Background
Methods
Subjects and clinical tests
SNP selection and genotyping
SNP ID | Gene or nearby region | Location | Position | Traits | OR [95% CI] | References |
---|---|---|---|---|---|---|
rs3751812 |
FTO
| 16q12.2 | Intron 1 | Obesity | 1.42 [1.33–1.52] | Frayling et al., 2007 [60] |
rs8050136 |
FTO
| 16q12.2 | Intron 1 | T2DM; obesity | 1.22 [1.07–1.40] 1.45 [1.09–1.93] | Liu et al., 2010 [26] |
rs9939609 |
FTO
| 16q12.2 | Intron 1 | T2DM; obesity | 1.19 [1.04–1.37]; 1.39 [1.04–1.85] | Liu et al., 2010 [26] |
rs10811661 |
CDKN2A/B
| 9p21.3 | Intergenic | T2DM | 1.20 [1.14–1.25] | Zeggini et al., 2007 [27] |
rs2383208 |
CDKN2A/B
| 9p21.3 | Intergenic | T2DM | 1.34 [1.27–1.41] | Takeuchi et al., 2009 [28] |
rs1111875 |
HHEX
| 10q23.33 | 3′-UTR | T2DM | 1.21 [1.15–1.28] | Takeuchi et al., 2009 [28] |
rs5015480 |
HHEX
| 10q23.33 | Intergenic | T2DM | 1.17 [1.11–1.24] | Zegginietal., 2008 |
rs13266634 |
SLC30A8
| 8q24.11 | Exon 8, missense | T2DM | 1.16 [1.10–1.22] | |
rs4506565 |
TCF7L2
| 10q25.3 | Intron 3 | T2DM | 1.36 [1.20–1.54] | Wellcome Trust Case Control Consortium (2007) [30] |
rs7903146 |
TCF7L2
| 10q25.3 | Intron 4 | T2DM | 1.49 [1.39–1.59] | Timpson et al., 2009 [31] |
rs4402960 |
IGF2BP2
| 3q27.2 | Intron 2 | T2DM | 1.14 [1.08–1.21] | Takeuchi et al., 2009 [28] |
rs5215 |
KCNJ11
| 11p15.1 | Exon 1 | T2DM | 1.16 [1.09–1.23] | Zeggini et al., 2008 [12] |
rs7756992 |
CDKAL1
| 6p22.3 | Intron 5 | T2DM | 1.20 [1.13–1.27] | Steinthorsdottir et al., 2007 [32] |
rs4712523 |
CDKAL1
| 6p22.3 | Intron 5 | T2DM | 1.27 [1.21–1.33] | Takeuchi et al., 2009 [28] |
rs9465871 |
CDKAL1
| 6p22.3 | Intron 5 | T2DM | 1.18 [1.04–1.34] | Wellcome Trust Case Control Consortium (2007) [30] |
rs7961581 | nearTSPAN8/LGR5
| 12q21.1 | Intergenic | T2DM | 1.09 [1.06–1.12] | Zeggini et al., 2008 [12] |
rs864745 |
JAZF1
| 7p15.2-p15.1 | Intron 1 | T2DM | 1.10 [1.07–1.13] | Zeggini et al., 2008 [12] |
rs12779790 | nearCDC123/CAMK1D
| 10p13 | Intergenic | T2DM | 1.11 [1.07–1.14] | Zeggini et al., 2008 [12] |
rs10490072 |
BCL11A
| 2p16.1 | 3′ ofgene | T2DM | 1.05 [1.03–1.08] | Zeggini et al., 2008 [12] |
rs10923931 |
NOTCH2
| 1p13-p11 | Intron 5 | T2DM | 1.13 [1.08–1.17] | Zeggini et al., 2008 [12] |
rs7578597 |
THADA
| 2p21 | Exon 24, missense | T2DM | 1.15 [1.10–1.20] | Zeggini et al., 2008 [12] |
rs2025804 |
LEPR
| 1p31 | Intron 2 | BMI | Traurig et al., 2012 [33] | |
rs2641348 |
ADAM30
| 1p12 | Exon 1, missense | T2DM | 1.10 [1.06–1.15] | Zeggini et al., 2008 [12] |
rs9472138 | near VEGFA
| 6p21.1 | Intergenic | T2DM | 1.06 [1.04–1.09] | Zeggini et al., 2008 [12] |
rs1042714 |
ADRB2
| 5q31-q32 | Exon 1, missense | T2DM | 0.56 [0.36–0.91] | Pinelli et al., 2006 [34] |
rs4994 |
ADRB3
| 8p12 | Exon 1, missense | T2DM | 1.27 [1.07–1.51] | Jing et al., 2012 [35] |
rs1799883 |
FABP2
| 4q28-q31 | Exon 2, missense | T2DM | 1.29 [1.08–1.49] | Qiu et al., 2014 [8] |
rs1801282 |
PPARG
| 3p25 | Exon 4, missense | T2DM | 1.14 [1.08–1.20] | Scott et al., 2007 [11] |
rs8192678 |
PPARGC1A
| 4p15.1 | Exon 8, missense | T2DM | 1.07 [1.00–1.15] | Barroso et al., 2006 [37] |
rs780094 |
GCKR
| 2p23 | Intron 16 | T2DM | 0.71 [0.58–0.85] | Onuma et al., 2010 [38] |
rs7944584 |
MADD
| 11p11.2 | Intron 25 | T2DM | 1.63 [1.32–2.02] | Hu et al., 2010 [39] |
rs1153188 |
DCD-VDAC1P5
| 12q13 | Intergenic | T2DM | 1.08 [1.05–1.11] | Zeggini et al., 2008 [12] |
Statistical analysis
Results
General T2DM and control cohorts
Control subjects | Type 2 diabetic patients |
P-value | |
---|---|---|---|
N | 928 | 408 | |
Male,% (n) | 27.7% (257) | 44.6% (182) | <10−5
|
Age, years | 32 (18–61) | 59 (29–84) | <10−5
|
Weight, kg | 63 (40–147) | 80 (46–135) | <10−5
|
Height, cm | 165 (140–197) | 165 (148–188) | 0.154 |
BMI, kg/m2
| 23.0 (15.1–54.0) | 29.3 (18.2–47.6) | <10−5
|
Systolic blood pressure, mm Hg | 110 (60–150) | 130 (100–220) | <10−5
|
Diastolic blood pressure, mm Hg | 70 (50–100) | 80 (60–130) | <10−5
|
Waist circumference, cm | 80 (48–180) | 94 (60–160) | <10−5
|
Hip circumference, cm | - | 100 (62–165) | - |
Waist/hip ratio | - | 0.95 (0.54–1.83) | - |
Glucose, mmol/L | 4.9 (3.2–7.8) | 9.6 (3.6–30.5) | <10−5
|
Cholesterol, mmol/L | 4.2 (2.0–11.8) | 5.2 (2.1–16.7) | <10−5
|
Triglycerides, mmol/L | 1.0 (0.2–6.5) | 1.8 (0.2–17.6) | <10−5
|
Low-density lipoproteins, mmol/L | 3.88 (1.05–15.5) | 4.775 (0.23–8.67) | <10−5
|
High-density lipoproteins, mmol/L | 1.32 (0.59–2.8) | 1.27 (0.6–3.6) | 0.001 |
HbA1c, % | 5.4 (4.0–7.3) | 7.6 (4.4–16.4) | <10−5
|
Insulin, μIU/mL | - | 12.10 (0.02–97.0) | - |
C-peptide, ng/mL | - | 4.20 (0.08–36.30) | - |
Age-matched T2DM and control cohorts
Control subjects | Type 2 diabetic subjects |
P-value | |
---|---|---|---|
N | 141 | 223 | |
Male,% (n) | 41,1% (58) | 46,6% (104) | 0.39 |
Age, years | 52 (43–61) | 53 (40–63) | 0.11 |
Weight, kg | 72 (47–125) | 82 (46–135) | <10−5
|
Height, cm | 165 (140–192) | 166 (148–188) | 0.31 |
BMI, kg/m2
| 26.56 (17.2–43.1) | 29.74 (18.4–47.2) | <10−5
|
Systolic blood pressure, mm Hg | 120 (90–140) | 130.0 (100–220) | <10−5
|
Diastolic blood pressure, mm Hg | 80 (60–90) | 80 (60–130) | <10−5
|
Waist circumference, cm | 89 (60–180) | 94 (60–160) | 0.01 |
Hip circumference, cm | - | 100 (63–165) | - |
Waist/hip ratio | - | 0.95 (0.54–1.83) | - |
Glucose, mmol/L | 5.15 (3.8–6.5) | 9.2 (4.1–30.5) | <10−5
|
Cholesterol, mmol/L | 4.9 (2.4–11.8) | 5.2 (2.8–16.7) | 0.12 |
Triglycerides, mmol/L | 1.2 (0.4–3.8) | 1.9 (0.2–17.6) | <10−5
|
Low-density lipoproteins, mmol/L | 4.57 (1.78–15.50) | 4.71 (1.56–8.67) | 0.47 |
High-density lipoproteins, mmol/L | 1.32 (0.7–2.8) | 1.23 (0.62–3.6) | 0.009 |
HbA1c, % | 5.9 (4.5–6.7) | 7.65 (4.4–16.4) | <10−5
|
Insulin, μIU/mL | - | 12.70 (0.02–97.0) | - |
C-peptide, ng/mL | - | 4.20 (0.14–12.0) | - |
Genetic analysis ofT2DM markersin the age-matched and general T2DM and control cohorts
SNP | Gene | Major/ Minor allele | Minor allele frequency | Odds ratio (95% CI) |
P-value | |
---|---|---|---|---|---|---|
Control (n = 141) | T2DM (n = 223) | |||||
rs3751812 |
FTO
| G/T | 0.24 | 0.29 | 1.41 (0.97–2.07) | 0.07 |
rs8050136 |
FTO
| C/A | 0.25 | 0.3 | 1.37 (0.94–2.01) | 0.09 |
rs9939609 |
FTO
| T/A | 0.23 | 0.29 | 1.52 (1.03–2.26) |
0.04
|
rs10811661 |
CDKN2A/B
| T/C | 0.23 | 0.24 | 1.03 (0.71–1.50) | 0.86 |
rs2383208 |
CDKN2A/B
| A/G | 0.22 | 0.22 | 0.99 (0.67–1.48) | 0.96 |
rs1111875 |
HHEX
| T/C | 0.38 | 0.42 | 1.19 (0.87–1.64) | 0.26 |
rs13266634 |
SLC30A8
| C/T | 0.4 | 0.32 | 0.68 (0.49–0.93) |
0.02
|
rs4506565 |
TCF7L2
| A/T | 0.16 | 0.19 | 1.22 (0.82–1.84) | 0.34 |
rs5215 |
KCNJ11
| T/C | 0.33 | 0.36 | 1.15 (0.83–1.59) | 0.4 |
rs7756992 |
CDKAL1
| A/G | 0.31 | 0.33 | 1.11 (0.79–1.56) | 0.55 |
rs4712523 |
CDKAL1
| A/G | 0.3 | 0.34 | 1.18 (0.85–1.65) | 0.31 |
rs9465871 |
CDKAL1
| T/C | 0.29 | 0.31 | 1.07 (0.76–1.51) | 0.67 |
rs7961581 |
near TSPAN8/LGR5
| T/C | 0.21 | 0.29 | 1.54 (1.05–2.27) |
0.03
|
rs864745 |
JAZF1
| T/C | 0.38 | 0.39 | 1.04 (0.77–1.43) | 0.76 |
rs12779790 |
near CDC123/CAMK1D
| A/G | 0.18 | 0.16 | 0.89 (0.55–1.44) | 0.64 |
rs10490072 |
BCL11A
| T/C | 0.12 | 0.12 | 0.96 (0.57–1.61) | 0.88 |
rs10923931 |
NOTCH2
| G/T | 0.05 | 0.07 | 1.56 (0.77–3.34) | 0.22 |
rs7578597 |
THADA
| T/C | 0.06 | 0.05 | 0.91 (0.46–1.80) | 0.78 |
rs2025804 |
LEPR
| A/G | 0.67 | 0.6 | 0.76 (0.55–1.06) | 0.12 |
rs2641348 |
ADAM30
| A/G | 0.04 | 0.07 | 1.85 (0.90–4.14) | 0.11 |
rs9472138 |
near VEGFA
| C/T | 0.19 | 0.2 | 1.05 (0.71–1.58) | 0.79 |
rs1042714 |
ADRB2
| C/G | 0.31 | 0.3 | 0.97 (0.68–1.37) | 0.87 |
rs4994 |
ADRB3
| A/G | 0.16 | 0.19 | 1.16 (0.76–1.78) | 0.48 |
rs1799883 |
FABP2
| C/T | 0.3 | 0.39 | 1.51 (1.06–2.13) |
0.02
|
rs1801282 |
PPARG
| C/G | 0.11 | 0.13 | 1.23 (0.78–2.00) | 0.37 |
rs8192678 |
PPARGC1A
| C/T | 0.36 | 0.32 | 0.82 (0.59–1.15) | 0.26 |
rs780094 |
GCKR
| C/T | 0.4 | 0.38 | 0.9 (0.58–1.39) | 0.63 |
rs7944584 |
MADD
| A/T | 0.11 | 0.15 | 1.46 (0.77–2.98) | 0.26 |
Genetic analysis of BMI, obesity, and other metabolic parameters in the general unmatched control cohort
Comparison of allele frequencies in Kazakh population with population data from the HapMap database
Exact test of population differentiation (P value) | |||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|
SNP | ASW | CEU | CHB | CHD | GIH | JPT | LWK | MEX | MKK | TSI | YRI |
rs3751812 | 0.26/0.11 (0.003) | 0.26/0.46 (<10−5) | 0.26/0.15 (0.01) | 0.26/0.15 (0.009) | 0.26/0.26 (1.000) | 0.26/0.18 (0.1) | 0.26/0.02 (<10−5) | 0.26/0.17 (0.06) | 0.26/0.13 (<10−5) | 0.26/0.46 (<10−5) | 0.26/0.07 (<10−5) |
rs8050136 | 0.26/0.45 (<10−4) | 0.26/0.46 (<10−5) | 0.26/0.14 (0.002) | .26/0.16 (0.02) | 0.26/0.26 (1.000) | 0.26/0.18 (0.08) | 0.26/0.49 (<10−5) | 0.26/0.20 (0.09) | 0.26/0.48 (<10−5) | 0.26/0.46 (<10−5) | 0.26/0.46 (<10−5) |
rs9939609 | 0.25/0.49 (<10−5) | 0.25/0.46 (<10−5) | 0.25/0.15 (0.01) | .25/0.16 (0.03) | 0.25/0.27 (0.8) | 0.25/0.19 (0.2) | 0.25/0.38 (<10−5) | NA | .25/0.47 (<10−5) | 0.25/0.47 (<10−5) | 0.25/0.49 (<10−5) |
rs10811661 | 0.28/0.09 (<10−4) | 0.28/0.20 (0.02) | 0.28/0.42 (0.001) | 0.28/0.44 (<10−3) | 0.28/0.09 (<10−5) | 0.28/0.48 (<10−5) | 0.28/0.06 (<10−5) | 0.28/0.11 (<10−3) | 0.28/0.10 (<10−5) | 0.28/0.19 (0.01) | 0.28/0.02 (<10−5) |
rs2383208 | 0.28/0.24 (0.5) | 0.28/0.21 (0.09) | .28/0.40 (0.004) | 0.28/0.41 (0.001) | 0.28/0.09 (<10−5) | 0.28/0.45 (<10−4) | 0.28/0.21 (0.2) | 0.28/0.14 (0.01) | .28/0.32 (0.2) | 0.28/0.19 (0.02) | 0.28/0.12 (<10−5) |
rs1111875 | 0.41/0.23 (<10−5) | 0.41/0.42 (<10−5) | 0.41/0.32 (0.04) | 0.41/0.31 (0.06) | 0.41/0.41 (0.9) | 0.41/0.35 (0.09) | 0.41/0.19 (<10−5) | 0.41/0.26 (<10−5) | 0.41/0.24 (<10−5) | 0.41/0.40 (<10−5) | 0.41/0.13 (<10−5) |
rs13266634 | 0.37/0.19 (<10−3) | 0.37/0.24 (<10−3) | 0 .37/0.47 (0.04) | 0.37/0.44 (0.2) | 0.37/0.23 (0.001) | .37/0.44 (0.2) | 0.37/0.06 (<10−5) | 0.37/0.19 (0.002) | 0.37/0.05(<10−5) | 0.37/0.25 (0.006) | 0.37/0.07(<10−5) |
rs4506565 | 0.15/0.49 (<10−5) | 0.15/0.30 (<10−5) | 0.15/0.07 (0.01) | 0.15/0.04 (<10−3) | 0.15/0.30 (<10−5) | 0.15/0.03 (<10−4) | .15/0.49 (<10−5) | 0.15/0.28 (0.005) | 0.15/0.40 (<10−5) | 0.15/0.39 (<10−5) | 0.15/0.44 (<10−5) |
rs5215 | 0 .34/0.19 (<10−5) | .34/0.40 (0.09) | 0.34/0.35 (0.7) | 0.34/0.35 (0.8) | 0.34/0.40 (0.2) | 0.34/0.34 (1.0) | 0.34/0.03 (<10−5) | 0.34/0.42 (0.3) | 0.34/0.06 (<10−5) | 0.34/0.29 (0.4) | 0.34/0.01 (<10−5) |
rs7756992 | 0.33/0.46 (<10−5) | 0.33/0.28 (0.2) | 0.33/0.48 (<10−3) | 0.33/0.49 (<10−5) | 0.33/0.24 (0.07) | 0.33/0.46 (0.001) | 0.33/0.42 (<10−5) | 0.33/0.34 (0.9) | 0.33/0.41 (<10−5) | 0.33/0.24 (0.02) | 0.33/0.39 (<10−5) |
rs4712523 | 0.32/0.40 (<10−5) | 0.32/0.24 (0.8) | 0.32/0.42 (0.02) | 0.32/0.41 (0.02) | 0.32/0.23 (0.04) | 0.32/0.41 (0.04) | 0.32/0.34 (<10−5) | 0.32/0.31 (0.6) | 0.32/0.46 (<10−5) | 0.32/0.28 (0.1) | 0.32/0.31 (<10−5) |
rs9465871 | 0.30/0.46 (<10−5) | 0.30/0.16 (<10−5) | 0.30/0.50 (<10−5) | 0.30/0.48 (<10−5) | 0.30/0.22 (0.05) | 0.30/0.44 (<10−5) | 0.30/0.45 (<10−3) | 0.30/0.32 (0.8) | 0.30/0.46 (<10−5) | 0.30/0.16 (<10−4) | 0.30/0.39 (<10−5) |
rs7961581 | 0.25/0.17 (0.2) | 0.25/0.25 (0.4) | 0.25/0.20 (0.06) | 0.25/0.19 (0.05) | 0.25/0.36 (0.003) | 0.25/0.23 (0.9) | 0.25/0.20 (0.3) | 0.25/0.15 (0.06) | 0.25/0.20 (0.3) | 0.25/0.40 (<10−3) | 0.25/0.17 (0.02) |
rs864745 | 0.38/0.23 (0.01) | 0.38/0.49 (0.001) | 0.38/0.24 (0.002) | 0.38/0.22 (<10−3) | 0.38/0.22 (<10−3) | 0.38/0.21 (<10−5) | 0.38/0.20 (<10−5) | 0.38/0.38 (0.6) | 0.38/0.26 (<10−3) | 0.38/0.49 (0.006) | 0.38/0.23 (<10−4) |
rs12779790 | NA | 0.17/0.23 (0.04) | 0.17/0.13 (0.8) | NA | NA | 0.17/0.12 (0.3) | NA | NA | NA | NA | 0.17/0.05 (0.001) |
rs10490072 | 0.13/0.15 (0.6) | 0.13/0.27 (<10−5) | 0.13/0.02 (<10−4) | NA | 0.13/0.15 (0.3) | 0.13/0.01(<10−5) | 0.13/0.04(0.001) | 0.13/0.20(0.05) | 0.13/0.02(<10−5) | 0.13/0.21(0.009) | 0.13/0.04 (0.001) |
rs10923931 | 0.06/0.35 (<10−5) | 0.06/0.09 (0.07) | 0.06/0.02 (0.3) | 0.06/0.02 (0.2) | 0.06/0.21 (<10−5) | 0.06/0.02 (0.2) | 0.06/0.46 (<10−5) | 0.06/0.09 (0.2) | 0.06/0.36 (<10−5) | 0.06/0.07 (0.2) | 0.06/0.38 (<10−5) |
rs7578597 | 0.06/0.27 (<10−5) | 0.06/0.12 (<10−3) | 0.06/0.14 (<10−5) | 0.06/0.01 (0.008) | 0.06/0.17 (<10−5) | 0.06/0.01 (0.008) | 0.06/0.36 (<10−5) | 0.06/0.02 (0.3) | 0.06/0.19 (<10−5) | 0.06/0.06 (0.6) | 0.06/0.33 (<10−5) |
rs2025804 | 0.36/0.17 (<10−5) | 0.36/0.38 (<10−5) | 0.36/0.16 (<10−5) | 0.36/0.11 (<10−5) | 0.36/0.21 (<10−5) | 0.36/0.15 (<10−5) | 0.36/0.22 (<10−5) | 0.36/0.35 (<10−5) | 0.36/0.15 (<10−5) | 0.36/0.27 (<10−5) | 0.36/0.23 (<10−5) |
rs2641348 | 0.05/0.35 (<10−5) | 0.05/0.10 (0.01) | 0.05/0.02 (0.09) | 0.05/0.02 (0.08) | 0.05/0.22 (<10−5) | 0.05/0.02 (0.09) | 0.05/0.46 (<10−5) | 0.05/0.10 (0.06) | 0.05/0.36 (<10−5) | 0.05/0.08 (0.07) | 0.05/0.38 (<10−5) |
rs9472138 | 0.19/0.13 (0.2) | 0.19/0.23 (0.2) | 0.19/0.13 (0.07) | NA | 0.19/0.22 (0.4) | 0.19/0.09 (0.001) | 0.19/0.23 (0.3) | 0.19/0.20 (0.4) | NA | 0.19/0.31 (<10−4) | 0.19/0.15 (0.1) |
rs1042714 | NA | 0.28/0.47 (<10−5) | 0.28/0.12 (0.002) | NA | NA | 0.28/0.08 (<10−3) | NA | NA | NA | NA | 0.28/0.18 (0.03) |
rs4994 | 0.17/0.08 (0.04) | 0.17/0.09 (0.003) | 0.17/0.11 (0.2) | 0.17/0.14 (0.2) | 0.17/0.11 (0.1) | 0.17/0.19 (0.06) | 0.17/ 0.09 (0.02) | 0.17/ 0.09 (0.03) | 0.17/0.13 (0.1) | 0.17/0.04 (<10−5) | 0.17/0.06 (<10−5) |
rs1799883 | 0.35/0.22 (0.01) | 0.35/0.33 (0.2) | 0.35/0.32 (0.6) | 0.35/0.21 (0.001) | 0.35/0.36 (0.9) | 0.35/0.32 (0.6) | 0.35/0.19 (<10−5) | 0.35/0.30 (0.6) | 0.35/0.18 (<10−5) | 035/0.25 (0.04) | NA |
rs1801282 | 0.14/0.02 (<10−3) | 0.14/0.10(0.2 | 0.14/0.05 (0.001) | 0.14/0.03 (<10−5) | 0.14/ 0.09 (0.09) | 0.14/0.03 (<10−4) | NA | 0.14/0.09 (0.5) | 0.14/0.02 (<10−5) | 0.14/0.07 (0.07) | 0.14/0 (<10−5) |
rs8192678 | 0.39/0.07 (<10−5) | 0.39/0.35 (0.2) | 0.39/0.40 (0.6) | 0.39/0.40 (0.9) | 0.39/0.30 (0.05) | 0.39/0.47 (0.001) | 0.39/0.02 (<10−5) | 0.39/0.21 (<10−3) | 0.39/0.08 (<10−5) | 0.39/0.43 (0.5) | 0.39/0.04 (<10−5) |
rs780094 | 0.35/0.12 (<10−5) | 0.35/0.41 (0.3) | 0.35/0.41 (<10−5) | NA | 0.35/0.20 (<10−4) | 0.35/0.42 (<10−5) | 0.35/0.10 (<10−5) | 0.35/0.34 (0.7) | NA | .35/0.50 (<10−4) | 0.35/0.12 (<10−5) |
rs7944584 | 0.13/0.06 (<10−5) | 0.13/0.30 (<10−5) | 0.13/0.05 (<10−5) | NA | 0.13/0.22 (<10−5) | 0.13/0.02 (<10−5) | 0.13/0 (<10−5) | 0.13/0.19 (<10−5) | NA | 0.13/0.36 (<10−5) | 0.13/0 (<10−5) |