Biomedical subjects

John Loughlin

Publications and source records attributed to John Loughlin.

24 records · Page 2Linked to original sources

PubMed2003

Genetics of osteoarthritis and potential for drug development.

Genome-wide linkage scans for the mapping of osteoarthritis susceptibility loci have come to the fore in recent years, driven by the failure of candidate gene association studies. Four scans have been published, with several strong linkages reported. These do not encompass the major cartilage structural genes that many consider the most likely susceptibility loci. This has increased the probability that the biological pathways responsible for susceptibility are modifiable by drug treatment, which one would not reasonably expect for a structural protein. This in itself has stimulated the interest of several pharmaceutical companies. Such interest will be to the benefit of patients, but will require candid co-operation between academics and industry if the delay in transferring research findings from the laboratory to the clinic is to be minimised.

Drug Delivery Systems↗

PubMed2002

A novel allelic variant of the human TSG-6 gene encoding an amino acid difference in the CUB module. Chromosomal localization, frequency analysis, modeling, and expression.

Tumor necrosis factor-stimulated gene-6 (TSG-6) encodes a 35-kDa protein, which is comprised of contiguous Link and CUB modules. TSG-6 protein has been detected in the articular joints of osteoarthritis (OA) patients, with little or no constitutive expression in normal adult tissues. It interacts with components of cartilage matrix (e.g. hyaluronan and aggrecan) and thus may be involved in extracellular remodeling during joint disease. In addition, TSG-6 has been found to have anti-inflammatory properties in models of acute and chronic inflammation. Here we have mapped the human TSG-6 gene to 2q23.3, a region of chromosome 2 linked with OA. A single nucleotide polymorphism was identified that involves a non-synonymous G --> A transition at nucleotide 431 of the TSG-6 coding sequence, resulting in an Arg to Gln alteration in the CUB module (at residue 144 in the preprotein). Molecular modeling of the CUB domain indicated that this amino acid change might lead to functional differences. Typing of 400 OA cases and 400 controls revealed that the A(431) variant identified here is the major TSG-6 allele in Caucasians (with over 75% being A(431) homozygotes) but that this polymorphism is not a marker for OA susceptibility in the patients we have studied. Expression of the Arg(144) and Gln(144) allotypes in Drosophila Schneider 2 cells, and functional characterization, showed that there were no significant differences in the ability of these full-length proteins to bind hyaluronan or form a stable complex with inter-alpha-inhibitor.

Adenine↗

PubMed2002

Association of the interleukin-1 gene cluster on chromosome 2q13 with knee osteoarthritis.

OBJECTIVE: To investigate whether the interleukin-1 (IL-1) ligand gene cluster at 2q13 encodes for genetic susceptibility to primary osteoarthritis (OA). METHODS: Seven single-nucleotide polymorphisms (SNPs) and a variable-number tandem repeat (VNTR) polymorphism from within the IL-1 ligand genes IL1A, IL1B, and IL1RN were genotyped in a cohort of 557 OA cases and 557 age-matched controls. RESULTS: None of the variants demonstrated association in the unstratified data set. However, when cases were stratified according to sex and site of disease (hip or knee), 4 SNPs showed marginal evidence for association (P < 0.1) in knee cases (n = 136) and male knee cases (n = 58). For 2 of these SNPs, evidence for association was enhanced when probands from 60 knee-only affected sibling pair families were genotyped and combined with the original knee cases (P < or = 0.05). Further analysis revealed that the associated alleles at 2 of these SNPs were markers for the same haplotype, the frequency of which was significantly elevated when knee cases and knee probands were combined (P = 0.01, odds ratio [OR] 1.4) and when male knee cases and male knee probands were combined (P = 0.009, OR 1.7). Furthermore, linkage analysis of 2q revealed suggestive evidence for linkage to the IL-1 gene clusters in affected sibling pairs concordant for knee OA but no evidence for linkage in affected sibling pairs concordant for hip OA. CONCLUSION: The IL-1 ligand cluster encodes for susceptibility to knee OA but not to hip OA, highlighting the genetic heterogeneity of this common, complex disease.

Aged↗

PubMed2002

Finer linkage mapping of primary hip osteoarthritis susceptibility on chromosome 11q in a cohort of affected female sibling pairs.

OBJECTIVE: To finer linkage-map a primary osteoarthritis (OA) susceptibility locus as a prerequisite to linkage disequilibrium/association analysis. METHODS: A 50-cM interval of chromosome 11q that we had previously identified as harboring susceptibility to hip OA in a female sibling-pair cohort was subjected to finer linkage mapping. Thirty-five microsatellite markers with a mean marker interval of 1.4 cM were genotyped in 146 families containing female sibling pairs who were concordant for hip OA, as ascertained by total hip replacement. RESULTS: Two-point and multipoint linkage analysis revealed 2 distinct regions of linkage within the 50-cM interval. The first locus had a linkage interval of 11.9 cM and was centered at 81.5 cM from the 11p telomere, with a maximum multipoint logarithm of odds (LOD) score of 2.4. The second region had a linkage interval of 6.5 cM and was centered at 93.1 cM from the 11p telomere, with a maximum multipoint LOD score of 1.8. CONCLUSION: Dense linkage mapping has highlighted the presence of 2 loci on chromosome 11q, each conferring susceptibility to hip OA. Both loci are sufficiently narrow for association analysis to be undertaken.

Chromosome Mapping↗

PubMed2002

Genome studies and linkage in primary osteoarthritis.

Genetic epidemiologic studies have demonstrated that primary OA has a major genetic component that segregates in families in a complex manner. Some of these studies suggest that genetic susceptibility may be more relevant to female OA than to male OA and that genes may have a greater role in OA development and progression at certain joint groups compared with others. These observations are not universal, however, and discrepancies between different studies may simply serve to highlight the complex nature of the transmittance of OA susceptibility. The numerous OA linkage studies that have now been performed have revealed a number of regions of the human genome that are likely to harbor genes predisposing to OA. Several of these regions, particularly those identified in genome-wide scans of ASPs, have relatively low LOD scores; as a result, their reliability must be questioned. Nevertheless, a few of these regions have already been linked in more than one study, and these linkages can be considered as more robust. Such confirmation is a prerequisite to finer linkage mapping, which should narrow the linkage intervals to a point at which comprehensive association analysis of DNA sequence variants can be undertaken.

Genetic Linkage↗

PubMed2002

Finer linkage mapping of a primary hip osteoarthritis susceptibility locus on chromosome 6.

Primary osteoarthritis (OA) is a common late-onset disease that exhibits complex genetic transmittance. A previous genome-wide linkage scan of OA affected sibling pair families (ascertained by total joint replacement surgery) identified a region of suggestive linkage on chromosome 6, with a maximum multipoint-LOD score (MLS) of 2.9 in 194 families containing sibling pairs concordant for total hip replacement (THR-families). However, up to 50 cM of the chromosome had a multipoint-LOD score >2.0, indicating that the susceptibility locus was poorly mapped. We have now genotyped chromosome 6 to a higher density in an expanded cohort of 378 THR-families. We obtained an MLS of 2.8 to an 11.4 cM interval defined by markers D6S452 and 509-8B2, which map between 70.5 to 81.9 cM from the 6p-telomere. Stratification by gender revealed that this linkage was completely accounted for by female THR-families (n=146), with an MLS of 4.0 and with the highest two-point LOD score being 4.6 for marker D6S1573 (75.9 cM). The 11.4 cM interval just encompasses the candidate gene COL9A1 (81.9 cM). We identified and then genotyped twenty common single nucleotide polymorphisms (SNPs) from within COL9A1 in the 146 probands from our female THR-families and in 215 age-matched female controls. No SNP allele, genotype or haplotype demonstrated association to disease. Overall, we have narrowed the chromosome 6 OA susceptibility locus to a point at which linkage disequilibrium/association analysis is feasible, we have demonstrated that this locus is female specific, and found no evidence that COL9A1 encodes for the susceptibility.

Chromosome Mapping↗