Abstract
Linkage studies of complex diseases have so far had limited success in producing significant and replicable results, in part owing to genetic heterogeneity. We recently reported the results of a large genome-wide linkage scan for coronary artery disease (CAD) based on 1933 families. The greatest evidence for linkage was to a region of chromosome 2, with a logarithm of odds (LOD) score of 1.86, based on the non-parametric SALL statistic, which did not reach genome-wide significance (P>0.3). Inclusion of a covariate in linkage analysis can be a powerful method of accounting for disease heterogeneity. As CAD is a heterogeneous disease, we carried out a linkage analysis of chromosome 2 incorporating covariates. Increased evidence for linkage was found when hypercholesterolemia was considered (LOD score including covariate of 4.4) reaching genome-wide significance as assessed by simulation (P=0.04). Results showed that the original evidence for linkage was largely attributable to the subset of 108 non-hypercholesterolemic affected sibling pairs. In separate linkage analyses of subsets of hypercholesterolemic and non-hypercholesterolemic sibling pairs, the maximum LOD scores were 1.09 in the former group and 3.74 in the latter. This result illustrates the potential to increase the power of linkage analysis in the presence of heterogeneity by inclusion of covariates. This linked locus on chromosome 2 should now be investigated further to identify the gene(s) influencing risk of CAD in subjects with a normal level of total cholesterol. Candidate genes include the interleukin 1 cluster and two potential regulators of high-density lipoprotein cholesterol level, PLA2R1 and OSBPL6.
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Acknowledgements
The Family Heart Study was supported by a program grant from the British Heart Foundation (RG2000010). We thank all families who participated in the study, as well as staff in hospitals and general practices throughout the UK who helped in the collection of DNA samples and validation of medical records.
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Stephen Ball, Anthony Balmforth, Jenny Barrett, Lynne Barthorpe, Timothy Bishop, Natalie Burtonwood, Richard Cuthbert, Micha Dorsch, Nigel Durham, Stacey Ellis, Claire Forest, Joanne Fox, Alistair Hall, Vera Hall, Beryl Jackson, Natasha Kelly, Richard Lawrance, Azhar Maqbool, Samantha Mason, Lynne Midgley, Christine Morrell, Jérémie Nsengimana, Julia Oldham, Sarah Pickett, Mark Platts, Natalie Pleasants, Elizabeth Rennie, Adrian Smith, Samantha Thompson, Peter Tooze, Kevin Walters and Nadira Yuldasheva.
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Sue Adams, Claire Bodycote, Peter Braund, Paul Burton, Jenny-Rebecca Clemitson, Pat de Souza, Rick Dixon, Julie Faulkes, Laura Hopwood, Andrea Koekemoer, Elaine Logtens, Massimo Mangino, Jenny Ogleby, Stuart Raleigh, Cathy Ridge, Nilesh Samani, Katrina Scurrah, Nuala Sheehan, Ravi Singh and Julian Stribling.
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Nsengimana, J., Samani, N., Hall, A. et al. Enhanced linkage of a locus on chromosome 2 to premature coronary artery disease in the absence of hypercholesterolemia. Eur J Hum Genet 15, 313–319 (2007). https://doi.org/10.1038/sj.ejhg.5201752
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DOI: https://doi.org/10.1038/sj.ejhg.5201752
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