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A Marlow

Publications and source records attributed to A Marlow.

5 recordsLinked to original sources
PubMed1997

Investigation of candidate disease susceptibility genes in rheumatoid arthritis: principles and strategies.

It has been estimated that a number of non-HLA susceptibility loci exist in rheumatoid arthritis (RA), each making relatively small contributions (lambda s < 2). Previous approaches for whole genome screening are unlikely to be sufficiently sensitive to detect such loci. As the pathology of RA already indicates several molecules that may be of potential importance in disease susceptibility, we propose an alternative approach, targeting candidate genes directly. Highly polymorphic dinucleotide markers within a candidate gene sequence or close to the gene can be used as markers, and the selection of the most appropriate markers is discussed. RA sibling pair families from the Arthritis and Rheumatism Council National Repository (n = 200) are used in linkage analysis studies. The data generated are analyzed using sib pair analysis methods to examine evidence of linkage. The interpretation of such results is also discussed, in particular, minimizing the possibility of type I errors, and the interpretation of negative results.

Arthritis, Rheumatoid↗
PubMed1997

The sensitivity of different analytical methods to detect disease susceptibility genes in rheumatoid arthritis sibling pair families.

Our aim was to compare the sensitivity of 4 analytical methods to detect linkage to a known disease susceptibility locus, HLA-DRB1, in 100 rheumatoid arthritis sibling pair families with incomplete parental genotype information. Genotypes for the HLA-DRB1 and HLA-A loci were analyzed using (1) identity-by-descent (IBD), considering inheritance of maternal and paternal alleles separately; (2) maximum likelihood score-IBD (MLS-IBD), which infers missing parental genotypes; (3) identity-by-state (IBS), which does not require parental genotypes; and (4) transmission disequilibrium test (TDT), which uses affected offspring with a heterozygous parent. Due to the small number of informative meoisis for HLA-DRB1, the IBD analysis was not significant for linkage (p = 0.014). HLA-A was more informative (p = 0.0002). The MLS-IBD method for HLA-DRB1 (p = 0.00004) and HLA-A (p < or = 0.00001) was significant. Using IBS both loci gave highly significant evidence of linkage, (p < < 0.00001). The TDT detected HLA-DRB1*0401 as the allele associated with RA; no HLA-A allele was associated. Thus, sib pair families with limited parental genotypes can be used to detect disease susceptibility loci, but when selecting the method of analysis the informativeness of the markers should be taken into account.

Arthritis, Rheumatoid↗
PubMed1997

Linkage and association studies of the natural resistance associated macrophage protein 1 (NRAMP1) locus in rheumatoid arthritis.

OBJECTIVE: To determine if there is any evidence of linkage between the natural resistance associated macrophage protein gene, NRAMP1, and rheumatoid arthritis (RA). METHODS: Two dinucleotide markers, D2S1471, a highly polymorphic marker within 160 kb of NRAMP1, and a less polymorphic marker in the promoter region of NRAMP1, have been analyzed in 115 affected sib-pair RA families (35 with 2 parents, 18 with one parent) from the Arthritis and Rheumatism Council (ARC) National Repository and an additional 85 probands from the ARC National Twin Study and 96 controls. Individuals were typed for both markers by fluorescence based semiautomated polymerase chain reaction analysis. RESULTS: No evidence of increased allele sharing in affected sib-pairs was obtained using identity by descent (IBD), identity by state, and maximum likelihood score (MLS) analysis for the whole data set. A significant increase in allele sharing was observed with marker D2S1471 (LOD 0.74; p 0.05) in the HLA discordant subgroup using IBD and MLS-IBD. No significant differences in allele frequencies were observed for any markers in the association study. CONCLUSION: In a subset of sib-pairs that shared one or zero HLA haplotypes, LOD scores suggestive of linkage were observed. This suggests a role for NRAMP1 polymorphism in a subset of patients who do not possess HLA susceptibility alleles.

Alleles↗
PubMed1994

Genetic epidemiology of early onset breast cancer.

Risks for breast cancer when there is a family history of the disease are usually calculated using data from segregation analyses which favour a single dominant gene with high penetrance. There are, however, at least three loci known to be associated with familial breast cancer (p53, BRCA1, and an as yet unpublished locus) and the frequencies and penetrances of these genes are not likely to be the same. We have attempted to address the problem of which genetic parameters should be used to calculate risks for different patterns of familial breast cancer. Data from 384 nuclear families ascertained through a proband selected for early onset breast cancer were subjected to complex segregation analysis, correcting for ascertainment bias resulting from selection for severe phenotype. Age of onset of breast cancer, incorporated as severity, provides additional information to the segregation model over and above that given by assigning liability classes on the basis of age at observation. The use of this additional parameter in the analysis is described. There is fair agreement between estimates from this sample and previous predictions from consecutive probands and consultands. The differences suggest more than one rare dominant gene for susceptibility to breast cancer, with different penetrances. Although refinements of segregation analysis will help to delineate these different genes, perfect resolution will require identification of the mutant alleles. Methods to estimate genetic parameters under genotype specific mortality need to be developed. Meanwhile, we suggest that high and low estimates of penetrance be used in risk estimation for genetic counselling, and as a guide to candidates for entry into clinical trials of screening and chemoprevention in breast cancer.

Adult↗