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BMC Medical Genetics
Published in: BMC Medical Genetics 1/2009

Open Access 01-12-2009 | Research article

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

Authors: Mikkel H Schierup, Thomas Mailund, Heng Li, Jun Wang, Anne Tjønneland, Ulla Vogel, Lars Bolund, Bjørn A Nexø

Published in: BMC Medical Genetics | Issue 1/2009

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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.
Appendix
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Literature
1.
Vogel U, Nexo BA, Tjonneland A, Wallin H, Hertel O, Raaschou-Nielsen O: ERCC1, XPD and RAI mRNA levels in lymphocytes are not associated with lung cancer risk in a prospective study of Danes. Mutation research. 2006, 593 (1–2): 88-96.CrossRefPubMed
2.
Laska MJ, Strandbygard D, Kjeldgaard A, Mains M, Corydon TJ, Memon AA, Sorensen BS, Vogel U, Jensen UB, Nexo BA: Expression of the RAI gene is conducive to apoptosis: studies of induction and interference. Experimental cell research. 2007, 313 (12): 2611-2621. 10.1016/j.yexcr.2007.05.006.CrossRefPubMed
3.
Dybdahl M, Vogel U, Frentz G, Wallin H, Nexo BA: Polymorphisms in the DNA repair gene XPD: correlations with risk and age at onset of basal cell carcinoma. Cancer Epidemiol Biomarkers Prev. 1999, 8 (1): 77-81.PubMed
4.
Nexo BA, Vogel U, Olsen A, Ketelsen T, Bukowy Z, Thomsen BL, Wallin H, Overvad K, Tjonneland A: A specific haplotype of single nucleotide polymorphisms on chromosome 19q13.2-3 encompassing the gene RAI is indicative of post-menopausal breast cancer before age 55. Carcinogenesis. 2003, 24 (5): 899-904. 10.1093/carcin/bgg043.CrossRefPubMed
5.
Rockenbauer E, Bendixen MH, Bukowy Z, Yin J, Jacobsen NR, Hedayati M, Vogel U, Grossman L, Bolund L, Nexo BA: Association of chromosome 19q13.2-3 haplotypes with basal cell carcinoma: tentative delineation of an involved region using data for single nucleotide polymorphisms in two cohorts. Carcinogenesis. 2002, 23 (7): 1149-1153. 10.1093/carcin/23.7.1149.CrossRefPubMed
6.
Skjelbred CF, Saebo M, Nexo BA, Wallin H, Hansteen IL, Vogel U, Kure EH: Effects of polymorphisms in ERCC1, ASE-1 and RAI on the risk of colorectal carcinomas and adenomas: a case control study. BMC cancer. 2006, 6: 175-10.1186/1471-2407-6-175.CrossRefPubMedPubMedCentral
7.
Vogel U, Hedayati M, Dybdahl M, Grossman L, Nexo BA: Polymorphisms of the DNA repair gene XPD: correlations with risk of basal cell carcinoma revisited. Carcinogenesis. 2001, 22 (6): 899-904. 10.1093/carcin/22.6.899.CrossRefPubMed
8.
Vogel U, Laros I, Jacobsen NR, Thomsen BL, Bak H, Olsen A, Bukowy Z, Wallin H, Overvad K, Tjonneland A, et al: Two regions in chromosome 19q13.2-3 are associated with risk of lung cancer. Mutation research. 2004, 546 (1–2): 65-74.CrossRefPubMed
9.
Yin J, Vogel U, Ma Y, Qi R, Sun Z, Wang H: A haplotype encompassing the variant allele of DNA repair gene polymorphism ERCC2/XPD Lys751Gln but not the variant allele of Asp312Asn is associated with risk of lung cancer in a northeastern Chinese population. Cancer genetics and cytogenetics. 2007, 175 (1): 47-51. 10.1016/j.cancergencyto.2007.01.010.CrossRefPubMed
10.
Nexo BA, Vogel U, Olsen A, Nyegaard M, Bukowy Z, Rockenbauer E, Zhang X, Koca C, Mains M, Hansen B, et al: Linkage disequilibrium mapping of a breast cancer susceptibility locus near RAI/PPP1R13L/iASPP. BMC medical genetics. 2008, 9: 56-10.1186/1471-2350-9-56.CrossRefPubMedPubMedCentral
11.
Vangsted A, Gimsing P, Klausen TW, Nexo BA, Wallin H, Andersen P, Hokland P, Lillevang ST, Vogel U: Polymorphisms in the genes ERCC2, XRCC3 and CD3EAP influence treatment outcome in multiple myeloma patients undergoing autologous bone marrow transplantation. Int J Cancer. 2007, 120 (5): 1036-1045. 10.1002/ijc.22411.CrossRefPubMed
12.
Moreno V, Gemignani F, Landi S, Gioia-Patricola L, Chabrier A, Blanco I, Gonzalez S, Guino E, Capella G, Canzian F: Polymorphisms in genes of nucleotide and base excision repair: risk and prognosis of colorectal cancer. Clin Cancer Res. 2006, 12 (7 Pt 1): 2101-2108. 10.1158/1078-0432.CCR-05-1363.CrossRefPubMed
13.
Olaussen KA, Dunant A, Fouret P, Brambilla E, Andre F, Haddad V, Taranchon E, Filipits M, Pirker R, Popper HH, et al: DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy. The New England journal of medicine. 2006, 355 (10): 983-991. 10.1056/NEJMoa060570.CrossRefPubMed
14.
Park DJ, Zhang W, Stoehlmacher J, Tsao-Wei D, Groshen S, Gil J, Yun J, Sones E, Mallik N, Lenz HJ: ERCC1 gene polymorphism as a predictor for clinical outcome in advanced colorectal cancer patients treated with platinum-based chemotherapy. Clin Adv Hematol Oncol. 2003, 1 (3): 162-166.PubMed
15.
Helgason A, Palsson S, Thorleifsson G, Grant SFA, Emilsson V, Gunnarsdottir S, Adeyemo A, Chen YX, Chen GJ, Reynisdottir I, et al: Refining the impact of TCF7L2 gene variants on type 2 diabetes and adaptive evolution. Nature Genetics. 2007, 39 (2): 218-225. 10.1038/ng1960.CrossRefPubMed
16.
Blekhman R, Man O, Herrmann L, Boyko AR, Indap A, Kosiol C, Bustamante CD, Teshima KM, Przeworskil M: Natural selection on genes that underlie human disease susceptibility. Current Biology. 2008, 18 (12): 883-889. 10.1016/j.cub.2008.04.074.CrossRefPubMedPubMedCentral
17.
Gibson G: Human evolution: Thrifty genes and the dairy queen. Current Biology. 2007, 17 (8): R295-R296. 10.1016/j.cub.2007.02.011.CrossRefPubMed
18.
Novembre J, Pritchard JK, Coop G: Adaptive drool in the gene pool. Nature Genetics. 2007, 39 (10): 1188-1190. 10.1038/ng1007-1188.CrossRefPubMed
19.
Sulem P, Gudbjartsson DF, Stacey SN, Helgason A, Rafnar T, Magnusson KP, Manolescu A, Karason A, Palsson A, Thorleifsson G, et al: Genetic determinants of hair, eye and skin pigmentation in Europeans. Nature Genetics. 2007, 39 (12): 1443-1452. 10.1038/ng.2007.13.CrossRefPubMed
20.
Barrett JC, Fry B, Maller J, Daly MJ: Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics (Oxford, England). 2005, 21 (2): 263-265. 10.1093/bioinformatics/bth457.CrossRef
21.
Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, Blumenstiel B, Higgins J, DeFelice M, Lochner A, Faggart M, et al: The structure of haplotype blocks in the human genome. Science. 2002, 296 (5576): 2225-2229. 10.1126/science.1069424.CrossRefPubMed
22.
Mailund T, Besenbacher S, Schierup MH: Whole genome association mapping by incompatibilities and local perfect phylogenies. BMC Bioinformatics. 2006, 7: 454-10.1186/1471-2105-7-454.CrossRefPubMedPubMedCentral
23.
24.
25.
Frazer KA, Ballinger DG, Cox DR, Hinds DA, Stuve LL, Gibbs RA, Belmont JW, Boudreau A, Hardenbol P, Leal SM, et al: A second generation human haplotype map of over 3.1 million SNPs. Nature. 2007, 449 (7164): 851-U853. 10.1038/nature06258.CrossRefPubMed
26.
Scheet P, Stephens M: A fast and flexible statistical model for large-scale population genotype data: applications to inferring missing genotypes and haplotypic phase. Am J Hum Genet. 2006, 78 (4): 629-644. 10.1086/502802.CrossRefPubMedPubMedCentral
27.
Balaresque PL, Ballereau SJ, Jobling MA: Challenges in human genetic diversity: demographic history and adaptation. Human Molecular Genetics. 2007, 16: R134-R139. 10.1093/hmg/ddm242.CrossRefPubMed
28.
Bustamante CD, Fledel-Alon A, Williamson S, Nielsen R, Hubisz MT, Glanowski S, Tanenbaum DM, White TJ, Sninsky JJ, Hernandez RD, et al: Natural selection on protein-coding genes in the human genome. Nature. 2005, 437 (7062): 1153-1157. 10.1038/nature04240.CrossRefPubMed
29.
Kryukov GV, Pennacchio LA, Sunyaev SR: Most rare missense alleles are deleterious in humans: Implications for complex disease and association studies. American Journal of Human Genetics. 2007, 80 (4): 727-739. 10.1086/513473.CrossRefPubMedPubMedCentral
30.
McCarthy MI, Abecasis GR, Cardon LR, Goldstein DB, Little J, Ioannidis JPA, Hirschhorn JN: Genome-wide association studies for complex traits: consensus, uncertainty and challenges. Nature Reviews Genetics. 2008, 9 (5): 356-369. 10.1038/nrg2344.CrossRefPubMed
Metadata
Title
Haplotype frequencies in a sub-region of chromosome 19q13.3, related to risk and prognosis of cancer, differ dramatically between ethnic groups
Authors
Mikkel H Schierup
Thomas Mailund
Heng Li
Jun Wang
Anne Tjønneland
Ulla Vogel
Lars Bolund
Bjørn A Nexø
Publication date
01-12-2009
Publisher
BioMed Central
Published in
BMC Medical Genetics / Issue 1/2009
Electronic ISSN: 1471-2350
DOI
https://doi.org/10.1186/1471-2350-10-20

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