Comparison of 6q25 breast cancer hits from Asian and European Genome Wide Association Studies in the Breast Cancer Association Consortium (BCAC)

Abstract

The 6q25.1 locus was first identified via a genome-wide association study (GWAS) in Chinese women and marked by single nucleotide polymorphism (SNP) rs2046210, approximately 180 Kb upstream of ESR1. There have been conflicting reports about the association of this locus with breast cancer in Europeans, and a GWAS in Europeans identified a different SNP, tagged here by rs12662670. We examined the associations of both SNPs in up to 61,689 cases and 58,822 controls from forty-four studies collaborating in the Breast Cancer Association Consortium, of which four studies were of Asian and 39 of European descent. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). Case-only analyses were used to compare SNP effects in Estrogen Receptor positive (ER+) versus negative (ER-) tumours. Models including both SNPs were fitted to investigate whether the SNP effects were independent. Both SNPs are significantly associated with breast cancer risk in both ethnic groups. Per-allele ORs are higher in Asian than in European studies [rs2046210: OR (A/G) = 1.36 (95% CI 1.26-1.48), p = 7.6 × 10(-14) in Asians and 1.09 (95% CI 1.07-1.11), p = 6.8 × 10(-18) in Europeans. rs12662670: OR (G/T) = 1.29 (95% CI 1.19-1.41), p = 1.2 × 10(-9) in Asians and 1.12 (95% CI 1.08-1.17), p = 3.8 × 10(-9) in Europeans]. SNP rs2046210 is associated with a significantly greater risk of ER- than ER+ tumours in Europeans [OR (ER-) = 1.20 (95% CI 1.15-1.25), p = 1.8 × 10(-17) versus OR (ER+) = 1.07 (95% CI 1.04-1.1), p = 1.3 × 10(-7), p(heterogeneity) = 5.1 × 10(-6)]. In these Asian studies, by contrast, there is no clear evidence of a differential association by tumour receptor status. Each SNP is associated with risk after adjustment for the other SNP. These results suggest the presence of two variants at 6q25.1 each independently associated with breast cancer risk in Asians and in Europeans. Of these two, the one tagged by rs2046210 is associated with a greater risk of ER- tumours.

Figure 1. Association of rs2046210 with breast cancer in Europeans versus Asians.

Figure 2. Association of rs12662670 with breast cancer in Europeans versus Asians.

Figure 3. Association of rs2046210 with breast cancer in European ER

−*versus ER+*cases and controls. *Estrogen receptor negative; **Estrogen receptor positive.

Figure 4. Association of rs2046210 with breast cancer in Asian ER

−*versus ER+**cases and controls. *Estrogen receptor negative; **Estrogen receptor positive.

Figure 5. Association of rs12662670 with breast cancer in European ER

−*versus ER+**cases and controls. *Estrogen receptor negative; **Estrogen receptor positive.

Figure 6. Association of rs12662670 with breast cancer in Asian ER

−*versus ER+*cases and controls. *Estrogen receptor negative; **Estrogen receptor positive.

Figure 7. Linkage disequilibrium blocks in the ESR1 region.

Five SNPs tagged (at r2>0.9) by rs12662670 and three by rs2046210 are marked by arrows (dark and light grey respectively); rs12662670 and rs2046210 are marked by stars; rs3757318 and rs9397435 are marked by points; blocks were generated using data from the 1000 Genomes Project and HapMap; blocks include all single nucleotide polymorphisms with a minor allele frequency >0.05. The directions of translation of ESR1 and C6orf97 are marked and other genes in the locus are listed.