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Haplotype frequencies in a sub-region of chromosome 19q13.3, related to risk and prognosis of cancer, differ dramatically between ethnic groups.

Schierup MH, Mailund T, Li H, Wang J, Tjønneland A, Vogel U, Bolund L, Nexø BA - BMC Med. Genet. (2009)

Bottom Line: We found that the susceptibility haplotype in our European sample had increased from 2 to 50 percent very recently in the European population, and to almost the same extent in the Asian population.The cause of this increase is unknown.The data does not allow us to distinguish between these two scenarios.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute of Human Genetics, University of Aarhus, DK-8000 Aarhus C, Denmark. mheide@daimi.au.dk

ABSTRACT

Background: A small region of about 70 kb on human chromosome 19q13.3 encompasses 4 genes of which 3, ERCC1, ERCC2, and PPP1R13L (aka RAI) are related to DNA repair and cell survival, and one, CD3EAP, aka ASE1, may be related to cell proliferation. The whole region seems related to the cellular response to external damaging agents and markers in it are associated with risk of several cancers.

Methods: We downloaded the genotypes of all markers typed in the 19q13.3 region in the HapMap populations of European, Asian and African descent and inferred haplotypes. We combined the European HapMap individuals with a Danish breast cancer case-control data set and inferred the association between HapMap haplotypes and disease risk.

Results: We found that the susceptibility haplotype in our European sample had increased from 2 to 50 percent very recently in the European population, and to almost the same extent in the Asian population. The cause of this increase is unknown. The maximal proportion of overall genetic variation due to differences between groups for Europeans versus Africans and Europeans versus Asians (the Fst value) closely matched the putative location of the susceptibility variant as judged from haplotype-based association mapping.

Conclusion: The combined observation that a common haplotype causing an increased risk of cancer in Europeans and a high differentiation between human populations is highly unusual and suggests a causal relationship with a recent increase in Europeans caused either by genetic drift overruling selection against the susceptibility variant or a positive selection for the same haplotype. The data does not allow us to distinguish between these two scenarios. The analysis suggests that the region is not involved in cancer risk in Africans and that the susceptibility variants may be more finely mapped in Asian populations.

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The main haplotypes in the region for a) Europe), b) Asia and c) Africa. The haplotypes blocks were defined applying the criterion of Gabriel et al. [21] on the CEU data. Haplotypes in different blocks are connected with thick lines if shared more than 10% and with thin lines if shared 1–10%. Numbers between blocks indicate average linkage disequilibrium measured as D' between adjacent blocks The ancestral state of each SNP was inferred from the chimpanzee sequence, using the genome variation server. The haplotype CTCCATTTCGT (block 3) has an increased frequency in CEU and consists mainly of derived alleles. It is an inferred risk variant in the Breast Cancer data set (panel d) and is in strong LD with previously identified susceptibility markers (position of these shown above Figure, and frequency of Rai3'd1 is shown in panel d).
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Figure 5: The main haplotypes in the region for a) Europe), b) Asia and c) Africa. The haplotypes blocks were defined applying the criterion of Gabriel et al. [21] on the CEU data. Haplotypes in different blocks are connected with thick lines if shared more than 10% and with thin lines if shared 1–10%. Numbers between blocks indicate average linkage disequilibrium measured as D' between adjacent blocks The ancestral state of each SNP was inferred from the chimpanzee sequence, using the genome variation server. The haplotype CTCCATTTCGT (block 3) has an increased frequency in CEU and consists mainly of derived alleles. It is an inferred risk variant in the Breast Cancer data set (panel d) and is in strong LD with previously identified susceptibility markers (position of these shown above Figure, and frequency of Rai3'd1 is shown in panel d).

Mentions: To elucidate further the ethnic differences in this region of 19q13.3 we calculated the frequencies of haplotypes in the region for the three ethnic groups using the chimpanzee genome to identifying the ancestral form. The SNPs used for this analysis are shown in Figure 5. Haplotypes were phased by the default method in Haploview based on pedigree information from the trio making up the data sets for YRI and CEU. The haplotypes spanning the region of maximal Fst could be broken down into several sub-regions with considerable recombination in between. A core region of 11 SNPs (from rs171140 to rs11878644 in Figure 5) seemed rather well preserved. In this core region one particular haplotype ACTCTGACTCC, which seemed closest related to the chimpanzee haplotype, constituted 91 percent of the African chromosomes, but only 15 percent of Europeans and 48 percent of the Asian. In contrast, the haplotype CTCCATTTCGT was only present on 2 percent of African chromosomes, but 50 percent European and 43 percent Asian chromosomes. Thus, major shifts of haplotype frequencies in this region seem to have taken place in the evolution of the European and Asian populations. Remarkably, the haplotype CTCCATTTCGT, which has increased in the European and Asian populations, is in very strong LD with the prime candidate SNP for association with breast cancer, RAI-3'd1 (Figure 5d), in that all chromosomes carrying the CTCCATTTCGT haplotype also carries the risk allele at RAI-3'd1. Therefore, the CTCCATTTCGT haplotype is also an inferred risk allele by a test of independence (P < 0.05).


Haplotype frequencies in a sub-region of chromosome 19q13.3, related to risk and prognosis of cancer, differ dramatically between ethnic groups.

Schierup MH, Mailund T, Li H, Wang J, Tjønneland A, Vogel U, Bolund L, Nexø BA - BMC Med. Genet. (2009)

The main haplotypes in the region for a) Europe), b) Asia and c) Africa. The haplotypes blocks were defined applying the criterion of Gabriel et al. [21] on the CEU data. Haplotypes in different blocks are connected with thick lines if shared more than 10% and with thin lines if shared 1–10%. Numbers between blocks indicate average linkage disequilibrium measured as D' between adjacent blocks The ancestral state of each SNP was inferred from the chimpanzee sequence, using the genome variation server. The haplotype CTCCATTTCGT (block 3) has an increased frequency in CEU and consists mainly of derived alleles. It is an inferred risk variant in the Breast Cancer data set (panel d) and is in strong LD with previously identified susceptibility markers (position of these shown above Figure, and frequency of Rai3'd1 is shown in panel d).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2654437&req=5

Figure 5: The main haplotypes in the region for a) Europe), b) Asia and c) Africa. The haplotypes blocks were defined applying the criterion of Gabriel et al. [21] on the CEU data. Haplotypes in different blocks are connected with thick lines if shared more than 10% and with thin lines if shared 1–10%. Numbers between blocks indicate average linkage disequilibrium measured as D' between adjacent blocks The ancestral state of each SNP was inferred from the chimpanzee sequence, using the genome variation server. The haplotype CTCCATTTCGT (block 3) has an increased frequency in CEU and consists mainly of derived alleles. It is an inferred risk variant in the Breast Cancer data set (panel d) and is in strong LD with previously identified susceptibility markers (position of these shown above Figure, and frequency of Rai3'd1 is shown in panel d).
Mentions: To elucidate further the ethnic differences in this region of 19q13.3 we calculated the frequencies of haplotypes in the region for the three ethnic groups using the chimpanzee genome to identifying the ancestral form. The SNPs used for this analysis are shown in Figure 5. Haplotypes were phased by the default method in Haploview based on pedigree information from the trio making up the data sets for YRI and CEU. The haplotypes spanning the region of maximal Fst could be broken down into several sub-regions with considerable recombination in between. A core region of 11 SNPs (from rs171140 to rs11878644 in Figure 5) seemed rather well preserved. In this core region one particular haplotype ACTCTGACTCC, which seemed closest related to the chimpanzee haplotype, constituted 91 percent of the African chromosomes, but only 15 percent of Europeans and 48 percent of the Asian. In contrast, the haplotype CTCCATTTCGT was only present on 2 percent of African chromosomes, but 50 percent European and 43 percent Asian chromosomes. Thus, major shifts of haplotype frequencies in this region seem to have taken place in the evolution of the European and Asian populations. Remarkably, the haplotype CTCCATTTCGT, which has increased in the European and Asian populations, is in very strong LD with the prime candidate SNP for association with breast cancer, RAI-3'd1 (Figure 5d), in that all chromosomes carrying the CTCCATTTCGT haplotype also carries the risk allele at RAI-3'd1. Therefore, the CTCCATTTCGT haplotype is also an inferred risk allele by a test of independence (P < 0.05).

Bottom Line: We found that the susceptibility haplotype in our European sample had increased from 2 to 50 percent very recently in the European population, and to almost the same extent in the Asian population.The cause of this increase is unknown.The data does not allow us to distinguish between these two scenarios.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute of Human Genetics, University of Aarhus, DK-8000 Aarhus C, Denmark. mheide@daimi.au.dk

ABSTRACT

Background: A small region of about 70 kb on human chromosome 19q13.3 encompasses 4 genes of which 3, ERCC1, ERCC2, and PPP1R13L (aka RAI) are related to DNA repair and cell survival, and one, CD3EAP, aka ASE1, may be related to cell proliferation. The whole region seems related to the cellular response to external damaging agents and markers in it are associated with risk of several cancers.

Methods: We downloaded the genotypes of all markers typed in the 19q13.3 region in the HapMap populations of European, Asian and African descent and inferred haplotypes. We combined the European HapMap individuals with a Danish breast cancer case-control data set and inferred the association between HapMap haplotypes and disease risk.

Results: We found that the susceptibility haplotype in our European sample had increased from 2 to 50 percent very recently in the European population, and to almost the same extent in the Asian population. The cause of this increase is unknown. The maximal proportion of overall genetic variation due to differences between groups for Europeans versus Africans and Europeans versus Asians (the Fst value) closely matched the putative location of the susceptibility variant as judged from haplotype-based association mapping.

Conclusion: The combined observation that a common haplotype causing an increased risk of cancer in Europeans and a high differentiation between human populations is highly unusual and suggests a causal relationship with a recent increase in Europeans caused either by genetic drift overruling selection against the susceptibility variant or a positive selection for the same haplotype. The data does not allow us to distinguish between these two scenarios. The analysis suggests that the region is not involved in cancer risk in Africans and that the susceptibility variants may be more finely mapped in Asian populations.

Show MeSH
Related in: MedlinePlus