Introduction
Methods
Number (women/men) | 84 (32/52) |
Age (years) | 57.1 ± 10.3 |
BMI (kg/m2) | 25.9 ± 3.6 |
HbA1c (%) | 5.6 ± 0.4 |
HbA1c (mmol/mol) | 48.1 ± 5 |
SNP ID | Candidate gene | Risk allele | Chr. | SNP position (build 37.1) | SNP location | Reference |
---|---|---|---|---|---|---|
CpG-SNPs where risk alleles remove a CpG site (n = 8) | ||||||
rs5945326 |
DUSP9
a
| A | X | 152899922 | Intergenic | Voight et al (2010) [20] |
rs564398 |
CDKN2A
a
| A | 9 | 22029547 | Intergenic | Zeggini et al (2007) [21] |
rs11708067 |
ADCY5
a
| A | 3 | 123065778 | Intron | Dupuis et al (2010) [22] |
rs1801214 |
WFS1
a
| T | 4 | 6303022 | Cds-synon | Voight et al (2010) [20] |
rs2334499 |
DUSP8
a
| A | 11 | 1696849 | Intergenic | Kong et al (2009) [23] |
rs7578326 |
IRS1
a
| A | 2 | 227020653 | Intergenic | Voight et al (2010) [20] |
rs5219 |
KCNJ11
b
| T | 11 | 17409572 | Cds-nonsynon | Scott et al (2007) [24] |
rs1801282 |
PPARG
a
| C | 3 | 12393125 | Cds-nonsynon | Scott et al (2007) [24] |
CpG-SNPs where risk alleles introduce a CpG site (n = 11) | ||||||
rs13292136 |
CHCHD9
a
| C | 9 | 81952128 | Intergenic | Voight et al (2010) [20] |
rs7901695 |
TCF7L2
a
| G | 10 | 114754088 | Intron | Zeggini et al (2007) [21] |
rs7754840 |
CDKAL1
a
| C | 6 | 20661250 | Intron | Scott et al (2007) [24] |
rs391300 |
SRR
a
| G | 17 | 2216258 | Intron | Tsai et al (2010) [25] |
rs5015480 |
HHEX
a
| G | 10 | 94465559 | Intergenic | Voight et al (2010) [20] |
rs13266634 |
SLC30A8
a
| G | 8 | 118184783 | Cds-nonsynon | Sladek et al (2007) [26] |
rs4457053 |
ZBED3
c
| G | 5 | 76424949 | Intergenic | Voight et al (2010) [20] |
rs7961581 |
TSPAN8
a
| C | 12 | 71663102 | Intergenic | Zeggini et al (2008) [27] |
rs1531343 |
HMGA2
a
| C | 12 | 66174894 | Intergenic | Voight et al (2010) [20] |
rs2237895 |
KCNQ1
a
| C | 11 | 2857194 | Intron | Yasuda et al (2008) [28] |
rs12779790 |
CDC123
c
| G | 10 | 12328010 | Intergenic | Zeggini et al (2008) [27] |
Non-CpG SNPs (n = 21) | ||||||
rs243021 |
BCL11A
| A | 2 | 60584819 | Intergenic | Voight et al (2010) [20] |
rs10830963 |
MTNR1B
| G | 11 | 92708710 | Intron | Dupuis et al (2010) [22] |
rs7578597 |
THADA
| T | 2 | 43732823 | Missense | Zeggini et al (2008) [27] |
rs17584499 |
PTPRD
| T | 9 | 8879118 | Intron | Tsai et al (2010) [25] |
rs10923931 |
NOTCH2
| T | 1 | 120517959 | Intron | Zeggini et al (2008) [27] |
rs7593730 |
RBMS1
| C | 2 | 161171454 | Intron | Qi et al (2010) [29] |
rs4607103 |
ADAMTS9
| C | 3 | 64711904 | Intergenic | Zeggini et al (2008) [27] |
rs1470579 |
IGF2BP2
| C | 3 | 185529080 | Intron | Voight et al (2010) [20] |
rs864745 |
JAZF1
| T | 7 | 28180556 | Intron | Zeggini et al (2008) [27] |
rs972283 |
KLF14
| G | 7 | 130466854 | Intergenic | Voight et al (2010) [20] |
rs896854 |
TP53INP1
| T | 8 | 95960511 | Intron | Voight et al (2010) [20] |
rs1552224 |
CENTD2
| A | 11 | 72433098 | Intron | Voight et al (2010) [20] |
rs7957197 |
HNF1A
| T | 12 | 121460686 | Intron | Voight et al (2010) [20] |
rs11634397 |
ZFAND6
| G | 15 | 80432222 | Intergenic | Voight et al (2010) [20] |
rs8042680 |
PRC1
| A | 15 | 91521337 | Intron | Voight et al (2010) [20] |
rs9939609 |
FTO
| A | 16 | 53820527 | Intron | Frayling et al (2007) [30] |
rs4607517 |
GCK
| A | 7 | 44235668 | Intergenic | Dupuis et al (2010) [22] |
rs2191349 |
DGKB
| T | 7 | 15064309 | Intergenic | Dupuis et al (2010) [22] |
rs780094 |
GCKR
| C | 2 | 27741237 | Intron | Dupuis et al (2010) [22] |
rs340874 |
PROX1
| C | 1 | 214159256 | Intergenic | Dupuis et al (2010) [22] |
rs4430796 |
HNF1B
| G | 17 | 36098040 | Intron | Voight et al (2010) [20] |
Results
Chr. | SNP ID | Gene | SNP location | Genotype |
n
| Gene expression | ||
---|---|---|---|---|---|---|---|---|
Mean ± SD | β (SEM) |
p value | ||||||
17 | rs391300 |
RPA1
| ∼413.4 kb down | A A | 12 | 574.3 ± 54.3 | −0.056 (0.027) | 0.040 |
A G | 47 | 562.1 ± 57.4 | ||||||
G G | 22 | 537.1 ± 60.5 | ||||||
X | rs5945326 |
AVPR2
| ∼268.1 kb up | A A | 50 | 66.8 ± 9.0 | −0.052 (0.024) | 0.034 |
A G | 9 | 64.1 ± 5.1 | ||||||
G G | 22 | 62.3 ± 8.7 |
SNP ID | Gene | Affymetrix transcript cluster ID | Affymetrix probe set ID | Exon annotation for probe set | AA vs Aa | AA vs aa | Aa vs aa | |||
---|---|---|---|---|---|---|---|---|---|---|
Splice index |
p value | Splice index |
p value | Splice index |
p value | |||||
rs13266634 |
SLC30A8
| 8148003 | 8148008 | Exon 3 | 0.066 | 0.39 | 0.34 | 0.031 | 0.28 | 0.085 |
8148003 | 8148011 | Exon 7 | −0.005 | 0.88 | −0.14 | 0.030 | −0.13 | 0.039 | ||
8148003 | 8148015 | Exon 11 | −0.056 | 0.21 | −0.26 | 0.0048 | −0.21 | 0.028 | ||
rs1801214 |
WFS1
| 8093906 | 8093909 | Exon 2 | −0.029 | 0.70 | 0.20 | 0.040 | 0.23 | 0.011 |
rs7754840 |
CDKAL1
| 8117140 | 8117152 | Exon 10 | −0.039 | 0.40 | −0.15 | 0.035 | −0.12 | 0.10 |
rs7901695 |
TCF7L2
| 7930537 | 7930538 | Exon 1 | −0.38 | 0.045 | −0.34 | 0.56 | 0.033 | 0.96 |
Phenotype | SNP ID | Candidate gene | Genotype |
n
| Mean ± SD | β (SEM) |
p value |
---|---|---|---|---|---|---|---|
Insulin secretion (SI) | rs11708067 |
ADCY5
| AA | 48 | 7.1 ± 7.8 | 0.18 (0.08) | 0.031 |
AG | 28 | 13.2 ± 20.1 | |||||
GG | 2 | 16.2 ± 17.7 | |||||
rs5015480 |
HHEX
| GG | 21 | 5.4 ± 5.9 | 0.14 (0.08) | 0.036 | |
AG | 44 | 9.5 ± 10.1 | |||||
AA | 13 | 16.1 ± 27.1 | |||||
Glucagon (pg islet−1 h−1, 8.3 mmol/l glucose)a
| rs11708067 |
ADCY5
| AA | 3 | 7.0 ± 2.6 | −0.64 (0.15) | 0.027 |
AG | 5 | 3.2 ± 2.7 | |||||
Glucagon (pg islet−1 h−1, 16.7 mmol/l glucose) | rs2237895 |
KCNQ1
| AA | 17 | 8.6 ± 10.6 | 0.26 (0.12) | 0.042 |
AC | 19 | 23.6 ± 26.1 | |||||
CC | 8 | 35.2 ± 42.2 | |||||
Insulin content (ng/ng DNA) | rs564398 |
CDKN2A
| AA | 24 | 4.5 ± 2.5 | 0.10 (0.04) | 0.023 |
AG | 36 | 6.9 ± 3.9 | |||||
GG | 11 | 6.5 ± 4.1 |
Candidate SNP | Candidate gene | LD SNPs (n) | LD CpG-SNPs (n) |
---|---|---|---|
rs11708067 |
ADCY5
| 14 | 2 |
rs12779790 |
CDC123
| 2 | 1 |
rs13266634 |
SLC30A8
| 5 | 3 |
rs13292136 |
CHCHD9
| 22 | 3 |
rs1531343 |
HMGA2
| 26 | 5 |
rs1801214 |
WFS1
| 94 | 41 |
rs1801282 |
PPARG
| 21 | 7 |
rs2237895 |
KCNQ1
| 0 | 0 |
rs2334499 |
DUSP8
| 4 | 0 |
rs391300 |
SRR
| 2 | 0 |
rs4457053 |
ZBED3
| 4 | 0 |
rs5015480 |
HHEX
| 11 | 7 |
rs5219 |
KCNJ11
| 15 | 5 |
rs564398 |
CDKN2A
| 22 | 6 |
rs5945326 |
DUSP9
| 1 | 0 |
rs7578326 |
IRS1
| 9 | 1 |
rs7754840 |
CDKAL1
| 30 | 7 |
rs7901695 |
TCF7L2
| 7 | 2 |
rs7961581 |
TSPAN8
| 6 | 1 |
∑295 | ∑91 |