Biomedical subjects

Lorraine Southam

Publications and source records attributed to Lorraine Southam.

7 recordsLinked to original sources

PubMed2007

Extreme context specificity in differential allelic expression.

Variability in cis-regulation of gene expression has been implicated in the phenotypic manifestation of complex traits including common, multifactorial diseases. The differential expression of alleles due to polymorphism in cis-regulatory elements is common in the human genome, but there is a paucity of information about the context specificity of these control elements. In this study, we examined the differential allelic expression (DAE) of BMP5 in human mesenchymal tissues obtained from 16 donors undergoing joint replacement for treatment of osteoarthritis. We observed significant differences in BMP5 allelic output, with allelic ratios greater than 4:1 (P < 10(-20)) in the tissues of some donors. We also discovered a significant variability in allelic expression within the different tissues of donors. For 12 of our donors, we examined the allelic expression of BMP5 in two different regions of cartilage: cartilage adjacent to the site of the osteoarthritic lesion and cartilage distal from the lesion. Five of these 12 donors demonstrated highly significant differences (P < or = 10(-8)) in allelic expression between the different regions of their cartilage. Using DAE as a phenotype, we attempted to map tissue-specific cis-regulatory polymorphisms, and we identified a single nucleotide polymorphism located downstream of BMP5, which was significantly associated with DAE in some but not all of the examined tissues. These findings suggest that allelic expression can be highly context specific and that when interrogating the cis-regulatory control of a particular gene, one cannot necessarily assume that allelic expression is conserved across different tissues or even across different regions of the same tissue.

Alleles↗

PubMed2004

Functional variants within the secreted frizzled-related protein 3 gene are associated with hip osteoarthritis in females.

Osteoarthritis (OA) is a leading cause of disability in Western society with multiple risk factors, including a complex genetic pattern. Identifying loci involved in the heredity of OA might lead to insights into the molecular pathogenesis of this common disorder. A previous genome scan mapped a primary hip OA susceptibility locus to chromosome 2q with a maximum multipoint logarithm of odds score of 1.6 in 378 affected sibling pair families. Here, microsatellite targeting of eight candidate genes in this region from 2q23-2q32 demonstrated significant associations with the tumor necrosis factor alpha-induced protein 6 gene in all probands and the integrin alpha 6 and frizzled motif associated with bone development (FRZB) genes in female probands. However, genotyping showed lack of association for a nonsynonymous single-nucleotide polymorphism in tumor necrosis factor alpha-induced protein 6, whereas a single-nucleotide polymorphism in FRZB resulting in an Arg324Gly substitution at the carboxyl terminus was associated with hip OA in the female probands (P = 0.04). This association was confirmed in an independent cohort of female hip cases (n = 338; P = 0.04). In addition, a haplotype coding for substitutions of two highly conserved arginine residues (Arg200Trp and Arg324Gly) in FRZB was a strong risk factor for primary hip OA, with an odds ratio of 4.1 (P = 0.004). FRZB encodes secreted frizzled-related protein 3, which is a soluble antagonist of wingless (wnt) signaling. Variant secreted frizzled-related protein 3 with the Arg324Gly substitution had diminished ability to antagonize wnt signaling in vitro. Hence, functional polymorphisms within FRZB confer susceptibility for hip OA in females and implicate the wnt signaling pathway in the pathogenesis of this disease.

Arginine↗

PubMed2004

Finer linkage mapping of primary osteoarthritis susceptibility loci on chromosomes 4 and 16 in families with affected women.

OBJECTIVE: To more finely linkage-map primary osteoarthritis (OA) susceptibility loci on chromosomes 4 and 16. METHODS: Two hundred eighteen families, each with 2 or more women concordant for primary OA (ascertained by total hip replacement [THR] or total knee replacement), were genotyped using highly polymorphic microsatellite markers from chromosomes 4 and 16, at an average density of 1 marker every 4 cM. Two-point and multipoint linkage analyses were performed for all 218 families and for the 146 families from the 218 that included women concordant for THR (female-THR families). RESULTS: A single region of linkage was identified on chromosome 4q, with a maximum multipoint logarithm of odds (LOD) score (MLS) of 3.1 in the 146 female-THR families. This locus was centered 79 cM from the 4p telomere and had a 1-LOD support interval of 4 cM. Two regions of linkage were identified on chromosome 16, the first on 16p with an MLS of 1.7 in the female-THR families and the second on 16q with an MLS of 1.9 in all 218 families. The first locus was centered 46 cM and the second 89 cM from the p-telomere. The 1-LOD support intervals were 12 cM and 10 cM, respectively. CONCLUSION: Finer linkage mapping using a high density of microsatellite markers has narrowed female OA susceptibility loci on chromosomes 4 and 16. The regions have been narrowed sufficiently for association analysis.

Chromosome Mapping↗

PubMed2004

Microsatellite association mapping of a primary osteoarthritis susceptibility locus on chromosome 6p12.3-q13.

OBJECTIVE: To test a high density of microsatellite markers from within a primary osteoarthritis (OA) locus on chromosome 6 for association with OA as a means of narrowing and focusing our search for the susceptibility gene. METHODS: One hundred forty-six families, each with 2 or more women concordant for primary OA (ascertained by total hip replacement), were genotyped for 36 microsatellite markers from within a narrow interval at 6p12.3-q13 which we had previously shown to be linked to OA. Each marker was tested for linkage and for association, the latter by means of the transmission disequilibrium test and by a case-control analysis. RESULTS: The highest 2-point logarithm of odds (LOD) score was 4.8, with 11 markers having LOD scores > or =2.0. Several markers demonstrated evidence of association, in particular, a cluster of markers positioned within or near the functional candidate gene BMP5. CONCLUSION: Our linkage data reinforce the evidence of a major susceptibility locus on chromosome 6. We had previously failed to detect an association with BMP5 using gene-based single-nucleotide polymorphisms. The association data reported here prompt us to speculate that the chromosome 6 susceptibility may be coded for by cis-acting polymorphism in the regulatory elements of this gene, rather than by variation in its protein coding sequence.

Arthroplasty, Replacement, Hip↗

PubMed2002

Angiotensin-1-converting enzyme (ACE) plasma concentration is influenced by multiple ACE-linked quantitative trait nucleotides.

Circulating angiotensin-1-converting enzyme (ACE) is a highly heritable trait, and a major component of the genetic variance maps to the region of the ACE gene. The strong effect of the locus, and the interest in ACE as a candidate gene for cardiovascular disorders, has led to extensive investigation of its relationship to the ACE phenotype, providing one of the most complete examples of quantitative trait locus (QTL) analysis in humans. Resequencing of ACE followed by haplotype analysis in families of British and French origin has shown that the genetic variants that are primarily associated with the ACE trait map to an 18 kb interval flanked by two intragenic, ancestral recombination breakpoints. This critical interval contains dozens of ACE-associated variants in Caucasians, but identification of which of these directly influence ACE concentration is ambiguous because of the almost complete linkage disequilibrium in European populations. In a complementary sequencing and genotyping study of individuals from West African families, we show that this population has much greater haplotype diversity across the gene. Through analysis of the contrasting relationships of the trait phenotype with haplotypes that carry different allelic combinations from those observed in Caucasians, we demonstrate that (at least) two major intragenic sites within the critical interval and (at least) one minor promoter site are associated with the ACE quantitative trait through additive effects. These results point to the importance of analysing diverse populations with different gene genealogies in gene-association studies.

Black People↗

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

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↗