Nonsynonymous variants in PAX4 and GLP1R are associated with type 2 diabetes in an East Asian population

Soo Heon Kwak; Jeesoo Chae; Seungbok Lee; Sungkyoung Choi; Bo Kyung Koo; Ji Won Yoon; Jin Ho Park; Belong Cho; Min Kyong Moon; Soo Lim; Young Min Cho; Sanghoon Moon; Young Jin Kim; Sohee Han; Mi Yeong Hwang; Yoon Shin Cho; Myung Shik Lee; Hak C. Jang; Hyun Min Kang; Taesung Park; Nam H. Cho; Kyunga Kim; Jong Il Kim; Kyong Soo Park

doi:10.2337/db18-0361

Nonsynonymous variants in PAX4 and GLP1R are associated with type 2 diabetes in an East Asian population

Soo Heon Kwak, Jeesoo Chae, Seungbok Lee, Sungkyoung Choi, Bo Kyung Koo, Ji Won Yoon, Jin Ho Park, Belong Cho, Min Kyong Moon, Soo Lim, Young Min Cho, Sanghoon Moon, Young Jin Kim, Sohee Han, Mi Yeong Hwang, Yoon Shin Cho, Myung Shik Lee, Hak C. Jang, Hyun Min Kang, Taesung ParkNam H. Cho, Kyunga Kim, Jong Il Kim, Kyong Soo Park

Department of Physiology

Research output: Contribution to journal › Article › peer-review

37 Scopus citations

Abstract

We investigated ethnicity-specific exonic variants of type 2 diabetes (T2D) and its related clinical phenotypes in an East Asian population. We performed whole-exome sequencing in 917 T2D case and control subjects, and the findings were validated by exome array genotyping in 3,026 participants. In silico replication was conducted for seven nonsynonymous variants in an additional 13,122 participants. Single-variant and gene-based association tests for T2D were analyzed. A total of 728,838 variants were identified by whole-exome sequencing. Among nonsynonymous variants, PAX4 Arg192His increased risk of T2D and GLP1R Arg131Gln decreased risk of T2D in genome-wide significance (odds ratio [OR] 1.48, P = 4.47 3 10²¹⁶ and OR 0.84, P = 3.55 3 10²⁸, respectively). Another variant at PAX4 192 codon Arg192Ser was nominally associated with T2D (OR 1.62, P = 5.18 3 10²⁴). In T2D patients, PAX4 Arg192His was associated with earlier age at diagnosis, and GLP1R Arg131Gln was associated with decreased risk of cardiovascular disease. In control subjects without diabetes, the PAX4 Arg192His was associated with higher fasting glucose and GLP1R Arg131Gln was associated with lower fasting glucose and HbA_1c level. Gene-based analysis revealed that SLC30A8 was most significantly associated with decreased risk of T2D (P = 1.0 3 10²⁴). In summary, we have identified nonsynonymous variants associated with risk of T2D and related phenotypes in Koreans.

Original language	English
Pages (from-to)	1892-1902
Number of pages	11
Journal	Diabetes
Volume	67
Issue number	9
DOIs	https://doi.org/10.2337/db18-0361
State	Published - 1 Sep 2018

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Publisher Copyright:
© 2018 by the American Diabetes Association.

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10.2337/db18-0361

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Kwak, S. H., Chae, J., Lee, S., Choi, S., Koo, B. K., Yoon, J. W., Park, J. H., Cho, B., Moon, M. K., Lim, S., Cho, Y. M., Moon, S., Kim, Y. J., Han, S., Hwang, M. Y., Cho, Y. S., Lee, M. S., Jang, H. C., Kang, H. M., ... Park, K. S. (2018). Nonsynonymous variants in PAX4 and GLP1R are associated with type 2 diabetes in an East Asian population. Diabetes, 67(9), 1892-1902. https://doi.org/10.2337/db18-0361

@article{75b01ba5b70549c2bafb22d1fbd59006,

title = "Nonsynonymous variants in PAX4 and GLP1R are associated with type 2 diabetes in an East Asian population",

abstract = "We investigated ethnicity-specific exonic variants of type 2 diabetes (T2D) and its related clinical phenotypes in an East Asian population. We performed whole-exome sequencing in 917 T2D case and control subjects, and the findings were validated by exome array genotyping in 3,026 participants. In silico replication was conducted for seven nonsynonymous variants in an additional 13,122 participants. Single-variant and gene-based association tests for T2D were analyzed. A total of 728,838 variants were identified by whole-exome sequencing. Among nonsynonymous variants, PAX4 Arg192His increased risk of T2D and GLP1R Arg131Gln decreased risk of T2D in genome-wide significance (odds ratio [OR] 1.48, P = 4.47 3 10216 and OR 0.84, P = 3.55 3 1028, respectively). Another variant at PAX4 192 codon Arg192Ser was nominally associated with T2D (OR 1.62, P = 5.18 3 1024). In T2D patients, PAX4 Arg192His was associated with earlier age at diagnosis, and GLP1R Arg131Gln was associated with decreased risk of cardiovascular disease. In control subjects without diabetes, the PAX4 Arg192His was associated with higher fasting glucose and GLP1R Arg131Gln was associated with lower fasting glucose and HbA1c level. Gene-based analysis revealed that SLC30A8 was most significantly associated with decreased risk of T2D (P = 1.0 3 1024). In summary, we have identified nonsynonymous variants associated with risk of T2D and related phenotypes in Koreans.",

author = "Kwak, {Soo Heon} and Jeesoo Chae and Seungbok Lee and Sungkyoung Choi and Koo, {Bo Kyung} and Yoon, {Ji Won} and Park, {Jin Ho} and Belong Cho and Moon, {Min Kyong} and Soo Lim and Cho, {Young Min} and Sanghoon Moon and Kim, {Young Jin} and Sohee Han and Hwang, {Mi Yeong} and Cho, {Yoon Shin} and Lee, {Myung Shik} and Jang, {Hak C.} and Kang, {Hyun Min} and Taesung Park and Cho, {Nam H.} and Kyunga Kim and Kim, {Jong Il} and Park, {Kyong Soo}",

note = "Publisher Copyright: {\textcopyright} 2018 by the American Diabetes Association.",

year = "2018",

month = sep,

day = "1",

doi = "10.2337/db18-0361",

language = "English",

volume = "67",

pages = "1892--1902",

journal = "Diabetes",

issn = "0012-1797",

publisher = "American Diabetes Association Inc.",

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Kwak, SH, Chae, J, Lee, S, Choi, S, Koo, BK, Yoon, JW, Park, JH, Cho, B, Moon, MK, Lim, S, Cho, YM, Moon, S, Kim, YJ, Han, S, Hwang, MY, Cho, YS, Lee, MS, Jang, HC, Kang, HM, Park, T, Cho, NH, Kim, K, Kim, JI & Park, KS 2018, 'Nonsynonymous variants in PAX4 and GLP1R are associated with type 2 diabetes in an East Asian population', Diabetes, vol. 67, no. 9, pp. 1892-1902. https://doi.org/10.2337/db18-0361

TY - JOUR

T1 - Nonsynonymous variants in PAX4 and GLP1R are associated with type 2 diabetes in an East Asian population

AU - Kwak, Soo Heon

AU - Chae, Jeesoo

AU - Lee, Seungbok

AU - Choi, Sungkyoung

AU - Koo, Bo Kyung

AU - Yoon, Ji Won

AU - Park, Jin Ho

AU - Cho, Belong

AU - Moon, Min Kyong

AU - Lim, Soo

AU - Cho, Young Min

AU - Moon, Sanghoon

AU - Kim, Young Jin

AU - Han, Sohee

AU - Hwang, Mi Yeong

AU - Cho, Yoon Shin

AU - Lee, Myung Shik

AU - Jang, Hak C.

AU - Kang, Hyun Min

AU - Park, Taesung

AU - Cho, Nam H.

AU - Kim, Kyunga

AU - Kim, Jong Il

AU - Park, Kyong Soo

PY - 2018/9/1

Y1 - 2018/9/1

N2 - We investigated ethnicity-specific exonic variants of type 2 diabetes (T2D) and its related clinical phenotypes in an East Asian population. We performed whole-exome sequencing in 917 T2D case and control subjects, and the findings were validated by exome array genotyping in 3,026 participants. In silico replication was conducted for seven nonsynonymous variants in an additional 13,122 participants. Single-variant and gene-based association tests for T2D were analyzed. A total of 728,838 variants were identified by whole-exome sequencing. Among nonsynonymous variants, PAX4 Arg192His increased risk of T2D and GLP1R Arg131Gln decreased risk of T2D in genome-wide significance (odds ratio [OR] 1.48, P = 4.47 3 10216 and OR 0.84, P = 3.55 3 1028, respectively). Another variant at PAX4 192 codon Arg192Ser was nominally associated with T2D (OR 1.62, P = 5.18 3 1024). In T2D patients, PAX4 Arg192His was associated with earlier age at diagnosis, and GLP1R Arg131Gln was associated with decreased risk of cardiovascular disease. In control subjects without diabetes, the PAX4 Arg192His was associated with higher fasting glucose and GLP1R Arg131Gln was associated with lower fasting glucose and HbA1c level. Gene-based analysis revealed that SLC30A8 was most significantly associated with decreased risk of T2D (P = 1.0 3 1024). In summary, we have identified nonsynonymous variants associated with risk of T2D and related phenotypes in Koreans.

AB - We investigated ethnicity-specific exonic variants of type 2 diabetes (T2D) and its related clinical phenotypes in an East Asian population. We performed whole-exome sequencing in 917 T2D case and control subjects, and the findings were validated by exome array genotyping in 3,026 participants. In silico replication was conducted for seven nonsynonymous variants in an additional 13,122 participants. Single-variant and gene-based association tests for T2D were analyzed. A total of 728,838 variants were identified by whole-exome sequencing. Among nonsynonymous variants, PAX4 Arg192His increased risk of T2D and GLP1R Arg131Gln decreased risk of T2D in genome-wide significance (odds ratio [OR] 1.48, P = 4.47 3 10216 and OR 0.84, P = 3.55 3 1028, respectively). Another variant at PAX4 192 codon Arg192Ser was nominally associated with T2D (OR 1.62, P = 5.18 3 1024). In T2D patients, PAX4 Arg192His was associated with earlier age at diagnosis, and GLP1R Arg131Gln was associated with decreased risk of cardiovascular disease. In control subjects without diabetes, the PAX4 Arg192His was associated with higher fasting glucose and GLP1R Arg131Gln was associated with lower fasting glucose and HbA1c level. Gene-based analysis revealed that SLC30A8 was most significantly associated with decreased risk of T2D (P = 1.0 3 1024). In summary, we have identified nonsynonymous variants associated with risk of T2D and related phenotypes in Koreans.

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U2 - 10.2337/db18-0361

DO - 10.2337/db18-0361

M3 - Article

C2 - 29941447

AN - SCOPUS:85052683591

SN - 0012-1797

VL - 67

SP - 1892

EP - 1902

JO - Diabetes

JF - Diabetes

IS - 9

ER -

Nonsynonymous variants in PAX4 and GLP1R are associated with type 2 diabetes in an East Asian population

Abstract

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