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Genome-wide association analysis in East Asians identifies breast cancer susceptibility loci at 1q32.1, 5q14.3 and 15q26.1.

Cai Q, Zhang B, Sung H, Low SK, Kweon SS, Lu W, Shi J, Long J, Wen W, Choi JY, Noh DY, Shen CY, Matsuo K, Teo SH, Kim MK, Khoo US, Iwasaki M, Hartman M, Takahashi A, Ashikawa K, Matsuda K, Shin MH, Park MH, Zheng Y, Xiang YB, Ji BT, Park SK, Wu PE, Hsiung CN, Ito H, Kasuga Y, Kang P, Mariapun S, Ahn SH, Kang HS, Chan KY, Man EP, Iwata H, Tsugane S, Miao H, Liao J, Nakamura Y, Kubo M, DRIVE GAME-ON ConsortiumDelahanty RJ, Zhang Y, Li B, Li C, Gao YT, Shu XO, Kang D, Zheng W - Nat. Genet. (2014)

Bottom Line: In a three-stage genome-wide association study among East Asian women including 22,780 cases and 24,181 controls, we identified 3 genetic loci newly associated with breast cancer risk, including rs4951011 at 1q32.1 (in intron 2 of the ZC3H11A gene; P=8.82×10(-9)), rs10474352 at 5q14.3 (near the ARRDC3 gene; P=1.67×10(-9)) and rs2290203 at 15q26.1 (in intron 14 of the PRC1 gene; P=4.25×10(-8)).We replicated these associations in 16,003 cases and 41,335 controls of European ancestry (P=0.030, 0.004 and 0.010, respectively).Data from the ENCODE Project suggest that variants rs4951011 and rs10474352 might be located in an enhancer region and transcription factor binding sites, respectively.

View Article: PubMed Central - PubMed

Affiliation: Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.

ABSTRACT
In a three-stage genome-wide association study among East Asian women including 22,780 cases and 24,181 controls, we identified 3 genetic loci newly associated with breast cancer risk, including rs4951011 at 1q32.1 (in intron 2 of the ZC3H11A gene; P=8.82×10(-9)), rs10474352 at 5q14.3 (near the ARRDC3 gene; P=1.67×10(-9)) and rs2290203 at 15q26.1 (in intron 14 of the PRC1 gene; P=4.25×10(-8)). We replicated these associations in 16,003 cases and 41,335 controls of European ancestry (P=0.030, 0.004 and 0.010, respectively). Data from the ENCODE Project suggest that variants rs4951011 and rs10474352 might be located in an enhancer region and transcription factor binding sites, respectively. This study provides additional insights into the genetics and biology of breast cancer.

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Forest plots for risk variants in the three newly identified breast cancer risk loci by study site and stagePer-allele ORs are presented. The size of the box is proportional to the number of cases and controls in each study. (a): rs4951011, (b): rs10474352, (c): rs2290203.
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Figure 1: Forest plots for risk variants in the three newly identified breast cancer risk loci by study site and stagePer-allele ORs are presented. The size of the box is proportional to the number of cases and controls in each study. (a): rs4951011, (b): rs10474352, (c): rs2290203.

Mentions: For Stage 3, the top 50 SNPs were selected for further replication in an independent set of 14,195 cases and 16,249 controls from 10 studies participating in the ABCC based on the following criteria: (1) P < 0.005 in the meta-analysis of Stage 1 and 2 data and (2) same direction of association in both Stages 1 and 2. Of the 50 SNPs evaluated in Stage 3, 11 SNPs showed an association with breast cancer risk at P < 0.05 (Supplementary Table 2). Combined analyses of data from all three stages identified three SNPs that were associated with breast cancer risk at the genome-wide significance level (P < 5.0 × 10−8): rs4951011 at 1q32.1, odds ratio (OR) = 1.09, P = 8.82 × 10−9; rs10474352 at 5q14.3, OR = 1.09, P = 1.67 × 10−9; and rs2290203 at 15q26.1, OR = 1.08, P = 4.25 × 10−8 (Table 1). The association between breast cancer risk and each of these three SNPs was consistent across the studies included in the ABCC (Figure 1), and none of the tests for heterogeneity were statistically significant (P > 0.05) (Table 1). No significant heterogeneity was found for the association of these three SNPs with breast cancer risk among Chinese, Japanese, or Korean women (Supplementary Table 3). One additional SNP showed an association with breast cancer risk with a P-value near the conventional GWAS significance level (rs11082321 at 18q11.2, OR = 1.08, P = 6.77× 10−7) (Supplementary Table 2).


Genome-wide association analysis in East Asians identifies breast cancer susceptibility loci at 1q32.1, 5q14.3 and 15q26.1.

Cai Q, Zhang B, Sung H, Low SK, Kweon SS, Lu W, Shi J, Long J, Wen W, Choi JY, Noh DY, Shen CY, Matsuo K, Teo SH, Kim MK, Khoo US, Iwasaki M, Hartman M, Takahashi A, Ashikawa K, Matsuda K, Shin MH, Park MH, Zheng Y, Xiang YB, Ji BT, Park SK, Wu PE, Hsiung CN, Ito H, Kasuga Y, Kang P, Mariapun S, Ahn SH, Kang HS, Chan KY, Man EP, Iwata H, Tsugane S, Miao H, Liao J, Nakamura Y, Kubo M, DRIVE GAME-ON ConsortiumDelahanty RJ, Zhang Y, Li B, Li C, Gao YT, Shu XO, Kang D, Zheng W - Nat. Genet. (2014)

Forest plots for risk variants in the three newly identified breast cancer risk loci by study site and stagePer-allele ORs are presented. The size of the box is proportional to the number of cases and controls in each study. (a): rs4951011, (b): rs10474352, (c): rs2290203.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4127632&req=5

Figure 1: Forest plots for risk variants in the three newly identified breast cancer risk loci by study site and stagePer-allele ORs are presented. The size of the box is proportional to the number of cases and controls in each study. (a): rs4951011, (b): rs10474352, (c): rs2290203.
Mentions: For Stage 3, the top 50 SNPs were selected for further replication in an independent set of 14,195 cases and 16,249 controls from 10 studies participating in the ABCC based on the following criteria: (1) P < 0.005 in the meta-analysis of Stage 1 and 2 data and (2) same direction of association in both Stages 1 and 2. Of the 50 SNPs evaluated in Stage 3, 11 SNPs showed an association with breast cancer risk at P < 0.05 (Supplementary Table 2). Combined analyses of data from all three stages identified three SNPs that were associated with breast cancer risk at the genome-wide significance level (P < 5.0 × 10−8): rs4951011 at 1q32.1, odds ratio (OR) = 1.09, P = 8.82 × 10−9; rs10474352 at 5q14.3, OR = 1.09, P = 1.67 × 10−9; and rs2290203 at 15q26.1, OR = 1.08, P = 4.25 × 10−8 (Table 1). The association between breast cancer risk and each of these three SNPs was consistent across the studies included in the ABCC (Figure 1), and none of the tests for heterogeneity were statistically significant (P > 0.05) (Table 1). No significant heterogeneity was found for the association of these three SNPs with breast cancer risk among Chinese, Japanese, or Korean women (Supplementary Table 3). One additional SNP showed an association with breast cancer risk with a P-value near the conventional GWAS significance level (rs11082321 at 18q11.2, OR = 1.08, P = 6.77× 10−7) (Supplementary Table 2).

Bottom Line: In a three-stage genome-wide association study among East Asian women including 22,780 cases and 24,181 controls, we identified 3 genetic loci newly associated with breast cancer risk, including rs4951011 at 1q32.1 (in intron 2 of the ZC3H11A gene; P=8.82×10(-9)), rs10474352 at 5q14.3 (near the ARRDC3 gene; P=1.67×10(-9)) and rs2290203 at 15q26.1 (in intron 14 of the PRC1 gene; P=4.25×10(-8)).We replicated these associations in 16,003 cases and 41,335 controls of European ancestry (P=0.030, 0.004 and 0.010, respectively).Data from the ENCODE Project suggest that variants rs4951011 and rs10474352 might be located in an enhancer region and transcription factor binding sites, respectively.

View Article: PubMed Central - PubMed

Affiliation: Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.

ABSTRACT
In a three-stage genome-wide association study among East Asian women including 22,780 cases and 24,181 controls, we identified 3 genetic loci newly associated with breast cancer risk, including rs4951011 at 1q32.1 (in intron 2 of the ZC3H11A gene; P=8.82×10(-9)), rs10474352 at 5q14.3 (near the ARRDC3 gene; P=1.67×10(-9)) and rs2290203 at 15q26.1 (in intron 14 of the PRC1 gene; P=4.25×10(-8)). We replicated these associations in 16,003 cases and 41,335 controls of European ancestry (P=0.030, 0.004 and 0.010, respectively). Data from the ENCODE Project suggest that variants rs4951011 and rs10474352 might be located in an enhancer region and transcription factor binding sites, respectively. This study provides additional insights into the genetics and biology of breast cancer.

Show MeSH
Related in: MedlinePlus