Genome-Wide Association Study Identifies Two Novel Loci with Sex-Specific Effects for Type 2 Diabetes Mellitus and Glycemic Traits in a Korean Population

被引：25

作者：

Go, Min Jin ^{[1
]}

Hwang, Joo-Yeon ^{[1
]}

Park, Tae-Joon ^{[1
]}

Kim, Young Jin ^{[1
]}

Oh, Ji Hee ^{[1
]}

Kim, Yeon-Jung ^{[1
]}

Han, Bok-Ghee ^{[1
]}

Kim, Bong-Jo ^{[1
]}

机构：

[1] Korea Natl Inst Hlth, Ctr Genome Sci, Div Struct & Funct Genom, Cheongwon, South Korea

来源：

DIABETES & METABOLISM JOURNAL | 2014年 / 38卷 / 05期

关键词：

Genome-wide association study; Glycemic trait; Sex-specific; Type; 2; diabetes;

D O I：

10.4093/dmj.2014.38.5.375

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Background: Until recently, genome-wide association study (GWAS)-based findings have provided a substantial genetic contribution to type 2 diabetes mellitus (T2DM) or related glycemic traits. However, identification of allelic heterogeneity and population-specific genetic variants under consideration of potential confounding factors will be very valuable for clinical applicability. To identify novel susceptibility loci for T2DM and glycemic traits, we performed a two-stage genetic association study in a Korean population. Methods: We performed a logistic analysis for T2DM, and the first discovery GWAS was analyzed for 1,042 cases and 2,943 controls recruited from a population-based cohort (KARE, n=8,842). The second stage, de novo replication analysis, was performed in 1,216 cases and 1,352 controls selected from an independent population-based cohort (Health 2, n=8,500). A multiple linear regression analysis for glycemic traits was further performed in a total of 14,232 nondiabetic individuals consisting of 7,696 GWAS and 6,536 replication study participants. A meta-analysis was performed on the combined results using effect size and standard errors estimated for stage 1 and 2, respectively. Results: A combined meta-analysis for T2DM identified two new (rs11065756 and rs2074356) loci reaching genome-wide significance in CCDC63 and C12orf51 on the 12q24 region. In addition, these variants were significantly associated with fasting plasma glucose and homeostasis model assessment of beta-cell function. Interestingly, two independent single nucleotide polymorphisms were associated with sex-specific stratification in this study. Conclusion: Our study showed a strong association between T2DM and glycemic traits. We further observed that two novel loci with multiple diverse effects were highly specific to males. Taken together, these findings may provide additional insights into the clinical assessment or subclassification of disease risk in a Korean population.

引用

页码：375 / 387

页数：13

共 50 条

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Baik, Inkyung ;

Cho, Nam H. ;

Kim, Seong Hwan ;

Han, Bok-Ghee ;

Shin, Chol .

AMERICAN JOURNAL OF CLINICAL NUTRITION, 2011, 93 (04) :809-816

[2] Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes [J].

Barrett, Jeffrey C. ;

Clayton, David G. ;

Concannon, Patrick ;

Akolkar, Beena ;

Cooper, Jason D. ;

Erlich, Henry A. ;

Julier, Cecile ;

Morahan, Grant ;

Nerup, Jorn ;

Nierras, Concepcion ;

Plagnol, Vincent ;

Pociot, Flemming ;

Schuilenburg, Helen ;

Smyth, Deborah J. ;

Stevens, Helen ;

Todd, John A. ;

Walker, Neil M. ;

Rich, Stephen S. .

NATURE GENETICS, 2009, 41 (06) :703-707

[3] Population-Specific Risk of Type 2 Diabetes Conferred by HAT4A P2 Promoter Variants A Lesson for Replication Studies [J].

Barroso, Ines ;

Luan, Jian'an ;

Wheeler, Eleanor ;

Whittaker, Pamela ;

Wasson, Jon ;

Zeggini, Eleftheria ;

Weedon, Michael N. ;

Hunt, Sarah ;

Venkatesh, Ranganath ;

Frayling, Timothy M. ;

Delgado, Marcos ;

Neuman, Rosalind J. ;

Zhao, Jinghua ;

Sherva, Richard ;

Glaser, Benjamin ;

Walker, Mark ;

Hitman, Graham ;

McCarthy, Mark I. ;

Hattersley, Andrew T. ;

Permutt, M. Alan ;

Wareham, Nicholas J. ;

Deloukas, Panagiotis .

DIABETES, 2008, 57 (11) :3161-3165

[4] A polymorphism within the G6PC2 gene is associated with fasting plasma glucose levels [J].

Bouatia-Naji, Nabila ;

Rocheleau, Ghislain ;

Van Lommel, Leentje ;

Lemaire, Katleen ;

Schuit, Frans ;

Cavalcanti-Proenca, Christine ;

Marchand, Marion ;

Hartikainen, Anna-Liisa ;

Sovio, Ulla ;

De Graeve, Franck ;

Rung, Johan ;

Vaxillaire, Martine ;

Tichet, Jean ;

Marre, Michel ;

Balkau, Beverley ;

Weill, Jacques ;

Elliott, Paul ;

Jarvelin, Marjo-Riitta ;

Meyre, David ;

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Dina, Christian ;

Sladek, Robert ;

Froguel, Philippe .

SCIENCE, 2008, 320 (5879) :1085-1088

[5] A variant near MTNR1B is associated with increased fasting plasma glucose levels and type 2 diabetes risk [J].

Bouatia-Naji, Nabila ;

Bonnefond, Amelie ;

Cavalcanti-Proenca, Christine ;

Sparso, Thomas ;

Holmkvist, Johan ;

Marchand, Marion ;

Delplanque, Jerome ;

Lobbens, Stephane ;

Rocheleau, Ghislain ;

Durand, Emmanuelle ;

De Graeve, Franck ;

Chevre, Jean-Claude ;

Borch-Johnsen, Knut ;

Hartikainen, Anna-Liisa ;

Ruokonen, Aimo ;

Tichet, Jean ;

Marre, Michel ;

Weill, Jacques ;

Heude, Barbara ;

Tauber, Maithe ;

Lemaire, Katleen ;

Schuit, Frans ;

Elliott, Paul ;

Jorgensen, Torben ;

Charpentier, Guillaume ;

Hadjadj, Samy ;

Cauchi, Stephane ;

Vaxillaire, Martine ;

Sladek, Robert ;

Visvikis-Siest, Sophie ;

Balkau, Beverley ;

Levy-Marchal, Claire ;

Pattou, Francois ;

Meyre, David ;

Blakemore, Alexandra I. F. ;

Jarvelin, Marjo-Riita ;

Walley, Andrew J. ;

Hansen, Torben ;

Dina, Christian ;

Pedersen, Oluf ;

Froguel, Philippe .

NATURE GENETICS, 2009, 41 (01) :89-94

[6] Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls [J].

Burton, Paul R. ;

Clayton, David G. ;

Cardon, Lon R. ;

Craddock, Nick ;

Deloukas, Panos ;

Duncanson, Audrey ;

Kwiatkowski, Dominic P. ;

McCarthy, Mark I. ;

Ouwehand, Willem H. ;

Samani, Nilesh J. ;

Todd, John A. ;

Donnelly, Peter ;

Barrett, Jeffrey C. ;

Davison, Dan ;

Easton, Doug ;

Evans, David ;

Leung, Hin-Tak ;

Marchini, Jonathan L. ;

Morris, Andrew P. ;

Spencer, Chris C. A. ;

Tobin, Martin D. ;

Attwood, Antony P. ;

Boorman, James P. ;

Cant, Barbara ;

Everson, Ursula ;

Hussey, Judith M. ;

Jolley, Jennifer D. ;

Knight, Alexandra S. ;

Koch, Kerstin ;

Meech, Elizabeth ;

Nutland, Sarah ;

Prowse, Christopher V. ;

Stevens, Helen E. ;

Taylor, Niall C. ;

Walters, Graham R. ;

Walker, Neil M. ;

Watkins, Nicholas A. ;

Winzer, Thilo ;

Jones, Richard W. ;

McArdle, Wendy L. ;

Ring, Susan M. ;

Strachan, David P. ;

Pembrey, Marcus ;

Breen, Gerome ;

St Clair, David ;

Caesar, Sian ;

Gordon-Smith, Katherine ;

Jones, Lisa ;

Fraser, Christine ;

Green, Elain K. .

NATURE, 2007, 447 (7145) :661-678

[7] Variations in the G6PC2/ABCB11 genomic region are associated with fasting glucose levels [J].

Chen, Wei-Min ;

Erdos, Michael R. ;

Jackson, Anne U. ;

Saxena, Richa ;

Sanna, Serena ;

Silver, Kristi D. ;

Timpson, Nicholas J. ;

Hansen, Torben ;

Orru, Marco ;

Piras, Maria Grazia ;

Bonnycastle, Lori L. ;

Willer, Cristen J. ;

Lyssenko, Valeriya ;

Shen, Haiqing ;

Kuusisto, Johanna ;

Ebrahim, Shah ;

Sestu, Natascia ;

Duren, William L. ;

Spada, Maria Cristina ;

Stringham, Heather M. ;

Scott, Laura J. ;

Olla, Nazario ;

Swift, Amy J. ;

Najjar, Samer ;

Mitchell, Braxton D. ;

Lawlor, Debbie A. ;

Smith, George Davey ;

Ben-Shlomo, Yoav ;

Andersen, Gitte ;

Borch-Johnsen, Knut ;

Jorgensen, Torben ;

Saramies, Jouko ;

Valle, Timo T. ;

Buchanan, Thomas A. ;

Shuldiner, Alan R. ;

Lakatta, Edward ;

Bergman, Richard N. ;

Uda, Manuela ;

Tuomilehto, Jaakko ;

Pedersen, Oluf ;

Cao, Antonio ;

Groop, Leif ;

Mohlke, Karen L. ;

Laakso, Markku ;

Schlessinger, David ;

Collins, Francis S. ;

Altshuler, David ;

Abecasis, Goncalo R. ;

Boehnke, Michael ;

Scuteri, Angelo .

JOURNAL OF CLINICAL INVESTIGATION, 2008, 118 (07) :2620-2628

[8] Type 2 diabetes-associated genetic variants discovered in the recent genome-wide association studies are related to gestational diabetes mellitus in the Korean population [J].

Cho, Y. M. ;

Kim, T. H. ;

Lim, S. ;

Choi, S. H. ;

Shin, H. D. ;

Lee, H. K. ;

Park, K. S. ;

Jang, H. C. .

DIABETOLOGIA, 2009, 52 (02) :253-261

[9] Meta-analysis of genome-wide association studies identifies eight new loci for type 2 diabetes in east Asians [J].

Cho, Yoon Shin ;

Chen, Chien-Hsiun ;

Hu, Cheng ;

Long, Jirong ;

Ong, Rick Twee Hee ;

Sim, Xueling ;

Takeuchi, Fumihiko ;

Wu, Ying ;

Go, Min Jin ;

Yamauchi, Toshimasa ;

Chang, Yi-Cheng ;

Kwak, Soo Heon ;

Ma, Ronald C. W. ;

Yamamoto, Ken ;

Adair, Linda S. ;

Aung, Tin ;

Cai, Qiuyin ;

Chang, Li-Ching ;

Chen, Yuan-Tsong ;

Gao, Yutang ;

Hu, Frank B. ;

Kim, Hyung-Lae ;

Kim, Sangsoo ;

Kim, Young Jin ;

Lee, Jeannette Jen-Mai ;

Lee, Nanette R. ;

Li, Yun ;

Liu, Jian Jun ;

Lu, Wei ;

Nakamura, Jiro ;

Nakashima, Eitaro ;

Ng, Daniel Peng-Keat ;

Tay, Wan Ting ;

Tsai, Fuu-Jen ;

Wong, Tien Yin ;

Yokota, Mitsuhiro ;

Zheng, Wei ;

Zhang, Rong ;

Wang, Congrong ;

So, Wing Yee ;

Ohnaka, Keizo ;

Ikegami, Hiroshi ;

Hara, Kazuo ;

Cho, Young Min ;

Cho, Nam H. ;

Chang, Tien-Jyun ;

Bao, Yuqian ;

Hedman, Asa K. ;

Morris, Andrew P. ;

McCarthy, Mark I. .

NATURE GENETICS, 2012, 44 (01) :67-U97

[10] A large-scale genome-wide association study of Asian populations uncovers genetic factors influencing eight quantitative traits [J].

Cho, Yoon Shin ;

Go, Min Jin ;

Kim, Young Jin ;

Heo, Jee Yeon ;

Oh, Ji Hee ;

Ban, Hyo-Jeong ;

Yoon, Dankyu ;

Lee, Mi Hee ;

Kim, Dong-Joon ;

Park, Miey ;

Cha, Seung-Hun ;

Kim, Jun-Woo ;

Han, Bok-Ghee ;

Min, Haesook ;

Ahn, Younjhin ;

Park, Man Suk ;

Han, Hye Ree ;

Jang, Hye-Yoon ;

Cho, Eun Young ;

Lee, Jong-Eun ;

Cho, Nam H. ;

Shin, Chol ;

Park, Taesung ;

Park, Ji Wan ;

Lee, Jong-Keuk ;

Cardon, Lon ;

Clarke, Geraldine ;

McCarthy, Mark I. ;

Lee, Jong-Young ;

Lee, Jong-Koo ;

Oh, Bermseok ;

Kim, Hyung-Lae .

NATURE GENETICS, 2009, 41 (05) :527-534

← 1 2 3 4 5 →

共 50 条

[1] Genome-wide association studies identify genetic loci related to alcohol consumption in Korean men [J].

Baik, Inkyung ;

Cho, Nam H. ;

Kim, Seong Hwan ;

Han, Bok-Ghee ;

Shin, Chol .

AMERICAN JOURNAL OF CLINICAL NUTRITION, 2011, 93 (04) :809-816

[2] Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes [J].

Barrett, Jeffrey C. ;

Clayton, David G. ;

Concannon, Patrick ;

Akolkar, Beena ;

Cooper, Jason D. ;

Erlich, Henry A. ;

Julier, Cecile ;

Morahan, Grant ;

Nerup, Jorn ;

Nierras, Concepcion ;

Plagnol, Vincent ;

Pociot, Flemming ;

Schuilenburg, Helen ;

Smyth, Deborah J. ;

Stevens, Helen ;

Todd, John A. ;

Walker, Neil M. ;

Rich, Stephen S. .

NATURE GENETICS, 2009, 41 (06) :703-707

[3] Population-Specific Risk of Type 2 Diabetes Conferred by HAT4A P2 Promoter Variants A Lesson for Replication Studies [J].

Barroso, Ines ;

Luan, Jian'an ;

Wheeler, Eleanor ;

Whittaker, Pamela ;

Wasson, Jon ;

Zeggini, Eleftheria ;

Weedon, Michael N. ;

Hunt, Sarah ;

Venkatesh, Ranganath ;

Frayling, Timothy M. ;

Delgado, Marcos ;

Neuman, Rosalind J. ;

Zhao, Jinghua ;

Sherva, Richard ;

Glaser, Benjamin ;

Walker, Mark ;

Hitman, Graham ;

McCarthy, Mark I. ;

Hattersley, Andrew T. ;

Permutt, M. Alan ;

Wareham, Nicholas J. ;

Deloukas, Panagiotis .

DIABETES, 2008, 57 (11) :3161-3165

[4] A polymorphism within the G6PC2 gene is associated with fasting plasma glucose levels [J].

Bouatia-Naji, Nabila ;

Rocheleau, Ghislain ;

Van Lommel, Leentje ;

Lemaire, Katleen ;

Schuit, Frans ;

Cavalcanti-Proenca, Christine ;

Marchand, Marion ;

Hartikainen, Anna-Liisa ;

Sovio, Ulla ;

De Graeve, Franck ;

Rung, Johan ;

Vaxillaire, Martine ;

Tichet, Jean ;

Marre, Michel ;

Balkau, Beverley ;

Weill, Jacques ;

Elliott, Paul ;

Jarvelin, Marjo-Riitta ;

Meyre, David ;

Polychronakos, Constantin ;

Dina, Christian ;

Sladek, Robert ;

Froguel, Philippe .

SCIENCE, 2008, 320 (5879) :1085-1088

[5] A variant near MTNR1B is associated with increased fasting plasma glucose levels and type 2 diabetes risk [J].

Bouatia-Naji, Nabila ;

Bonnefond, Amelie ;

Cavalcanti-Proenca, Christine ;

Sparso, Thomas ;

Holmkvist, Johan ;

Marchand, Marion ;

Delplanque, Jerome ;

Lobbens, Stephane ;

Rocheleau, Ghislain ;

Durand, Emmanuelle ;

De Graeve, Franck ;

Chevre, Jean-Claude ;

Borch-Johnsen, Knut ;

Hartikainen, Anna-Liisa ;

Ruokonen, Aimo ;

Tichet, Jean ;

Marre, Michel ;

Weill, Jacques ;

Heude, Barbara ;

Tauber, Maithe ;

Lemaire, Katleen ;

Schuit, Frans ;

Elliott, Paul ;

Jorgensen, Torben ;

Charpentier, Guillaume ;

Hadjadj, Samy ;

Cauchi, Stephane ;

Vaxillaire, Martine ;

Sladek, Robert ;

Visvikis-Siest, Sophie ;

Balkau, Beverley ;

Levy-Marchal, Claire ;

Pattou, Francois ;

Meyre, David ;

Blakemore, Alexandra I. F. ;

Jarvelin, Marjo-Riita ;

Walley, Andrew J. ;

Hansen, Torben ;

Dina, Christian ;

Pedersen, Oluf ;

Froguel, Philippe .

NATURE GENETICS, 2009, 41 (01) :89-94

[6] Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls [J].

Burton, Paul R. ;

Clayton, David G. ;

Cardon, Lon R. ;

Craddock, Nick ;

Deloukas, Panos ;

Duncanson, Audrey ;

Kwiatkowski, Dominic P. ;

McCarthy, Mark I. ;

Ouwehand, Willem H. ;

Samani, Nilesh J. ;

Todd, John A. ;

Donnelly, Peter ;

Barrett, Jeffrey C. ;

Davison, Dan ;

Easton, Doug ;

Evans, David ;

Leung, Hin-Tak ;

Marchini, Jonathan L. ;

Morris, Andrew P. ;

Spencer, Chris C. A. ;

Tobin, Martin D. ;

Attwood, Antony P. ;

Boorman, James P. ;

Cant, Barbara ;

Everson, Ursula ;

Hussey, Judith M. ;

Jolley, Jennifer D. ;

Knight, Alexandra S. ;

Koch, Kerstin ;

Meech, Elizabeth ;

Nutland, Sarah ;

Prowse, Christopher V. ;

Stevens, Helen E. ;

Taylor, Niall C. ;

Walters, Graham R. ;

Walker, Neil M. ;

Watkins, Nicholas A. ;

Winzer, Thilo ;

Jones, Richard W. ;

McArdle, Wendy L. ;

Ring, Susan M. ;

Strachan, David P. ;

Pembrey, Marcus ;

Breen, Gerome ;

St Clair, David ;

Caesar, Sian ;

Gordon-Smith, Katherine ;

Jones, Lisa ;

Fraser, Christine ;

Green, Elain K. .

NATURE, 2007, 447 (7145) :661-678

[7] Variations in the G6PC2/ABCB11 genomic region are associated with fasting glucose levels [J].

Chen, Wei-Min ;

Erdos, Michael R. ;

Jackson, Anne U. ;

Saxena, Richa ;

Sanna, Serena ;

Silver, Kristi D. ;

Timpson, Nicholas J. ;

Hansen, Torben ;

Orru, Marco ;

Piras, Maria Grazia ;

Bonnycastle, Lori L. ;

Willer, Cristen J. ;

Lyssenko, Valeriya ;

Shen, Haiqing ;

Kuusisto, Johanna ;

Ebrahim, Shah ;

Sestu, Natascia ;

Duren, William L. ;

Spada, Maria Cristina ;

Stringham, Heather M. ;

Scott, Laura J. ;

Olla, Nazario ;

Swift, Amy J. ;

Najjar, Samer ;

Mitchell, Braxton D. ;

Lawlor, Debbie A. ;

Smith, George Davey ;

Ben-Shlomo, Yoav ;

Andersen, Gitte ;

Borch-Johnsen, Knut ;

Jorgensen, Torben ;

Saramies, Jouko ;

Valle, Timo T. ;

Buchanan, Thomas A. ;

Shuldiner, Alan R. ;

Lakatta, Edward ;

Bergman, Richard N. ;

Uda, Manuela ;

Tuomilehto, Jaakko ;

Pedersen, Oluf ;

Cao, Antonio ;

Groop, Leif ;

Mohlke, Karen L. ;

Laakso, Markku ;

Schlessinger, David ;

Collins, Francis S. ;

Altshuler, David ;

Abecasis, Goncalo R. ;

Boehnke, Michael ;

Scuteri, Angelo .

JOURNAL OF CLINICAL INVESTIGATION, 2008, 118 (07) :2620-2628

[8] Type 2 diabetes-associated genetic variants discovered in the recent genome-wide association studies are related to gestational diabetes mellitus in the Korean population [J].

Cho, Y. M. ;

Kim, T. H. ;

Lim, S. ;

Choi, S. H. ;

Shin, H. D. ;

Lee, H. K. ;

Park, K. S. ;

Jang, H. C. .

DIABETOLOGIA, 2009, 52 (02) :253-261

[9] Meta-analysis of genome-wide association studies identifies eight new loci for type 2 diabetes in east Asians [J].

Cho, Yoon Shin ;

Chen, Chien-Hsiun ;

Hu, Cheng ;

Long, Jirong ;

Ong, Rick Twee Hee ;

Sim, Xueling ;

Takeuchi, Fumihiko ;

Wu, Ying ;

Go, Min Jin ;

Yamauchi, Toshimasa ;

Chang, Yi-Cheng ;

Kwak, Soo Heon ;

Ma, Ronald C. W. ;

Yamamoto, Ken ;

Adair, Linda S. ;

Aung, Tin ;

Cai, Qiuyin ;

Chang, Li-Ching ;

Chen, Yuan-Tsong ;

Gao, Yutang ;

Hu, Frank B. ;

Kim, Hyung-Lae ;

Kim, Sangsoo ;

Kim, Young Jin ;

Lee, Jeannette Jen-Mai ;

Lee, Nanette R. ;

Li, Yun ;

Liu, Jian Jun ;

Lu, Wei ;

Nakamura, Jiro ;

Nakashima, Eitaro ;

Ng, Daniel Peng-Keat ;

Tay, Wan Ting ;

Tsai, Fuu-Jen ;

Wong, Tien Yin ;

Yokota, Mitsuhiro ;

Zheng, Wei ;

Zhang, Rong ;

Wang, Congrong ;

So, Wing Yee ;

Ohnaka, Keizo ;

Ikegami, Hiroshi ;

Hara, Kazuo ;

Cho, Young Min ;

Cho, Nam H. ;

Chang, Tien-Jyun ;

Bao, Yuqian ;

Hedman, Asa K. ;

Morris, Andrew P. ;

McCarthy, Mark I. .

NATURE GENETICS, 2012, 44 (01) :67-U97

[10] A large-scale genome-wide association study of Asian populations uncovers genetic factors influencing eight quantitative traits [J].

Cho, Yoon Shin ;

Go, Min Jin ;

Kim, Young Jin ;

Heo, Jee Yeon ;

Oh, Ji Hee ;

Ban, Hyo-Jeong ;

Yoon, Dankyu ;

Lee, Mi Hee ;

Kim, Dong-Joon ;

Park, Miey ;

Cha, Seung-Hun ;

Kim, Jun-Woo ;

Han, Bok-Ghee ;

Min, Haesook ;

Ahn, Younjhin ;

Park, Man Suk ;

Han, Hye Ree ;

Jang, Hye-Yoon ;

Cho, Eun Young ;

Lee, Jong-Eun ;

Cho, Nam H. ;

Shin, Chol ;

Park, Taesung ;

Park, Ji Wan ;

Lee, Jong-Keuk ;

Cardon, Lon ;

Clarke, Geraldine ;

McCarthy, Mark I. ;

Lee, Jong-Young ;

Lee, Jong-Koo ;

Oh, Bermseok ;

Kim, Hyung-Lae .

NATURE GENETICS, 2009, 41 (05) :527-534

← 1 2 3 4 5 →