Prion susceptibility and protective alleles exhibit marked geographic differences

Abstract

A total of 616 chromosomes from control individuals of all major continental groups, and six individuals affected by either Creutzfeldt-Jakob disease (CJD) or fatal familial insomnia (FFI), were typed with a new single-reaction protocol method and were also sequenced, with total reproducibility to screen variation at important positions (385A>G: M129V and 655G>A: E219K) in the human prion protein gene (PRNP). We have found, for the first time, that 129V allele is highly represented in some populations from the Americas, and that 129M and 129V are in similar frequencies in Africa. The 129M susceptibility allele was found at high frequencies in Old World populations, very high in the Pacific (~81%) and up to 93% in Central and East Asia, but at a low frequency (~30%) in Native Americans. The protective 219L allele was restricted to Asian and Pacific populations. Susceptibility alleles exhibit marked geographic differences in frequency, and thus, differences in probability to develop prion diseases. © 2003 Wiley-Liss, Inc.KEY WORDS: prion; PRNP; SNP; population genetics; Creutzfeldt-Jakob disease; CJD; fatal familial insomnia; FFI INTRODUCTIONFamilial Creutzfeldt-Jakob disease (CJD; MIM# 123400), fatal familial insomnia (FFI; MIM# 600072) and Gerstmann-Sträussler-Scheinker disease (GSD; MIM# 137440) are frequently caused by mutations in the prion gene ( PRNP; MIM# 176640; GenBank U29185) in codons 200, 178 and 102. CJD can also be sporadic (representing 85% of the cases) or acquired, which includes iatrogenic CJD, kuru and variant CJD. In these cases some polymorphic positions, codons 129 (385A>G: M129V) and 219 (655G>A: E219K) of the PRNP are particularly important for susceptibility to prion diseases.Codon 129 is known to be implicated in the development of sporadic Laplanche et al., 1994;Salvatore et al., 1994;Alperovitch et al., 1999], acquired (iatrogenic, ; kuru, [Lee et al., 2001]) and variant CJD [Zeidler and Ironside, 2000], with increased susceptibility observed for the M/M 2 Soldevila et al.genotype. This finding was interpreted as suggesting that dimerization of the prion protein is an important element in the pathogenesis of CJD and that this is more likely to occur in Met homozygotes than in heterozygotes. The relative frequencies of the codon 129 alleles in Europeans were estimated to be 68% M and 32% V [Owen et al., 1990]. Similar frequencies were obtained in other studies of normal European populations Bratosiewicz et al., 2001]. The frequency of 129M allele is higher in Japanese (95.8%; [Doh-ura et al., 1991]), Han Chinese (98.5%; [Tsai et al., 2001]), Turkish (74%; [Erginel-Unaltuna et al., 2001]) and in Cretans (75.5%; [Plaitakis et al., 2001]). The importance of codon 129 was highlighted in this last study, where an increased incidence of sporadic Creutzfeldt-Jakob disease was associated with a high rate of M homozygosity. These data is the first to relate a high regional incidence rate for sCJD to the distribution of PRNP 129 genotypes. To date, all studies of PRNP codon 129 have mainly focuse...

No association of prion protein gene polymorphisms with Alzheimer's disease in Korean population

“…This polymorphism is not found in Caucacians (Petraroli and Pocchiari, 1996). Thus, these data suggest that the genetic risk for AD by the codon 219 polymorphism seems to be minimal although it may lower and counteract the susceptibility to CJD by the codon 129 polymorphism (Soldevila et al, 2003).…”

“…The M allele frequency is highest in Central and East Asia (＞ 90%), high in the Pacific (approximately 81%), in Europe (57-75%) and low (approximately 30%) in Native Americans (Palmer, ApoE-4 (-) (n = 306) ApoE-4 (+) (n = 181) 1991; Soldevila et al, 2003;Jeong et al, 2004;Yu et al, 2004;Lucotte and Mercier, 2005). Similarly, the MM genotype is highly abundant (＞ 93%) in East Asia.…”

“…The survival period was shorter for homozygotes (MM and VV) than heterozygote (MV) (P ＜ 0.0001) (Pocchiari et al, 2004) and MV heterozygote individuals had some protection against kuru epidemic among the Fore tribe of Papua New Guinea (Mead et al, 2003). In case of polymorphism at codon 219 of the PRNP gene in which lysine is substituted for glutamic acid (E219K), the K allele was found to be protective against sporadic CJD in Asia and Pacific (Soldevila et al, 2003). Berr et al (1998) observed the correlation bet-ween the codon 129 polymorphisms and cognitive performance.…”

Characterization of Variant Creutzfeldt-Jakob Disease Prions in Prion Protein-humanized Mice Carrying Distinct Codon 129 Genotypes

“…Indeed, two vCJD patients with the 219E/K genotype were reported subsequently (30). Therefore, our transmission study using humanized knock-in mice could properly predict that individuals with the 219E/K genotype, which is rarely observed in the European population (31,32), have a potential risk for vCJD infection. Taken together, the present intracerebral transmission data raise the concern that individuals with the 129V/V genotype are more susceptible to secondary vCJD infection than had been expected.…”

Prion disease genetics

“…Despite this conservation, a number of human coding polymorphisms have been characterised in different populations that achieve intermediate frequencies. 79,80 First and foremost among these is a polymorphism at PRNP codon 129 between methionine and valine, which has a strong disease susceptibility and phenotype modifying effect. 81 There are marked differences in codon 129 allele frequency worldwide: in the UK and Northern European population, the 129M allele frequency is around 0.65 with a slightly increasing cline through Europe into Africa 79,82 and a marked increasing cline through Asia, 67,83,84 129V is rare in Japan.…”