Estimation of the relative risk of developing clinical scrapie: the role of prion protein (PrP) genotype and selection bias

Abstract

Prion protein (PrP) genotype data from statutory confirmed cases and from three non-case datasets have been used to calculate the odds ratio (or) for the development of clinical scrapie for an individual sheep of a given PrP genotype, compared with one possessing the "wild-type" ARQ/ARQ genotype. Logistic regression has been used to estimate the ors, and a multiple-test procedure has been used to evaluate the statistical significance of each comparison. The results are similar to those observed in other studies: the VRQ/VRQ genotype has or point estimates greater than 20; the ARQ/VRQ and ARH/VRQ genotypes have or point estimates between 5 and 20; AHQ/VRQ between 0.03 and 0.1; ARR/VRQ 0.4 and 0.5; all the other PrP genotypes, excluding ARR/ARR, ARR/ARH and AHQ/ARH for which no clinical cases have been recorded have or point estimates of less than 0.3. The estimates derived from each dataset are comparable, but not identical. This can be explained by plausible biases inherent in the sampling of the non-case populations.

Prevalence of sheep infected with classical scrapie in Great Britain: integrating multiple sources of surveillance data for 2002

“…With the exception of the ARH/VRQ genotype, however, the relative risk of infection was typically higher than that of clinical disease (figure 2; cf. Baylis et al 2004;Gubbins & Roden 2006;Tongue et al 2006). Moreover, the greatest discrepancies between the relative risk of infection and that of disease occurred in those PrP genotypes that have a later age at onset (figure 2; see the electronic supplementary material, appendix B), reflecting the fact that relatively few infected animals of these PrP genotypes survive to disease onset.…”

“…No unbiased population-level PrP genotype data are available for the GB national flock ( Tongue et al 2006). Two sources of data were used to estimate the number of sheep of each PrP genotype in a birth cohort: sheep sampled as part of the National Scrapie Plan for GB (NSP; Eglin et al 2005) and sheep from scrapie-affected and unaffected flocks sampled as part of a case-control study run by the Institute for Animal Health (IAH; Baylis et al 2004; see the electronic supplementary material, appendix A).…”

“…Differences in the estimates obtained for the relative risk of infection when using different population-level PrP genotype frequencies (IAH or NSP; figure 2) can be explained by biases in these datasets (e.g. Tongue et al 2006). The IAH dataset was derived from approximately 30 affected and 30 unaffected flocks (Baylis et al 2004;Goldmann et al 2005).…”

“…However, scrapie has a strong host genetic component at the ovine prion protein (PrP) gene, which influences both the risk of infection and the incubation period (Detwiler & Baylis 2003;Baylis et al 2004;Gubbins & Roden 2006;Tongue et al 2006). Five alleles of the PrP gene (defined by the amino acids at codons 136, 154 and 171) are commonly found in British sheep, which, in the order of increasing risk of clinical disease and decreasing age at onset, are: ARR; AHQ; ARH; ARQ; and VRQ.…”

The evidence of associations between prion protein genotype and production, reproduction, and health traits in sheep

“…The AHQ, ARH, ARQ, and VRQ alleles are generally associated with susceptibility. The degree of, and the ranking for, susceptibility appears to be breed dependent, with the VRQ allele (when present within a breed) generally considered the most susceptible [7,8,31,44,61,64,77,79]. There is also evidence to suggest that polymorphisms at other codons within the PrP gene may modify the degree of resistance associated with the ARQ allele [82].…”