, but results of these studies are not validated by independent approaches. We conducted a genome-wide mapping analysis of lung cancer phenotypes in mouse strains and compared our results with those in three previous studies. We found that most of the loci identified in the earlier studies do not replicate. When we combined genome-wide association study with genetic linkage analysis, representing the gold standard of causal inference for allelic effects, the Pas1 locus detected in only one of the three previous genome-wide studies did replicate in genetic crosses, whereas the reportedly functional Lasc1 D102E polymorphism lacked allelic effects in two independent crosses. Our study supports the notion that association mapping in the population of inbred mouse strains is characterized by a high false-positive rate and that such a method must be carried out in conjunction with linkage analysis to detect relevant loci. These results point to the need for independent confirmations in population-based studies.
PMCID: PMC2614123  PMID: 19132132
16.  Genetic aspects of adolescent idiopathic scoliosis in a family with multiple affected members: a research article 
Scoliosis  2010;5:7.
The etiology of idiopathic scoliosis remains unknown and different factors have been suggested as causal. Hereditary factors can also determine the etiology of the disease; however, the pattern of inheritance remains unknown. Autosomal dominant, X-linked and multifactorial patterns of inheritances have been reported. Other studies have suggested possible chromosome regions related to the etiology of idiopathic scoliosis. We report the genetic aspects of and investigate chromosome regions for adolescent idiopathic scoliosis in a Brazilian family.
Evaluation of 57 family members, distributed over 4 generations of a Brazilian family, with 9 carriers of adolescent idiopathic scoliosis. The proband presented a scoliotic curve of 75 degrees, as determined by the Cobb method. Genomic DNA from family members was genotyped.
Locating a chromosome region linked to adolescent idiopathic scoliosis was not possible in the family studied.
While it was not possible to determine a chromosome region responsible for adolescent idiopathic scoliosis by investigation of genetic linkage using microsatellites markers during analysis of four generations of a Brazilian family with multiple affected members, analysis including other types of genomic variations, like single nucleotide polymorphisms (SNPs) could contribute to the continuity of this study.
PMCID: PMC2873229  PMID: 20374654
17.  Genetic Association and Gene-Gene Interaction Analyses in African American Dialysis Patients With Nondiabetic Nephropathy 
African Americans (AAs) have increased susceptibility to non-diabetic nephropathy relative to European Americans.
Study Design
Follow-up of a pooled genome-wide association study (GWAS) in AA dialysis patients with nondiabetic nephropathy; novel gene-gene interaction analyses.
Setting & Participants
Wake Forest sample: 962 AA nondiabetic nephropathy cases; 931 non-nephropathy controls. Replication sample: 668 Family Investigation of Nephropathy and Diabetes (FIND) AA nondiabetic nephropathy cases; 804 non-nephropathy controls.
Individual genotyping of top 1420 pooled GWAS-associated single nucleotide polymorphisms (SNPs) and 54 SNPs in six nephropathy susceptibility genes.
APOL1 genetic association and additional candidate susceptibility loci interacting with, or independently from, APOL1.
The strongest GWAS associations included two non-coding APOL1 SNPs, rs2239785 (odds ratio [OR], 0.33; dominant; p = 5.9 × 10−24) and rs136148 (OR, 0.54; additive; p = 1.1 × 10−7) with replication in FIND (p = 5.0 × 10−21 and 1.9 × 10−05, respectively). Rs2239785 remained significantly associated after controlling for the APOL1 G1 and G2 coding variants. Additional top hits included a CFH SNP(OR from meta-analysis in above 3367 AA cases and controls, 0.81; additive; p = 6.8 × 10−4). The 1420 SNPs were tested for interaction with APOL1 G1 and G2 variants. Several interactive SNPs were detected, the most significant was rs16854341 in the podocin gene (NPHS2) (p = 0.0001).
Non-pooled GWAS have not been performed in AA nondiabetic nephropathy.
This follow-up of a pooled GWAS provides additional and independent evidence that APOL1 variants contribute to nondiabetic nephropathy in AAs and identified additional associated and interactive non-diabetic nephropathy susceptibility genes.
PMCID: PMC3259209  PMID: 22119407
African American; APOL1; CFH; end-stage renal disease; FIND; FSGS; hypertension
18.  Single Nucleotide Polymorphisms in JAZF1 and BCL11A gene are nominally associated with Type 2 Diabetes in African American Families from the GENNID Study 
Journal of Human Genetics  2011;57(1):57-61.
Prior type 2 diabetes (T2D) genome-wide association studies (GWASs) have generated a list of well-replicated susceptibility loci in populations of European and Asian ancestry. In order to validate the trans-ethnic contribution of these GWAS SNPs, we performed a family-based association analysis of 32 selected GWAS SNPs in a cohort of 1496 African American (AA) subjects from the GENNID study. Functional roles of these SNPs were evaluated by screening cis-eQTLs in transformed lymphoblast cell lines available for a sub-group of GENNID families from Arkansas. Only three of the 32 GWAS-derived SNPs showed nominally significant association with T2D in our AA cohort. Among the replicated SNPs rs864745 in JAZF1 and rs10490072 in BCL11A gene (p= 0.006 and 0.03, respectively, after adjustment for BMI) were within the 1-lod drop support interval of T2D linkage peaks reported in these families. Genotyping of 19 Tag-SNPs in these two loci revealed no further common SNPs or haplotypes that may be a stronger predictor of T2D susceptibility than the index SNPs. Six T2D GWAS SNPs (rs6698181, rs9472138, rs730497, rs10811661, rs11037909, and rs1153188) were associated with nearby transcript expression in transformed lymphoblast cell lines of GENNID AA subjects. Thus, our study indicates a nominal role for JAZF1 and BCL11A variants in T2D susceptibility in AAs and suggested little overlap in known susceptibility to T2D between European and African derived populations when considering GWAS SNPs alone.
PMCID: PMC3266455  PMID: 22113416
Association; Diabetes; eQTL; gene expression; linkage disequilibrium; SNP
19.  A Novel Unstable Duplication Upstream of HAS2 Predisposes to a Breed-Defining Skin Phenotype and a Periodic Fever Syndrome in Chinese Shar-Pei Dogs 
PLoS Genetics  2011;7(3):e1001332.
Hereditary periodic fever syndromes are characterized by recurrent episodes of fever and inflammation with no known pathogenic or autoimmune cause. In humans, several genes have been implicated in this group of diseases, but the majority of cases remain unexplained. A similar periodic fever syndrome is relatively frequent in the Chinese Shar-Pei breed of dogs. In the western world, Shar-Pei have been strongly selected for a distinctive thick and heavily folded skin. In this study, a mutation affecting both these traits was identified. Using genome-wide SNP analysis of Shar-Pei and other breeds, the strongest signal of a breed-specific selective sweep was located on chromosome 13. The same region also harbored the strongest genome-wide association (GWA) signal for susceptibility to the periodic fever syndrome (praw = 2.3×10−6, pgenome = 0.01). Dense targeted resequencing revealed two partially overlapping duplications, 14.3 Kb and 16.1 Kb in size, unique to Shar-Pei and upstream of the Hyaluronic Acid Synthase 2 (HAS2) gene. HAS2 encodes the rate-limiting enzyme synthesizing hyaluronan (HA), a major component of the skin. HA is up-regulated and accumulates in the thickened skin of Shar-Pei. A high copy number of the 16.1 Kb duplication was associated with an increased expression of HAS2 as well as the periodic fever syndrome (p<0.0001). When fragmented, HA can act as a trigger of the innate immune system and stimulate sterile fever and inflammation. The strong selection for the skin phenotype therefore appears to enrich for a pleiotropic mutation predisposing these dogs to a periodic fever syndrome. The identification of HA as a major risk factor for this canine disease raises the potential of this glycosaminoglycan as a risk factor for human periodic fevers and as an important driver of chronic inflammation.
Author Summary
Shar-Pei dogs have two unique features: a breed defining “wrinkled” skin phenotype and a genetic disorder called Familial Shar-Pei Fever (FSF). The wrinkled phenotype is strongly selected for and is the result of excessive hyaluronan (HA) deposited in the skin. HA is a molecule that may behave in a pro-inflammatory manner and create a “danger signal” by being analogous to molecules on the surface of pathogens. FSF is characterized by unprovoked episodes of fever and/or inflammation and resembles several human autoinflammatory syndromes. Here we show that the two features are connected and have the same genetic origin, a regulatory mutation located close to a HA synthesizing gene (HAS2). The mutation is a 16.1 Kb duplication, the copy number of which correlates with HAS2 expression and disease. We suggest that the large amount of HA responsible for the skin condition predisposes to sterile fever and inflammation. HAS2 was previously not known to associate with autoinflammatory disease, and this finding is of wide interest since approximately 60% of human patients with periodic fever syndrome remain genetically unexplained. This investigation also demonstrates how strong artificial selection may affect not only desired and selected phenotypes, but also the health of domestic animals.
PMCID: PMC3060080  PMID: 21437276
20.  Evaluation of GPR50, hMel-1B, and ROR-Alpha Melatonin-Related Receptors and the Etiology of Adolescent Idiopathic Scoliosis 
Journal of pediatric orthopedics  2010;30(6):539-543.
Adolescent idiopathic scoliosis (AIS) is the most common spinal deformity in children. Studies have shown low melatonin levels resulting from pinealectomy in chickens and mice result in the development scoliosis, while supplementation with melatonin after the pinealectomy prevented it. The mere characterization of low melatonin levels is not sufficient to explain the development of idiopathic scoliosis in primates and humans, but we hypothesize that a mutation in melatonin-related receptors may be involved with the development of scoliosis.
The coding, splice-site, and promoter regions of three melatonin-related receptors (hMel-1B, RORα, and GPR50) were evaluated by DNA sequencing for variants associated with the phenotype of adolescent idiopathic scoliosis. An initial screening of 50 scoliosis patients with adolescent idiopathic scoliosis was compared with 50 controls by DNA sequencing of the three receptors. Additional cases and controls were evaluated when genetic variants were observed (for a total of 885 individuals).
No significant differences were found in the hMel-1B and RORα receptors. We found two cSNPs in GPR50 (rs561077 and rs13440581) in the initial 50 patients. To evaluate the significance of these cSNPs, an additional 356 patients and 429 controls were analyzed. When the combined groups were analyzed, no significant associations were observed.
Despite the observed relationship between melatonin and scoliosis, there is no significant association between mutations found in any known melatonin-related receptors with adolescent idiopathic scoliosis. The strong evidence of a melatonin-related cause for the development of idiopathic scoliosis still encourages research into undiscovered melatonin-related receptors, melatonin-related hormones, and the catalytic enzymes for the serotonin-melatonin pathway.
Clinical Relevance
This investigation is a genetic testing of the remaining currently known melatonin-related receptors that have not previously been analyzed for association with AIS. Given the support in the literature of a relationship between melatonin and AIS, we have shown no mutations in any of the known melatonin-related receptor in patients with AIS.
PMCID: PMC2928583  PMID: 20733416
adolescent idiopathic scoliosis; melatonin; genetics
21.  XbaI and PvuII Polymorphisms of Estrogen Receptor 1 Gene in Females with Idiopathic Scoliosis: No Association with Occurrence or Clinical Form 
PLoS ONE  2013;8(10):e76806.
XbaI single nucleotide polymorphism (SNP) (A/G rs934099) in estrogen receptor 1 gene (ESR1) was described to be associated with curve severity in Japanese idiopathic scoliosis (IS) patients and in Chinese patients with both curve severity and predisposition to IS. PvuII SNP (C/T rs2234693) of ESR1 was described to be associated with the occurrence of IS in the Chinese population; however, two replication studies did not confirm the findings. The ESR1 SNPs have never been studied in Caucasian IS patients.
Case-control study. 287 females with IS underwent clinical, radiological and genetic examinations. The patients were divided into three groups according to curve progression velocity: non-progressive IS, slowly progressive IS (progression <1° per month), and rapidly progressive IS (progression ≥1° per month). The radiological maximum Cobb angle was measured and surgery rate established. A control group consisted of 182 healthy females.
All results followed Hardy-Weinberg equilibrium. In the case-control study, genotype frequency in the patients did not differ for the XbaI (AA = 33.5%, AG = 49.1%, GG = 17.4%), nor for the PvuII (TT = 26.8%, TC = 50.2%, CC = 23.0%) comparing to controls (AA = 33.5%, AG = 50.5%, GG = 15.9%) and (TT = 23.1%, TC = 51.1%, CC = 25.8%), respectively, p = 0.3685, p = 0.6046. The haplotype frequency for the patients (AT = 47.1%, GC = 39.2%, AC = 8.9%, GT = 2.8%) did not differ from the controls (AT = 44.8%, GC = 37.4%, AC = 14.0%, GT = 3.8%), p = 0.0645. No difference was found either in XbaI (p = 0.8671) or PvuII (p = 0.3601) allele distribution between the patients and the controls. In the case study, there was no significant difference in genotype frequency for the non-progressive, slowly progressive, and rapidly progressive scoliosis. No difference was found in genotype or haplotype distribution for the mean maximum Cobb angle or the surgery rate.
No association was found between ESR1 XbaI or ESR1 PvuII SNP and idiopathic scoliosis in Caucasian females. None of the previously reported associations could be confirmed, regarding curve severity, progression or operation rate.
PMCID: PMC3796567  PMID: 24155906
22.  Three-Dimensional Vertebral Wedging in Mild and Moderate Adolescent Idiopathic Scoliosis 
PLoS ONE  2013;8(8):e71504.
Vertebral wedging is associated with spinal deformity progression in adolescent idiopathic scoliosis. Reporting frontal and sagittal wedging separately could be misleading since these are projected values of a single three-dimensional deformation of the vertebral body. The objectives of this study were to determine if three-dimensional vertebral body wedging is present in mild scoliosis and if there are a preferential vertebral level, position and plane of deformation with increasing scoliotic severity.
Twenty-seven adolescent idiopathic scoliotic girls with mild to moderate Cobb angles (10° to 50°) participated in this study. All subjects had at least one set of bi-planar radiographs taken with the EOS® X-ray imaging system prior to any treatment. Subjects were divided into two groups, separating the mild (under 20°) from the moderate (20° and over) spinal scoliotic deformities. Wedging was calculated in three different geometric planes with respect to the smallest edge of the vertebral body.
Factorial analyses of variance revealed a main effect for the scoliosis severity but no main effect of vertebral Levels (apex and each of the three vertebrae above and below it) (F = 1.78, p = 0.101). Main effects of vertebral Positions (apex and above or below it) (F = 4.20, p = 0.015) and wedging Planes (F = 34.36, p<0.001) were also noted. Post-hoc analysis demonstrated a greater wedging in the inferior group of vertebrae (3.6°) than the superior group (2.9°, p = 0.019) and a significantly greater wedging (p≤0.03) along the sagittal plane (4.3°).
Vertebral wedging was present in mild scoliosis and increased as the scoliosis progressed. The greater wedging of the inferior group of vertebrae could be important in estimating the most distal vertebral segment to be restrained by bracing or to be fused in surgery. Largest vertebral body wedging values obtained in the sagittal plane support the claim that scoliosis could be initiated through a hypokyphosis.
PMCID: PMC3744570  PMID: 23977058
23.  New Breast Cancer Risk Variant Discovered at 10q25 in East Asian Women 
Recently, 41 new genetic susceptibility loci for breast cancer risk were identified in a genome-wide association study conducted in European descendants. Most of these risk variants have not been directly replicated in Asian populations.
We evaluated nine of those non-replication loci in East Asians in order to identify new risk variants for breast cancer in these regions. First, we analyzed single nucleotide polymorphisms (SNPs) in these regions using data from two GWAS conducted among Chinese and Korean women, including 5,083 cases and 4,376 controls (Stage 1). In each region we selected a SNP showing the strongest association with breast cancer risk for replication in an independent set of 7,294 cases and 9,404 controls of East Asian descents (Stage 2). Logistic regression models were used to calculate adjusted odds ratios (OR) and 95% confidence intervals (CI) as a measure of the association of breast cancer risk and genetic variants.
Two SNPs were replicated in Stage 2 at P < 0.05: rs1419026 at 6q14 (per allele OR = 1.07, 95% CI: 1.03-1.12, P = 3.0×10−4) and rs941827 at 10q25 (OR = 0.92, 95% CI: 0.89-0.96, P = 5.3×10−5). The association with rs941827 remained highly statistically significant after adjusting for the risk variant identified initially in women of European ancestry (OR = 0.88, 95% CI: 0.82-0.97, P = 5.3×10−5).
We identified a new breast cancer risk variant at 10q25 in East Asian women.
Results from this study improve the understanding of the genetic basis for breast cancer.
PMCID: PMC3720126  PMID: 23677579
breast cancer; genetic susceptibility; GWAS replication; single nucleotide polymorphism
24.  Effects of living environment on the postoperative Scoliosis Research Society-24 results in females with adolescent idiopathic scoliosis 
There are many factors influencing postoperative health-related quality of life of adolescent idiopathic scoliosis patients, including the degree of the deformity, culture, differences in geography, rural versus urban living environments, and social factors. The objective of this study was to analyze the significance of geographic factors and their differences influencing the postoperative quality of life in females with adolescent idiopathic scoliosis residing in urban and rural environments, by use of the Polish version of the SRS-24 questionnaire.
Forty urban and 20 rural postoperative patients with adolescent scoliosis with a minimum 2-year follow-up period after surgery were included in the study. The process of cross-cultural adaptation was performed according to the IQOLA Project.
General results of the Polish SRS-24 equalled 4.1 (SD 0.5) and 4.0 (SD.0.5) in the rural and urban groups of patients, respectively. The 2 groups do not differ in incidence of floor and ceiling effects. The Cronbach’s alpha values are excellent for the general result of SRS-24 in urban and rural groups (0.85 and 0.85, respectively). The sub-groups differed significantly in the self-image after surgery domain (p=0.048).
Patients from the rural group scored higher in the self-image after surgery domain but reported higher pain levels when compared to urban patients. The associations between SRS-24 results and radiographic parameters in the rural group of patients were strong, compared with moderate relations reported in the urban group.
PMCID: PMC3560694  PMID: 22847203
SRS-24; self-image; pain; adolescent idiopathic scoliosis; living environment
25.  Analysis of GWAS-linked loci in Parkinson disease reaffirms PARK16 as a susceptibility locus 
Neurology  2010;75(6):508-512.
A genome-wide association study (GWAS) in the Japanese population identified 2 new Parkinson disease (PD) susceptibility loci on 1q32 (PARK16) (OMIM 613164) and BST1. We analyzed single nucleotide polymorphism (SNPs) located at the GWAS-linked loci (PARK16, PARK8, PARK1, and BST1) in a Chinese population and also conducted a meta-analysis in Asians by pooling 2 independent replication studies from Japan.
We conducted an analysis of 13 SNPs associated with PD GWAS-linked loci in 2 case-control cohorts comprised of 1,349 ethnic Chinese subjects.
PARK16, PARK8, and PARK1 loci but not BST1 were found to be associated with PD. PARK16 SNPs were associated with a decreased risk while PARK1 and PARK8 SNPs were associated with an increased risk of PD. A pooled analysis of our Chinese cohorts and 2 Japanese replication cohorts involving 1,366 subjects with PD and 16,669 controls revealed robust association with these 3 loci and also BST1. There was a trend toward a stronger protective effect of SNPs at the PARK16 locus in sporadic PD compared to familial cases and in older compared to younger subjects.
Our study reaffirms the role of GWAS-linked loci in PD in Asian subjects and the strength of association is similar between Chinese and Japanese subjects. Efforts to elucidate the associated gene within PARK16 locus are warranted.
= genome-wide association study;
= Parkinson disease;
= single nucleotide polymorphism.
PMCID: PMC2918477  PMID: 20697102

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