Insulin response according to genotype
| Gene . | n . | First-phase insulin response (pmol/l) . | Second-phase insulin response (pmol/l) . | ISI (μmol · min−1 · kg−1 · pmol−1 · l−1) . | DI (μmol · min−1 · kg−1) . | n (GLP-1, Arg) . | GLP-1–stimulated insulin release (pmol/l)* . | Arginine-stimulated insulin release (pmol/l)* . |
|---|---|---|---|---|---|---|---|---|
| JAZF1, rs864745 | ||||||||
| C/C | 73 | 727 (652–812) | 262 (236–292) | 0.141 (0.122–0.162) | 107 (95–121) | 26 | 1,034 (799–1,337) | 1,728 (1,495–1,998) |
| C/T | 161 | 723 (672–778) | 239 (223–255) | 0.155 (0.142–0.170) | 111 (103–120) | 48 | 1,374 (1,122–1,683) | 1,992 (1,727–2,297) |
| T/T | 100 | 759 (686–841) | 263 (243–286) | 0.160 (0.145–0.177) | 124 (111–139) | 49 | 1,200 (951–1,514) | 2,233 (1,969–2,532) |
| P | 0.54 | 0.80 | 0.15 | 0.07 | 0.63 | 0.018 | ||
| CDC123/ CAMK1D, rs12779790 | ||||||||
| A/A | 212 | 755 (704–810) | 260 (245–275) | 0.155 (0.143–0.168) | 117 (109–127) | 74 | 1,318 (1,094–1,588) | 2,181 (1,979–2,403) |
| A/G | 110 | 713 (656–774) | 238 (220–258) | 0.153 (0.138–0.169) | 112 (101–123) | 48 | 1,106 (881–1,389) | 1,817 (1,588–2,078) |
| G/G | 12 | 617 (478–797) | 200 (176–228) | 0.146 (0.108–0.198) | 94 (71–125) | 1 | 1,142 (913–1,428) | 1,486 (1,322–1,671) |
| P | 0.10 | 0.0049 | 0.68 | 0.16 | 0.24 | 0.015 | ||
| TSPAN8/LGR5, rs7961581 | ||||||||
| T/T | 159 | 738 (687–793) | 253 (237–270) | 0.149 (0.135–0.164) | 113 (103–123) | 47 | 1,253 (1,028–1,529) | 2,094 (1,860–2,357) |
| T/C | 141 | 724 (668–784) | 247 (229–265) | 0.158 (0.142–0.175) | 113 (105–123) | 65 | 1,222 (994–1,503) | 2,024 (1,797–2,280) |
| C/C | 34 | 738 (613–889) | 254 (219–295) | 0.160 (0.135–0.190) | 118 (97–142) | 11 | 1,148 (796–1,657) | 1,710 (1,362–2,146) |
| P | 0.88 | 0.84 | 0.34 | 0.72 | 0.73 | 0.24 | ||
| THADA, rs7578597 | ||||||||
| C/C | 3 | 905 (484–1694) | 365 (317–421) | 0.125 (0.067–0.230) | 121 (80–182) | 0 | NA | NA |
| C/T | 72 | 739 (662–825) | 271 (247–296) | 0.180 (0.160–0.204) | 127 (113–142) | 25 | 1,783 (1,352–2,352) | 2,605 (2,236–3,035) |
| T/T | 261 | 732 (689–778) | 244 (232–257) | 0.147 (0.137–0.158) | 110 (103–118) | 98 | 1,120 (970–1,292) | 1,897 (1,744–2,064) |
| P | 0.77† | 0.019† | 0.0069† | 0.039† | 0.0016† | 0.00023† | ||
| ADAMTS9, rs4607103 | ||||||||
| T/T | 20 | 549 (467–646) | 206 (172–246) | 0.136 (0.106–0.175) | 83 (69–99) | 7 | 777 (597–1,011) | 1,632 (1,335–1,994) |
| T/C | 119 | 725 (668–787) | 256 (238–274) | 0.152 (0.137–0.169) | 111 (101–123) | 47 | 1,291 (1,028–1,621) | 1,990 (1,753–2,260) |
| C/C | 187 | 767 (714–824) | 252 (237–268) | 0.157 (0.145–0.171) | 121 (112–130) | 69 | 1,244 (1,032–1,498) | 2,094 (1,866–2,350) |
| P | 0.0059 | 0.26 | 0.32 | 0.0026 | 0.38 | 0.18 | ||
| NOTCH2/ADAM30, rs2641348 | ||||||||
| A/A | 253 | 736 (692–782) | 248 (234–262) | 0.152 (0.141–0.163) | 114 (107–121) | 94 | 1,226 (1,045–1,438) | 2,035 (1,858–2,228) |
| A/G | 73 | 746 (661–841) | 256 (230–285) | 0.154 (0.133–0.179) | 113 (97–131) | 27 | 1,228 (896–1,683) | 2,036 (1,671–2,482) |
| G/G | 10 | 654 (502–852) | 278 (242–319) | 0.189 (0.156–0.229) | 121 (96–152) | 2 | 1,323 (1,100–1,593) | 1,398 (1,251–1,563) |
| P | 0.76 | 0.33 | 0.37 | 0.89 | 0.93 | 0.59 | ||
| DCD, rs1153188 | ||||||||
| T/T | 24 | 811 (670–982) | 279 (243–321) | 0.169 (0.136–0.210) | 128 (103–160) | 5 | 1,448 (1,143–1,834) | 2,068 (1,467–2,915) |
| T/A | 120 | 726 (675–781) | 248 (231–267) | 0.154 (0.138–0.171) | 113 (103–124) | 40 | 1,018 (757–1,368) | 1,976 (1,723–2,268) |
| A/A | 192 | 732 (678–790) | 247 (232–263) | 0.152 (0.140–0.165) | 113 (104–123) | 78 | 1,336 (1,151–1,551) | 2,043 (1,845–2,262) |
| P | 0.55 | 0.29 | 0.49 | 0.48 | 0.27 | 0.83 | ||
| VEGFA, rs9472138 | ||||||||
| C/C | 176 | 722 (674–774) | 245 (231–260) | 0.156 (0.145–0.169) | 114 (106–123) | 68 | 1,207 (1,014–1,436) | 1,908 (1,715–2,121) |
| C/T | 131 | 765 (704–832) | 263 (243–284) | 0.153 (0.136–0.172) | 117 (106–130) | 48 | 1,278 (989–1,652) | 2,203 (1,942–2,498) |
| T/T | 28 | 695 (578–835) | 229 (197–268) | 0.141 (0.115–0.174) | 101 (83–123) | 7 | 1,096 (556–2,161) | 1,922 (1,267–2,917) |
| P | 0.77 | 0.80 | 0.44 | 0.55 | 0.97 | 0.35 | ||
| BCL11A, rs10490072 | ||||||||
| C/C | 32 | 810 (703–934) | 226 (199–256) | 0.169 (0.141–0.201) | 132 (111–158) | 13 | 812 (595–1,108) | 1,774 (1,553–2,028) |
| C/T | 126 | 799 (738–866) | 255 (237–274) | 0.145 (0.131–0.161) | 120 (110–132) | 49 | 1,266 (978–1,639) | 2,073 (1,814–2,369) |
| T/T | 178 | 685 (637–737) | 251 (236–268) | 0.157 (0.144–0.171) | 107 (99–116) | 61 | 1,311 (1,139–1,508) | 2,040 (1,810–2,300) |
| P | 0.0031 | 0.39 | 0.92 | 0.010 | 0.060 | 0.41 | ||
| HNF1B, rs757210 | ||||||||
| C/C | 118 | 746 (696–799) | 255 (237–274) | 0.149 (0.134–0.166) | 112 (103–122) | 51 | 1,218 (966–1,535) | 2,049 (1,792–2,342) |
| C/T | 145 | 737 (672–809) | 251 (233–270) | 0.154 (0.139–0.170) | 116 (105–128) | 49 | 1,265 (1,034–1,546) | 2,034 (1,828–2,263) |
| T/T | 71 | 704 (634–782) | 240 (218–263) | 0.161 (0.144–0.179) | 111 (99–125) | 23 | 1,174 (874–1,577) | 1,946 (1,586–2,387) |
| P | 0.38 | 0.33 | 0.35 | 0.99 | 0.93 | 0.70 | ||
| WFS1, rs10010131 | ||||||||
| A/A | 39 | 623 (527–737) | 258 (217–306) | 0.160 (0.128–0.200) | 99 (84–117) | 11 | 1,564 (1,155–2,120) | 2,311 (1,773–3,011) |
| A/G | 176 | 751 (701–804) | 257 (243–272) | 0.149 (0.138–0.162) | 114 (106–123) | 66 | 1,298 (1,086–1,551) | 2,066 (1,854–2,303) |
| G/G | 119 | 749 (686–818) | 238 (221–257) | 0.158 (0.143–0.175) | 119 (108–131) | 46 | 1,072 (848–1,356) | 1,900 (1,663–2,171) |
| P | 0.14 | 0.21 | 0.81 | 0.09 | 0.058 | 0.18 | ||
| MTNR1B, rs10830963 | ||||||||
| C/C | 187 | 757 (706–813) | 239 (226–253) | 0.163 (0.150–0.177) | 122 (112–131) | 57 | 1,044 (865–1,259) | 1,869 (1,675–2,085) |
| C/G | 113 | 758 (700–821) | 270 (248–294) | 0.139 (0.123–0.157) | 110 (101–120) | 49 | 1,440 (1,142–1,814) | 2,157 (1,868–2,490) |
| G/G | 35 | 561 (487–647) | 239 (207–276) | 0.158 (0.132–0.190) | 90 (77–106) | 17 | 1,360 (1,084–1,705) | 2,231 (1,973–2,523) |
| P | 0.010 | 0.27 | 0.22 | 0.0015 | 0.026 | 0.037 | ||
| Gene . | n . | First-phase insulin response (pmol/l) . | Second-phase insulin response (pmol/l) . | ISI (μmol · min−1 · kg−1 · pmol−1 · l−1) . | DI (μmol · min−1 · kg−1) . | n (GLP-1, Arg) . | GLP-1–stimulated insulin release (pmol/l)* . | Arginine-stimulated insulin release (pmol/l)* . |
|---|---|---|---|---|---|---|---|---|
| JAZF1, rs864745 | ||||||||
| C/C | 73 | 727 (652–812) | 262 (236–292) | 0.141 (0.122–0.162) | 107 (95–121) | 26 | 1,034 (799–1,337) | 1,728 (1,495–1,998) |
| C/T | 161 | 723 (672–778) | 239 (223–255) | 0.155 (0.142–0.170) | 111 (103–120) | 48 | 1,374 (1,122–1,683) | 1,992 (1,727–2,297) |
| T/T | 100 | 759 (686–841) | 263 (243–286) | 0.160 (0.145–0.177) | 124 (111–139) | 49 | 1,200 (951–1,514) | 2,233 (1,969–2,532) |
| P | 0.54 | 0.80 | 0.15 | 0.07 | 0.63 | 0.018 | ||
| CDC123/ CAMK1D, rs12779790 | ||||||||
| A/A | 212 | 755 (704–810) | 260 (245–275) | 0.155 (0.143–0.168) | 117 (109–127) | 74 | 1,318 (1,094–1,588) | 2,181 (1,979–2,403) |
| A/G | 110 | 713 (656–774) | 238 (220–258) | 0.153 (0.138–0.169) | 112 (101–123) | 48 | 1,106 (881–1,389) | 1,817 (1,588–2,078) |
| G/G | 12 | 617 (478–797) | 200 (176–228) | 0.146 (0.108–0.198) | 94 (71–125) | 1 | 1,142 (913–1,428) | 1,486 (1,322–1,671) |
| P | 0.10 | 0.0049 | 0.68 | 0.16 | 0.24 | 0.015 | ||
| TSPAN8/LGR5, rs7961581 | ||||||||
| T/T | 159 | 738 (687–793) | 253 (237–270) | 0.149 (0.135–0.164) | 113 (103–123) | 47 | 1,253 (1,028–1,529) | 2,094 (1,860–2,357) |
| T/C | 141 | 724 (668–784) | 247 (229–265) | 0.158 (0.142–0.175) | 113 (105–123) | 65 | 1,222 (994–1,503) | 2,024 (1,797–2,280) |
| C/C | 34 | 738 (613–889) | 254 (219–295) | 0.160 (0.135–0.190) | 118 (97–142) | 11 | 1,148 (796–1,657) | 1,710 (1,362–2,146) |
| P | 0.88 | 0.84 | 0.34 | 0.72 | 0.73 | 0.24 | ||
| THADA, rs7578597 | ||||||||
| C/C | 3 | 905 (484–1694) | 365 (317–421) | 0.125 (0.067–0.230) | 121 (80–182) | 0 | NA | NA |
| C/T | 72 | 739 (662–825) | 271 (247–296) | 0.180 (0.160–0.204) | 127 (113–142) | 25 | 1,783 (1,352–2,352) | 2,605 (2,236–3,035) |
| T/T | 261 | 732 (689–778) | 244 (232–257) | 0.147 (0.137–0.158) | 110 (103–118) | 98 | 1,120 (970–1,292) | 1,897 (1,744–2,064) |
| P | 0.77† | 0.019† | 0.0069† | 0.039† | 0.0016† | 0.00023† | ||
| ADAMTS9, rs4607103 | ||||||||
| T/T | 20 | 549 (467–646) | 206 (172–246) | 0.136 (0.106–0.175) | 83 (69–99) | 7 | 777 (597–1,011) | 1,632 (1,335–1,994) |
| T/C | 119 | 725 (668–787) | 256 (238–274) | 0.152 (0.137–0.169) | 111 (101–123) | 47 | 1,291 (1,028–1,621) | 1,990 (1,753–2,260) |
| C/C | 187 | 767 (714–824) | 252 (237–268) | 0.157 (0.145–0.171) | 121 (112–130) | 69 | 1,244 (1,032–1,498) | 2,094 (1,866–2,350) |
| P | 0.0059 | 0.26 | 0.32 | 0.0026 | 0.38 | 0.18 | ||
| NOTCH2/ADAM30, rs2641348 | ||||||||
| A/A | 253 | 736 (692–782) | 248 (234–262) | 0.152 (0.141–0.163) | 114 (107–121) | 94 | 1,226 (1,045–1,438) | 2,035 (1,858–2,228) |
| A/G | 73 | 746 (661–841) | 256 (230–285) | 0.154 (0.133–0.179) | 113 (97–131) | 27 | 1,228 (896–1,683) | 2,036 (1,671–2,482) |
| G/G | 10 | 654 (502–852) | 278 (242–319) | 0.189 (0.156–0.229) | 121 (96–152) | 2 | 1,323 (1,100–1,593) | 1,398 (1,251–1,563) |
| P | 0.76 | 0.33 | 0.37 | 0.89 | 0.93 | 0.59 | ||
| DCD, rs1153188 | ||||||||
| T/T | 24 | 811 (670–982) | 279 (243–321) | 0.169 (0.136–0.210) | 128 (103–160) | 5 | 1,448 (1,143–1,834) | 2,068 (1,467–2,915) |
| T/A | 120 | 726 (675–781) | 248 (231–267) | 0.154 (0.138–0.171) | 113 (103–124) | 40 | 1,018 (757–1,368) | 1,976 (1,723–2,268) |
| A/A | 192 | 732 (678–790) | 247 (232–263) | 0.152 (0.140–0.165) | 113 (104–123) | 78 | 1,336 (1,151–1,551) | 2,043 (1,845–2,262) |
| P | 0.55 | 0.29 | 0.49 | 0.48 | 0.27 | 0.83 | ||
| VEGFA, rs9472138 | ||||||||
| C/C | 176 | 722 (674–774) | 245 (231–260) | 0.156 (0.145–0.169) | 114 (106–123) | 68 | 1,207 (1,014–1,436) | 1,908 (1,715–2,121) |
| C/T | 131 | 765 (704–832) | 263 (243–284) | 0.153 (0.136–0.172) | 117 (106–130) | 48 | 1,278 (989–1,652) | 2,203 (1,942–2,498) |
| T/T | 28 | 695 (578–835) | 229 (197–268) | 0.141 (0.115–0.174) | 101 (83–123) | 7 | 1,096 (556–2,161) | 1,922 (1,267–2,917) |
| P | 0.77 | 0.80 | 0.44 | 0.55 | 0.97 | 0.35 | ||
| BCL11A, rs10490072 | ||||||||
| C/C | 32 | 810 (703–934) | 226 (199–256) | 0.169 (0.141–0.201) | 132 (111–158) | 13 | 812 (595–1,108) | 1,774 (1,553–2,028) |
| C/T | 126 | 799 (738–866) | 255 (237–274) | 0.145 (0.131–0.161) | 120 (110–132) | 49 | 1,266 (978–1,639) | 2,073 (1,814–2,369) |
| T/T | 178 | 685 (637–737) | 251 (236–268) | 0.157 (0.144–0.171) | 107 (99–116) | 61 | 1,311 (1,139–1,508) | 2,040 (1,810–2,300) |
| P | 0.0031 | 0.39 | 0.92 | 0.010 | 0.060 | 0.41 | ||
| HNF1B, rs757210 | ||||||||
| C/C | 118 | 746 (696–799) | 255 (237–274) | 0.149 (0.134–0.166) | 112 (103–122) | 51 | 1,218 (966–1,535) | 2,049 (1,792–2,342) |
| C/T | 145 | 737 (672–809) | 251 (233–270) | 0.154 (0.139–0.170) | 116 (105–128) | 49 | 1,265 (1,034–1,546) | 2,034 (1,828–2,263) |
| T/T | 71 | 704 (634–782) | 240 (218–263) | 0.161 (0.144–0.179) | 111 (99–125) | 23 | 1,174 (874–1,577) | 1,946 (1,586–2,387) |
| P | 0.38 | 0.33 | 0.35 | 0.99 | 0.93 | 0.70 | ||
| WFS1, rs10010131 | ||||||||
| A/A | 39 | 623 (527–737) | 258 (217–306) | 0.160 (0.128–0.200) | 99 (84–117) | 11 | 1,564 (1,155–2,120) | 2,311 (1,773–3,011) |
| A/G | 176 | 751 (701–804) | 257 (243–272) | 0.149 (0.138–0.162) | 114 (106–123) | 66 | 1,298 (1,086–1,551) | 2,066 (1,854–2,303) |
| G/G | 119 | 749 (686–818) | 238 (221–257) | 0.158 (0.143–0.175) | 119 (108–131) | 46 | 1,072 (848–1,356) | 1,900 (1,663–2,171) |
| P | 0.14 | 0.21 | 0.81 | 0.09 | 0.058 | 0.18 | ||
| MTNR1B, rs10830963 | ||||||||
| C/C | 187 | 757 (706–813) | 239 (226–253) | 0.163 (0.150–0.177) | 122 (112–131) | 57 | 1,044 (865–1,259) | 1,869 (1,675–2,085) |
| C/G | 113 | 758 (700–821) | 270 (248–294) | 0.139 (0.123–0.157) | 110 (101–120) | 49 | 1,440 (1,142–1,814) | 2,157 (1,868–2,490) |
| G/G | 35 | 561 (487–647) | 239 (207–276) | 0.158 (0.132–0.190) | 90 (77–106) | 17 | 1,360 (1,084–1,705) | 2,231 (1,973–2,523) |
| P | 0.010 | 0.27 | 0.22 | 0.0015 | 0.026 | 0.037 | ||
Data are estimated means (95% CI) unless otherwise indicated. Alleles identified as risk alleles for type 2 diabetes are indicated in bold. All variables were log transformed before analysis. P values were computed for additive models using linear generalized estimating equations, which takes into account the family relatedness when computing the standard errors. First- and second-phase GSIS and GLP-1– and arginine-stimulated insulin secretion were adjusted for study center, family relatedness, glucose tolerance status, age, sex, BMI, and ISI. ISI and DI were adjusted for study center, family relatedness, glucose tolerance status, age, sex, and BMI.
*Available for 123 subjects from the NTR twin sample.
†P values are for the recessive model.