Objective
GDF5 and FRZB have been proposed as genetic loci conferring susceptibility to osteoarthritis (OA); however, the results of several studies investigating the association of OA with the ...rs143383 polymorphism of the GDF5 gene or the rs7775 and rs288326 polymorphisms of the FRZB gene have been conflicting or inconclusive. To examine these associations, we performed a large‐scale meta‐analysis of individual‐level data.
Methods
Fourteen teams contributed data on polymorphisms and knee, hip, and hand OA. For rs143383, the total number of cases and controls, respectively, was 5,789 and 7,850 for hip OA, 5,085 and 8,135 for knee OA, and 4,040 and 4,792 for hand OA. For rs7775, the respective sample sizes were 4,352 and 10,843 for hip OA, 3,545 and 6,085 for knee OA, and 4,010 and 5,151 for hand OA, and for rs288326, they were 4,346 and 8,034 for hip OA, 3,595 and 6,106 for knee OA, and 3,982 and 5,152 for hand OA. For each individual study, sex‐specific odds ratios (ORs) were calculated for each OA phenotype that had been investigated. The ORs for each phenotype were synthesized using both fixed‐effects and random‐effects models for allele‐based effects, and also for haplotype effects for FRZB.
Results
A significant random‐effects summary OR for knee OA was demonstrated for rs143383 (1.15 95% confidence interval 1.09–1.22) (P = 9.4 × 10−7), with no significant between‐study heterogeneity. Estimates of effect sizes for hip and hand OA were similar, but a large between‐study heterogeneity was observed, and statistical significance was borderline (for OA of the hip P = 0.016) or absent (for OA of the hand P = 0.19). Analyses for FRZB polymorphisms and haplotypes did not reveal any statistically significant signals, except for a borderline association of rs288326 with hip OA (P = 0.019).
Conclusion
Evidence of an association between the GDF5 rs143383 polymorphism and OA is substantially strong, but the genetic effects are consistent across different populations only for knee OA. Findings of this collaborative analysis do not support the notion that FRZB rs7775 or rs288326 has any sizable genetic effect on OA phenotypes.
We have used eight PCR-based DNA polymorphisms to determine the parental origin and mechanisms of formation in 9 patients with de novo nonmosaic tetrasomy 18p. The 9 patients, 4 girls and 5 boys, had ...clinical features characteristic of i(18p) syndrome. The supernumerary marker chromosome was identified by fluorescence in situ hybridization (FISH) analysis using centromeric probes and a flow-sorted 18p-specific library. The isochromosome was of maternal origin in all 9 cases. The formation of tetrasomy 18p cannot be explained by a single model. In 6 cases, meiosis II nondisjunction, followed by subsequent postzygotic misdivsion, and in 1 case postzygotic nondisjunction and postzygotic misdivision were the most likely mechanisms of formation. Alternative mechanisms are suggested in the remaining 2 cases.
We present a study of a mentally retarded and mildly dysmorphic female in whom initial cytogenetic studies identified the karyotype 46,X, + mar. Further characterisation of the structurally abnormal ...chromosome by fluorescence in situ hybridisation (FISH) showed that it is composed of both X and Y chromosome material with a centromere originating from the Y chromosome. The presence of the DMD gene and the absence of the XIST gene was shown by FISH using locus specific probes. The Y segment included the SRY and ZFY genes. Based on these findings, the karyotype was defined as 46, X,der(Y)t(X;Y) (p21.1;q11). This case illustrates male to female sex reversal owing to a partial duplication of the short arm of the X chromosome in the presence of SRY.
We describe 4 jaundiced neonates with acute pyelonephritis of whom family history was positive for or pointed to Gilbert's syndrome (GS). Uridine diphosphate glucuronosyltransferase 1A1 (UGT-1A1), ...(TA)7 polymorphism, associated with GS was found in these neonates. We suggest that extended (TA)7 promoter, acting as a predisposing factor, contributes substantially to hyperbilirubinaemia seen in a number of neonates with urinary tract infections (UTIs).
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objective
Given the recent characterization of ADAMTS‐5 as the main aggrecanase of cartilage destruction in mouse models, we explored whether genetic variation and, in particular, putative damaging ...polymorphisms in the ADAMTS‐5 gene modify susceptibility to osteoarthritis (OA).
Methods
Two likely deleterious nonsynonymous single‐nucleotide polymorphisms (SNPs) were identified in ADAMTS‐5 by bioinformatics analysis, rs2830585 in exon 5 affecting a thrombospondin 1 motif, and rs226794 in exon 7. Exploration of their role was carried out in 3 steps, discovery, extension, and replication, on samples obtained from 4 European Caucasian collections, comprising a total of 2,715 patients with knee, hip, or hand OA and 1,185 OA‐free controls. In addition, 6 tagSNPs were studied to fully evaluate genetic variation in the ADAMTS‐5 locus.
Results
Initial analyses of 2 sample collections (n = 277 and n = 159) showed a trend toward decreased frequency of the putative deleterious allele of rs226794 among patients with severe knee OA (P = 0.047 versus controls). However, results in patients with knee OA from 2 additional sample collections (n = 360 and n = 265) did not confirm this trend. No association was found with hip OA or hand OA. None of the other SNPs or haplotypes constructed with these SNPs showed a significant association with OA susceptibility.
Conclusion
Use of several collections of OA samples allowed us to obtain sound evidence against the participation of genetic variation in ADAMTS‐5 in OA susceptibility. These results indicate the need to further explore the function of this aggrecanase in human OA to determine whether it is as critical as has been observed in mouse models.
We describe 4 jaundiced neonates with acute pyelonephritis of whom family history was positive for or pointed to Gilbert's syndrome (GS). Uridine diphosphate glucuronosyltransferase 1A1 (UGT-1A1), ...(TA)7 polymorphism, associated with GS was found in these neonates. We suggest that extended (TA)7 promoter, acting as a predisposing factor, contributes substantially to hyperbilirubinaemia seen in a number of neonates with urinary tract infections (UTIs).
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To identify genes involved in osteoarthritis (OA), the most prevalent form of joint disease, we performed a genome-wide association study (GWAS) in which we tested 500,510 Single Nucelotide ...Polymorphisms (SNPs) in 1341 OA cases and 3496 Dutch Caucasian controls. SNPs associated with at least two OA-phenotypes were analysed in 14,938 OA cases and approximately 39,000 controls. The C-allele of rs3815148 on chromosome 7q22 (MAF 23%, 172 kb upstream of the
GPR22
gene) was consistently associated with a 1.14-fold increased risk (95%CI: 1.09–1.19) for knee- and/or hand-OA (p=8×10
−8
), and also with a 30% increased risk for knee-OA progression (95%CI: 1.03–1.64, p=0.03). This SNP is in almost complete linkage disequilibrium with rs3757713 (located 68 kb upstream of
GPR22
) which is associated with
GPR22
expression levels in lymphoblast cell lines (p=4×10
−12
).
GPR22
encodes an G-protein coupled receptor with unkown ligand (orphan receptor). Immunohistochemistry experiments showed absence of
GPR22
in normal mouse articular cartilage or synovium. However,
GPR22
positive chondrocytes were found in the upper layers of the articular cartilage of mouse knee joints that were challenged by
in vivo
papain treatment or in the presence of interleukin-1 driven inflammation.
GRP22
positive chondrocyte-like cells were also found in osteophytes in instability-induced OA. In addition,
GPR22
is also present in areas of the brain involved in locomotor function. Our findings reveal a novel common variant on chromosome 7q22 to influence susceptibility for prevalence and progression of OA.
The potential genotoxicity of nitrates and nitrites-contaminants of drinking water that have been implicated in carcinogenesis-was investigated in this study. Sister chromatid exchanges and frequency ...of chromatid/hromosome aberrations were studied in peripheral blood lymphocytes of 70 children who were 12-15 y of age. These children were permanent residents in geographical areas of Greece, where elevated concentrations of nitrates (i.e., 55.70-87.98 mg/l) existed in drinking water. The control group comprised 20 healthy children who resided in areas with very low nitrate concentrations (i.e., 0.7 mg/l). A significant increase in the mean number of chromatid/chromosome breaks was observed in children exposed to nitrate concentrations that exceeded 70.5 mg/l (p < .01), but there was no significant increase in the mean number of sister chromatid exchanges per cell. The results indicate that chronic administration of elevated concentrations of nitrate in drinking water has the capability of inducing cytogenetic effects.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The C-band heterochromatin polymorphisms of chromosomes 1, 9, and 16 were studied on peripheral lymphocytes of 67 children with acute lymphoblastic leukemia (ALL) and 50 control individuals. A ...statistically significant difference between patients and controls was found for large heterochromatin regions (level 3) of chromosomes 1 and 9 (P > 0.001) and for small heterochromatin regions (level 1) of chromosome 16 (P > 0.001). The patients also showed a significant increase in chromosomes 1 and 9 heteromorphism with respect to controls (P > 0.001).
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