Limits...
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.

Show MeSH

Related in: MedlinePlus

Association analysis on typed and imputed markers. A) Single marker association, B) Blossoc analysis. The blue dots indicate markers that were typed in the case/control data, while the red dots indicate markers that were imputed for the case/control individuals using GVS data.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC2654437&req=5

Figure 3: Association analysis on typed and imputed markers. A) Single marker association, B) Blossoc analysis. The blue dots indicate markers that were typed in the case/control data, while the red dots indicate markers that were imputed for the case/control individuals using GVS data.

Mentions: For the single marker test we used the tool chisq_sma available from[23] and for the Blossoc analysis we used the Blossoc tool from [24] We ran chisq_sma with default options and Blossoc with options "-m5-fH". Of the 125 SNPs we could not compute the single marker statistics in 29 cases, due to too few counts in at least one of the cells of the contingency table. Figure 3A thus only shows 96 points, rather than 125. The Blossoc method can compute scores for all 125 SNPs.


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)

Association analysis on typed and imputed markers. A) Single marker association, B) Blossoc analysis. The blue dots indicate markers that were typed in the case/control data, while the red dots indicate markers that were imputed for the case/control individuals using GVS data.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: Association analysis on typed and imputed markers. A) Single marker association, B) Blossoc analysis. The blue dots indicate markers that were typed in the case/control data, while the red dots indicate markers that were imputed for the case/control individuals using GVS data.
Mentions: For the single marker test we used the tool chisq_sma available from[23] and for the Blossoc analysis we used the Blossoc tool from [24] We ran chisq_sma with default options and Blossoc with options "-m5-fH". Of the 125 SNPs we could not compute the single marker statistics in 29 cases, due to too few counts in at least one of the cells of the contingency table. Figure 3A thus only shows 96 points, rather than 125. The Blossoc method can compute scores for all 125 SNPs.

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