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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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Fst values in the region: A) between Africa and Europe, B) between Europe and Asia.
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Figure 4: Fst values in the region: A) between Africa and Europe, B) between Europe and Asia.

Mentions: Next, we calculated Fst, the proportion of overall genetic variation due to differences between groups for Europeans versus Africans (Figure 4A) and Europeans versus Asians (Figure 4B), using the HapMap SNPs. In the samples, Europeans and Africans share 29 SNPs in the region and Europeans and Asians share 30 SNPs in the region. A genetic difference between Europeans and Africans was distinctly present immediately 3' to the PPP1L13L and to the left, while limited differences were present to the right, with maximal values from chromosome position 50,568,000 to 50,575,000 (Figure 4A). A similar difference is not found when comparing Asia and Europe (see Figure 4B), but we observed a similar tendency in the comparison of Asians and Africans (not shown) albeit with slightly lower values and possibly shifted slightly to the left. Although we would generally consider an Fst-value of 0.5 large, we still expect to find Fst > 0.5 in numerous places in the genome. Figure 2 shows the empirical distribution of Fst values between the HapMap European and African populations across the entire chromosome 19. The 95% percentile, shown as a vertical line, was 0.4281. The Fst of the markers in the region are shown as red dots. Of the 29 SNPs in the region, 13 are among the 5% most differentiated SNPs on the chromosome, but there are many other SNPs with similarly high Fst values. The relatively high differentiation combined with the known association with cancer, however, prompted our further investigation.


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)

Fst values in the region: A) between Africa and Europe, B) between Europe and Asia.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Fst values in the region: A) between Africa and Europe, B) between Europe and Asia.
Mentions: Next, we calculated Fst, the proportion of overall genetic variation due to differences between groups for Europeans versus Africans (Figure 4A) and Europeans versus Asians (Figure 4B), using the HapMap SNPs. In the samples, Europeans and Africans share 29 SNPs in the region and Europeans and Asians share 30 SNPs in the region. A genetic difference between Europeans and Africans was distinctly present immediately 3' to the PPP1L13L and to the left, while limited differences were present to the right, with maximal values from chromosome position 50,568,000 to 50,575,000 (Figure 4A). A similar difference is not found when comparing Asia and Europe (see Figure 4B), but we observed a similar tendency in the comparison of Asians and Africans (not shown) albeit with slightly lower values and possibly shifted slightly to the left. Although we would generally consider an Fst-value of 0.5 large, we still expect to find Fst > 0.5 in numerous places in the genome. Figure 2 shows the empirical distribution of Fst values between the HapMap European and African populations across the entire chromosome 19. The 95% percentile, shown as a vertical line, was 0.4281. The Fst of the markers in the region are shown as red dots. Of the 29 SNPs in the region, 13 are among the 5% most differentiated SNPs on the chromosome, but there are many other SNPs with similarly high Fst values. The relatively high differentiation combined with the known association with cancer, however, prompted our further investigation.

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