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Alleles were then transmitted from one generation to the next according to Mendelian laws using the true genetic map.
In these simulations, genotypes were randomly assigned to family founders at all markers based on allelic frequencies in the sample, assuming Hardy–Weinberg and linkage equilibrium.An alternative approach is to include suspected sources of heterogeneity as covariates in the statistical model.The use of covariates in linkage analysis has contributed to mapping or confirming the position of genes for prostate cancer, In this study, we report the results of a sibling pair linkage analysis of CAD on chromosome 2 using the British Heart Foundation (BHF) Family Heart Study including hypercholesterolemia as a covariate.Briefly, the BHF Family Heart Study comprises 1933 families including 4175 persons affected with CAD (1675 affected sibling pairs, 220 affected trios and 38 sibships or extended families with more than three affected individuals).Affection with CAD was defined as having had one or more of these conditions before age 66 years: MI, angina, percutaneous transluminal coronary angioplasty or coronary artery bypass surgery.Genetic heterogeneity may explain why, among the analyses showing suggestive or significant linkage, a relatively small proportion has so far been replicated, even when estimates of sib recurrence risk ratio are high.
One way of resolving the problem of heterogeneity is to use a more restrictive definition of phenotype at recruitment or to separately analyse subsets of the study participants with more homogeneous disease characteristics. reported significant evidence of linkage to a locus on chromosome 1 by considering subjects with myocardial infarction (MI), diagnosed by age 45 years in males or 50 years in females.
For hypercholesterolemia, participants were asked whether their general practitioner (family doctor) had ever told them that they had a high cholesterol level and whether they had ever taken any lipid-lowering treatment.
To investigate the effect of heterogeneity on linkage of CAD to chromosome 2, regression analyses were carried out expressing allele-sharing probabilities as a function of a series of covariates, using the method proposed by Rice Binary variables such as hypercholesterolemia give rise to a three-level factor for each sibling pair (0, 1 or 2 hypercholesterolemics in the pair).
Study participants reported clinical information about themselves by completing a questionnaire.
The study was approved by the Yorkshire Multicentre Research Ethics Committee and by 206 local research ethics committees across the UK.
The association between hypercholesterolemia, CAD subtypes and other risk factors was examined using The clinical data are summarised in Table 1.