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

R Hein; M Maranian; JL Hopper; MK Kapuscinski; MC Southey; DJ Park; Marjanka K Schmidt; A Broeks; FBL Hogervorst; HB Bueno-de-Mesquit; KR Muir; A Lophatananon; S Rattanamongkongul; P Puttawibul; PA Fasching; A Hein; AB Ekici; MW Beckmann; O Fletcher; N Johnson; ID Silva; J Peto; E Sawyer; I Tomlinson; M Kerin; N Miller; F Marmee; A Schneeweiss; C Sohn; B Burwinkel; P Guenel; E Cordina-Duverger; F Menegaux; SE Bojesen; BG Nordestgaard; H Flyger; RL Milne; JIA Perez; MP Zamora; J Benitez; H Anton-Culver; A Ziogas; L Bernstein; CA Clarke; H Brenner; H Muller; V Arndt; C Stegmaier; N Rahman; S Seal; C Turnbull; A Renwick; A Meindl; S Schott; CR Bartram; RK Schmutzler; H Brauch; U Hamann; YD Ko; S Wang-Gohrke; T Dork; P Schurmann; JH Karstens; P Hillemanns; H Nevanlinna; T Heikkinen; K Aittomaki; C Blomqvist; NV Bogdanova; IV Zalutsky; NN Antonenkova; M Bermisheva; D Prokovieva; A Farahtdinova; E Khusnutdinova; A Lindblom; S Margolin; A Mannermaa; V Kataja; VM Kosma; J Hartikainen; XQ Chen; J Beesley; D Lambrechts; H (Hui) Zhao; P Neven; H Wildiers; S Nickels; D Flesch-Janys; P Radice; P Peterlongo; S Manoukian; M Barile; FJ Couch; JE Olson; XS Wang; Z Fredericksen; GG Giles; L Baglietto; CA McLean; G Severi; K Offit; M Robson; MM Gaudet; J Vijai; GG Alnaes; V Kristensen; AL Borresen-Dale; EM John; A Miron; R Winqvist; K Pylkas; A Jukkola-Vuorinen; M Grip; IL Andrulis; JA Knight; G Glendon; AM Mulligan; JD Figueroa; M Garcia-Closas; J Lissowska; ME Sherman; M Hooning; John Martens; Caroline Seynaeve; M Collee; P Hall; K Humpreys; K Czene; JJ Liu; A Cox; IW Brock; SS Cross; MWR Reed; S (Shahana) Ahmed; M Ghoussaini; PDP Pharoah; D Kang; KY Yoo; DY Noh; A Jakubowska; K Jaworska; K Durda; E Zlowocka; S Sangrajrang; V Gaborieau; P Brennan; J Mckay; CY Shen; JC Yu; HM Hsu; MF Hou; N Orr; M Schoemaker; A Ashworth; A Swerdlow; A Trentham-Dietz; PA Newcomb; L Titus; KM Egan; G Chenevix-Trench; AC Antoniou; MK Humphreys; J Morrison; J Chang-Claude; DF Easton; AM Dunning; T Truong

doi:10.1371/journal.pone.0042380

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

R Hein, M Maranian, JL Hopper, MK Kapuscinski, MC Southey, DJ Park, Marjanka K Schmidt, A Broeks, FBL Hogervorst, HB Bueno-de-Mesquit, KR Muir, A Lophatananon, S Rattanamongkongul, P Puttawibul, PA Fasching, A Hein, AB Ekici, MW Beckmann, O Fletcher, N JohnsonID Silva, J Peto, E Sawyer, I Tomlinson, M Kerin, N Miller, F Marmee, A Schneeweiss, C Sohn, B Burwinkel, P Guenel, E Cordina-Duverger, F Menegaux, SE Bojesen, BG Nordestgaard, H Flyger, RL Milne, JIA Perez, MP Zamora, J Benitez, H Anton-Culver, A Ziogas, L Bernstein, CA Clarke, H Brenner, H Muller, V Arndt, C Stegmaier, N Rahman, S Seal, C Turnbull, A Renwick, A Meindl, S Schott, CR Bartram, RK Schmutzler, H Brauch, U Hamann, YD Ko, S Wang-Gohrke, T Dork, P Schurmann, JH Karstens, P Hillemanns, H Nevanlinna, T Heikkinen, K Aittomaki, C Blomqvist, NV Bogdanova, IV Zalutsky, NN Antonenkova, M Bermisheva, D Prokovieva, A Farahtdinova, E Khusnutdinova, A Lindblom, S Margolin, A Mannermaa, V Kataja, VM Kosma, J Hartikainen, XQ Chen, J Beesley, D Lambrechts, H (Hui) Zhao, P Neven, H Wildiers, S Nickels, D Flesch-Janys, P Radice, P Peterlongo, S Manoukian, M Barile, FJ Couch, JE Olson, XS Wang, Z Fredericksen, GG Giles, L Baglietto, CA McLean, G Severi, K Offit, M Robson, MM Gaudet, J Vijai, GG Alnaes, V Kristensen, AL Borresen-Dale, EM John, A Miron, R Winqvist, K Pylkas, A Jukkola-Vuorinen, M Grip, IL Andrulis, JA Knight, G Glendon, AM Mulligan, JD Figueroa, M Garcia-Closas, J Lissowska, ME Sherman, M Hooning, John Martens, Caroline Seynaeve, M Collee, P Hall, K Humpreys, K Czene, JJ Liu, A Cox, IW Brock, SS Cross, MWR Reed, S (Shahana) Ahmed, M Ghoussaini, PDP Pharoah, D Kang, KY Yoo, DY Noh, A Jakubowska, K Jaworska, K Durda, E Zlowocka, S Sangrajrang, V Gaborieau, P Brennan, J Mckay, CY Shen, JC Yu, HM Hsu, MF Hou, N Orr, M Schoemaker, A Ashworth, A Swerdlow, A Trentham-Dietz, PA Newcomb, L Titus, KM Egan, G Chenevix-Trench, AC Antoniou, MK Humphreys, J Morrison, J Chang-Claude, DF Easton, AM Dunning, T Truong

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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 = 7.6x10(-14) in Asians and 1.09 (95% CI 1.07-1.11), p = 6.8x10(-18) in Europeans. rs12662670: OR (G/T) = 1.29 (95% CI 1.19-1.41), p = 1.2x10(-9) in Asians and 1.12 (95% CI 1.08-1.17), p = 3.8x10(-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 = 1.8x10(-17) versus OR (ER+) = 1.07 (95% CI 1.04-1.1), p = 1.3x10(-7), p(heterogeneity) = 5.1x10(-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.

Original language	Undefined/Unknown
Journal	PLoS One (print)
Volume	7
Issue number	8
DOIs	https://doi.org/10.1371/journal.pone.0042380
Publication status	Published - 2012

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Cite this

Hein, R., Maranian, M., Hopper, JL., Kapuscinski, MK., Southey, MC., Park, DJ., Schmidt, M. K., Broeks, A., Hogervorst, FBL., Bueno-de-Mesquit, HB., Muir, KR., Lophatananon, A., Rattanamongkongul, S., Puttawibul, P., Fasching, PA., Hein, A., Ekici, AB., Beckmann, MW., Fletcher, O., ... Truong, T. (2012). Comparison of 6q25 Breast Cancer Hits from Asian and European Genome Wide Association Studies in the Breast Cancer Association Consortium (BCAC). PLoS One (print), 7(8). https://doi.org/10.1371/journal.pone.0042380

@article{450830c2089d48d9946d38b593fbbff1,

title = "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 = 7.6x10(-14) in Asians and 1.09 (95% CI 1.07-1.11), p = 6.8x10(-18) in Europeans. rs12662670: OR (G/T) = 1.29 (95% CI 1.19-1.41), p = 1.2x10(-9) in Asians and 1.12 (95% CI 1.08-1.17), p = 3.8x10(-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 = 1.8x10(-17) versus OR (ER+) = 1.07 (95% CI 1.04-1.1), p = 1.3x10(-7), p(heterogeneity) = 5.1x10(-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.",

author = "R Hein and M Maranian and JL Hopper and MK Kapuscinski and MC Southey and DJ Park and Schmidt, {Marjanka K} and A Broeks and FBL Hogervorst and HB Bueno-de-Mesquit and KR Muir and A Lophatananon and S Rattanamongkongul and P Puttawibul and PA Fasching and A Hein and AB Ekici and MW Beckmann and O Fletcher and N Johnson and ID Silva and J Peto and E Sawyer and I Tomlinson and M Kerin and N Miller and F Marmee and A Schneeweiss and C Sohn and B Burwinkel and P Guenel and E Cordina-Duverger and F Menegaux and SE Bojesen and BG Nordestgaard and H Flyger and RL Milne and JIA Perez and MP Zamora and J Benitez and H Anton-Culver and A Ziogas and L Bernstein and CA Clarke and H Brenner and H Muller and V Arndt and C Stegmaier and N Rahman and S Seal and C Turnbull and A Renwick and A Meindl and S Schott and CR Bartram and RK Schmutzler and H Brauch and U Hamann and YD Ko and S Wang-Gohrke and T Dork and P Schurmann and JH Karstens and P Hillemanns and H Nevanlinna and T Heikkinen and K Aittomaki and C Blomqvist and NV Bogdanova and IV Zalutsky and NN Antonenkova and M Bermisheva and D Prokovieva and A Farahtdinova and E Khusnutdinova and A Lindblom and S Margolin and A Mannermaa and V Kataja and VM Kosma and J Hartikainen and XQ Chen and J Beesley and D Lambrechts and Zhao, {H (Hui)} and P Neven and H Wildiers and S Nickels and D Flesch-Janys and P Radice and P Peterlongo and S Manoukian and M Barile and FJ Couch and JE Olson and XS Wang and Z Fredericksen and GG Giles and L Baglietto and CA McLean and G Severi and K Offit and M Robson and MM Gaudet and J Vijai and GG Alnaes and V Kristensen and AL Borresen-Dale and EM John and A Miron and R Winqvist and K Pylkas and A Jukkola-Vuorinen and M Grip and IL Andrulis and JA Knight and G Glendon and AM Mulligan and JD Figueroa and M Garcia-Closas and J Lissowska and ME Sherman and M Hooning and John Martens and Caroline Seynaeve and M Collee and P Hall and K Humpreys and K Czene and JJ Liu and A Cox and IW Brock and SS Cross and MWR Reed and Ahmed, {S (Shahana)} and M Ghoussaini and PDP Pharoah and D Kang and KY Yoo and DY Noh and A Jakubowska and K Jaworska and K Durda and E Zlowocka and S Sangrajrang and V Gaborieau and P Brennan and J Mckay and CY Shen and JC Yu and HM Hsu and MF Hou and N Orr and M Schoemaker and A Ashworth and A Swerdlow and A Trentham-Dietz and PA Newcomb and L Titus and KM Egan and G Chenevix-Trench and AC Antoniou and MK Humphreys and J Morrison and J Chang-Claude and DF Easton and AM Dunning and T Truong",

year = "2012",

doi = "10.1371/journal.pone.0042380",

language = "Undefined/Unknown",

volume = "7",

journal = "PLoS One (print)",

issn = "1932-6203",

publisher = "Public Library of Science",

number = "8",

}

Hein, R, Maranian, M, Hopper, JL, Kapuscinski, MK, Southey, MC, Park, DJ, Schmidt, MK, Broeks, A, Hogervorst, FBL, Bueno-de-Mesquit, HB, Muir, KR, Lophatananon, A, Rattanamongkongul, S, Puttawibul, P, Fasching, PA, Hein, A, Ekici, AB, Beckmann, MW, Fletcher, O, Johnson, N, Silva, ID, Peto, J, Sawyer, E, Tomlinson, I, Kerin, M, Miller, N, Marmee, F, Schneeweiss, A, Sohn, C, Burwinkel, B, Guenel, P, Cordina-Duverger, E, Menegaux, F, Bojesen, SE, Nordestgaard, BG, Flyger, H, Milne, RL, Perez, JIA, Zamora, MP, Benitez, J, Anton-Culver, H, Ziogas, A, Bernstein, L, Clarke, CA, Brenner, H, Muller, H, Arndt, V, Stegmaier, C, Rahman, N, Seal, S, Turnbull, C, Renwick, A, Meindl, A, Schott, S, Bartram, CR, Schmutzler, RK, Brauch, H, Hamann, U, Ko, YD, Wang-Gohrke, S, Dork, T, Schurmann, P, Karstens, JH, Hillemanns, P, Nevanlinna, H, Heikkinen, T, Aittomaki, K, Blomqvist, C, Bogdanova, NV, Zalutsky, IV, Antonenkova, NN, Bermisheva, M, Prokovieva, D, Farahtdinova, A, Khusnutdinova, E, Lindblom, A, Margolin, S, Mannermaa, A, Kataja, V, Kosma, VM, Hartikainen, J, Chen, XQ, Beesley, J, Lambrechts, D, Zhao, H, Neven, P, Wildiers, H, Nickels, S, Flesch-Janys, D, Radice, P, Peterlongo, P, Manoukian, S, Barile, M, Couch, FJ, Olson, JE, Wang, XS, Fredericksen, Z, Giles, GG, Baglietto, L, McLean, CA, Severi, G, Offit, K, Robson, M, Gaudet, MM, Vijai, J, Alnaes, GG, Kristensen, V, Borresen-Dale, AL, John, EM, Miron, A, Winqvist, R, Pylkas, K, Jukkola-Vuorinen, A, Grip, M, Andrulis, IL, Knight, JA, Glendon, G, Mulligan, AM, Figueroa, JD, Garcia-Closas, M, Lissowska, J, Sherman, ME, Hooning, M, Martens, J, Seynaeve, C, Collee, M, Hall, P, Humpreys, K, Czene, K, Liu, JJ, Cox, A, Brock, IW, Cross, SS, Reed, MWR, Ahmed, S, Ghoussaini, M, Pharoah, PDP, Kang, D, Yoo, KY, Noh, DY, Jakubowska, A, Jaworska, K, Durda, K, Zlowocka, E, Sangrajrang, S, Gaborieau, V, Brennan, P, Mckay, J, Shen, CY, Yu, JC, Hsu, HM, Hou, MF, Orr, N, Schoemaker, M, Ashworth, A, Swerdlow, A, Trentham-Dietz, A, Newcomb, PA, Titus, L, Egan, KM, Chenevix-Trench, G, Antoniou, AC, Humphreys, MK, Morrison, J, Chang-Claude, J, Easton, DF, Dunning, AM & Truong, T 2012, 'Comparison of 6q25 Breast Cancer Hits from Asian and European Genome Wide Association Studies in the Breast Cancer Association Consortium (BCAC)', PLoS One (print), vol. 7, no. 8. https://doi.org/10.1371/journal.pone.0042380

TY - JOUR

T1 - Comparison of 6q25 Breast Cancer Hits from Asian and European Genome Wide Association Studies in the Breast Cancer Association Consortium (BCAC)

AU - Hein, R

AU - Maranian, M

AU - Hopper, JL

AU - Kapuscinski, MK

AU - Southey, MC

AU - Park, DJ

AU - Schmidt, Marjanka K

AU - Broeks, A

AU - Hogervorst, FBL

AU - Bueno-de-Mesquit, HB

AU - Muir, KR

AU - Lophatananon, A

AU - Rattanamongkongul, S

AU - Puttawibul, P

AU - Fasching, PA

AU - Hein, A

AU - Ekici, AB

AU - Beckmann, MW

AU - Fletcher, O

AU - Johnson, N

AU - Silva, ID

AU - Peto, J

AU - Sawyer, E

AU - Tomlinson, I

AU - Kerin, M

AU - Miller, N

AU - Marmee, F

AU - Schneeweiss, A

AU - Sohn, C

AU - Burwinkel, B

AU - Guenel, P

AU - Cordina-Duverger, E

AU - Menegaux, F

AU - Bojesen, SE

AU - Nordestgaard, BG

AU - Flyger, H

AU - Milne, RL

AU - Perez, JIA

AU - Zamora, MP

AU - Benitez, J

AU - Anton-Culver, H

AU - Ziogas, A

AU - Bernstein, L

AU - Clarke, CA

AU - Brenner, H

AU - Muller, H

AU - Arndt, V

AU - Stegmaier, C

AU - Rahman, N

AU - Seal, S

AU - Turnbull, C

AU - Renwick, A

AU - Meindl, A

AU - Schott, S

AU - Bartram, CR

AU - Schmutzler, RK

AU - Brauch, H

AU - Hamann, U

AU - Ko, YD

AU - Wang-Gohrke, S

AU - Dork, T

AU - Schurmann, P

AU - Karstens, JH

AU - Hillemanns, P

AU - Nevanlinna, H

AU - Heikkinen, T

AU - Aittomaki, K

AU - Blomqvist, C

AU - Bogdanova, NV

AU - Zalutsky, IV

AU - Antonenkova, NN

AU - Bermisheva, M

AU - Prokovieva, D

AU - Farahtdinova, A

AU - Khusnutdinova, E

AU - Lindblom, A

AU - Margolin, S

AU - Mannermaa, A

AU - Kataja, V

AU - Kosma, VM

AU - Hartikainen, J

AU - Chen, XQ

AU - Beesley, J

AU - Lambrechts, D

AU - Zhao, H (Hui)

AU - Neven, P

AU - Wildiers, H

AU - Nickels, S

AU - Flesch-Janys, D

AU - Radice, P

AU - Peterlongo, P

AU - Manoukian, S

AU - Barile, M

AU - Couch, FJ

AU - Olson, JE

AU - Wang, XS

AU - Fredericksen, Z

AU - Giles, GG

AU - Baglietto, L

AU - McLean, CA

AU - Severi, G

AU - Offit, K

AU - Robson, M

AU - Gaudet, MM

AU - Vijai, J

AU - Alnaes, GG

AU - Kristensen, V

AU - Borresen-Dale, AL

AU - John, EM

AU - Miron, A

AU - Winqvist, R

AU - Pylkas, K

AU - Jukkola-Vuorinen, A

AU - Grip, M

AU - Andrulis, IL

AU - Knight, JA

AU - Glendon, G

AU - Mulligan, AM

AU - Figueroa, JD

AU - Garcia-Closas, M

AU - Lissowska, J

AU - Sherman, ME

AU - Hooning, M

AU - Martens, John

AU - Seynaeve, Caroline

AU - Collee, M

AU - Hall, P

AU - Humpreys, K

AU - Czene, K

AU - Liu, JJ

AU - Cox, A

AU - Brock, IW

AU - Cross, SS

AU - Reed, MWR

AU - Ahmed, S (Shahana)

AU - Ghoussaini, M

AU - Pharoah, PDP

AU - Kang, D

AU - Yoo, KY

AU - Noh, DY

AU - Jakubowska, A

AU - Jaworska, K

AU - Durda, K

AU - Zlowocka, E

AU - Sangrajrang, S

AU - Gaborieau, V

AU - Brennan, P

AU - Mckay, J

AU - Shen, CY

AU - Yu, JC

AU - Hsu, HM

AU - Hou, MF

AU - Orr, N

AU - Schoemaker, M

AU - Ashworth, A

AU - Swerdlow, A

AU - Trentham-Dietz, A

AU - Newcomb, PA

AU - Titus, L

AU - Egan, KM

AU - Chenevix-Trench, G

AU - Antoniou, AC

AU - Humphreys, MK

AU - Morrison, J

AU - Chang-Claude, J

AU - Easton, DF

AU - Dunning, AM

AU - Truong, T

PY - 2012

Y1 - 2012

N2 - 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 = 7.6x10(-14) in Asians and 1.09 (95% CI 1.07-1.11), p = 6.8x10(-18) in Europeans. rs12662670: OR (G/T) = 1.29 (95% CI 1.19-1.41), p = 1.2x10(-9) in Asians and 1.12 (95% CI 1.08-1.17), p = 3.8x10(-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 = 1.8x10(-17) versus OR (ER+) = 1.07 (95% CI 1.04-1.1), p = 1.3x10(-7), p(heterogeneity) = 5.1x10(-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.

AB - 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 = 7.6x10(-14) in Asians and 1.09 (95% CI 1.07-1.11), p = 6.8x10(-18) in Europeans. rs12662670: OR (G/T) = 1.29 (95% CI 1.19-1.41), p = 1.2x10(-9) in Asians and 1.12 (95% CI 1.08-1.17), p = 3.8x10(-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 = 1.8x10(-17) versus OR (ER+) = 1.07 (95% CI 1.04-1.1), p = 1.3x10(-7), p(heterogeneity) = 5.1x10(-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.

U2 - 10.1371/journal.pone.0042380

DO - 10.1371/journal.pone.0042380

M3 - Article

C2 - 22879957

SN - 1932-6203

VL - 7

JO - PLoS One (print)

JF - PLoS One (print)

IS - 8

ER -