Baseline characteristics
In total, 4,007 eligible subjects (596 non-OSA, and 3,411 moderate-to-severe OSA) were enrolled in this study (see flow chart in Fig. 1). Subjects with OSA were more obese and had higher levels of glucose, lipid profiles (except for HDL-C and APOA-I), SBP, DBP, and insulin resistance than those without OSA (Table 1). The percentages of insulin resistance in non-OSA, moderate, and severe OSA were 26.8%, 46.8%, and 63.4%, respectively. The percentages of MetS in non-OSA, moderate, and severe OSA were 27.2%, 50.2%, and 64.3%, respectively.
Table 1
Basic characteristics of the overall population by the severity of OSA
Variable | Non-OSA (n = 596) | Moderate OSA (n = 831) | Severe OSA (n = 2580) | P value |
Demographics | | | | |
Age, years | 34(29 ~ 43) | 43(35 ~ 53) | 41(34 ~ 51) | < 0.001 |
Male (%) | 596(100%) | 675(81.2%) | 2332(90.4%) | < 0.001 |
BMI, Kg/m2 | 24.2(22.3 ~ 26.0) | 26.0(24.07 ~ 28.0) | 27.7(25.8 ~ 30.1) | < 0.001 |
NC, cm | 38(36 ~ 40) | 39(37 ~ 41) | 41(39 ~ 43) | < 0.001 |
WC,cm | 89(83 ~ 94) | 94(89 ~ 99) | 99(94 ~ 105) | < 0.001 |
HC, cm | 98(94 ~ 101) | 100(96 ~ 104) | 103(99 ~ 108) | < 0.001 |
WHR | 0.91(0.87 ~ 0.95) | 0.94(0.91 ~ 0.98) | 0.96(0.93 ~ 1.0) | < 0.001 |
Biochemistry assays | | | | |
Glucose (mmol/L) | 5.07(4.71 ~ 5.36) | 5.23(4.9 ~ 5.69) | 5.39(5.05 ~ 5.95) | < 0.001 |
Insulin (uU/ml) | 7.56(5.2 ~ 11.34) | 10.24 (7.04 ~ 14.48) | 12.88(8.92 ~ 18.96) | < 0.001 |
HOMA-IR | 1.72(1.11 ~ 2.55) | 2.41(1.56 ~ 3.48) | 3.15(2.08 ~ 4.84) | < 0.001 |
SBP, mmHg | 120(112 ~ 128) | 124(115 ~ 134) | 127(120 ~ 138) | < 0.001 |
DBP, mmHg | 78(71 ~ 82) | 80(71 ~ 87) | 81(76 ~ 90) | < 0.001 |
TC | 4.37(3.84 ~ 4.96) | 4.73(4.17 ~ 5.40) | 4.84(4.28 ~ 5.44) | < 0.001 |
TG | 1.24(0.84–1.84) | 1.61(1.14–2.29) | 1.77(1.26–2.61) | < 0.001 |
HDL-C | 1.03(0.92–1.12) | 1.02(0.9–1.12) | 1(0.88–1.14) | < 0.001 |
LDL-C | 2.68(2.25–3.18) | 3(2.51–3.51) | 3.04(2.53–3.55) | < 0.001 |
ApoA-I | 1.02(0.92–1.15) | 1.03(0.92–1.17) | 1.04(0.93–1.16) | 0.379 |
ApoB | 0.77(0.65–0.89) | 0.84(0.73–0.98) | 0.88(0.76-1.0) | < 0.001 |
ApoB /ApoA-I | 0.74(0.61–0.89) | 0.81(0.67–0.97) | 0.84(0.71–0.98) | < 0.001 |
Sleep apnea | | | | |
AHI | 2(0.8 ~ 3.4) | 21.8(18.3–25.7) | 58.2(45.1–70.5) | < 0.001 |
Minimum SaO2 | 92(89–95) | 83(77–87) | 71(62–79) | < 0.001 |
ODI | 2.1(0.9–3.8) | 22.2(17.3–28.0) | 57.9(44-72.2) | < 0.001 |
MAI | 14.4(10.3–22.5) | 22.2(14.2–31.6) | 36.7(21.6–56.4) | < 0.001 |
Medical history | | | | |
ESS | 7(3–10) | 7(4–11) | 11(7–15) | < 0.001 |
Non-smoker, N(%) | 372(62.4%) | 488(58.7%) | 1300(50.4%) | < 0.001 |
Non-drinker, N(%) | 284(47.7%) | 405(48.7%) | 1131(43.8%) | 0.024 |
IR (%) | 160(26.8%) | 389(46.8%) | 1636(63.4%) | < 0.001 |
Met S (%) | 162(27.2%) | 417(50.2%) | 1660(64.3%) | < 0.001 |
The data are presented as means and standard deviation; skewed data are presented as the median (IQR), and categorical data as the number (percentage). GRS: genetic risk score; BMI, body mass index; NC, neck circumference; WC, waist circumference; HC, hip circumference; WHR, waist/hip ratio; HOMA-IR, homeostasis model assessment for insulin resistance; SBP, systolic blood pressure; DBP, diastolic blood pressure; TC, total cholesterol; TG, triglyceride; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein; cholesterol; ApoA-I, apolipoprotein A-I; ApoB, apolipoprotein B; ESS, Epworth Sleepiness Scale; AHI, apnoea–hypopnea index; SaO2, oxygen saturation; ODI, oxygen desaturation index; MAI, micro-arousal index. |
The basic characteristics of the SNPs and SNP’s β coefficients in GRS construction are listed in Table 2. APOA-I SNP rs964184, rs10047462, rs888246 had negative correlations (ß=-0.013, -0.008, -0.014, respectively) while rs9804646 had positive correlation with serum APOA-I levels (ß=0.015). APOB SNP 1042031, rs693, rs1367117 associated with APOB levels positively (ß=0.017, 0.009, 0.012, respectively), while rs2854725, rs12713956 associated with APOB levels negatively (both ß=-0.03).
Table 2
Information of each individual SNP
SNP | gene | Chromosome | Position | Minor allele | Major allele | Risk allele | Minor allele frequency | ß | P* |
rs964184 | APOA-І | 11 | 116648917 | G | C | C | 0.216 | -0.013 | 0.012 |
rs9804646 | APOA-І | 11 | 116665079 | T | C | T | 0.216 | 0.015 | 0.006 |
rs10047462 | APOA-І | 11 | 116722041 | G | T | T | 0.484 | -0.008 | 0.076 |
rs888246 | APOA-І | 11 | 116724232 | T | C | C | 0.0052 | -0.014 | 0.16 |
rs1042031 | APOB | 2 | 21225753 | T | C | T | 0.044 | 0.017 | 0.11 |
rs693 | APOB | 2 | 21232195 | A | G | G | 0.049 | 0.009 | 0.37 |
rs2854725 | APOB | 2 | 21237786 | G | T | T | 0.13 | -0.03 | < 0.001 |
rs1367117 | APOB | 2 | 21263900 | A | G | G | 0.12 | 0.012 | 0.008 |
rs12713956 | APOB | 2 | 21241505 | G | A | G | 0.042 | -0.03 | 0.004 |
Apolipoprotein A-I, APOA-I; Apolipoprotein B, APOB. P* value was adjusted for age, gender, BMI as confounding factors. |
We also assessed the clinical characteristics of the participants in the top quintiles of the APOA GRS and APOB GRS compared with those in the bottom fifth quintiles (Tables S1 and S2, respectively). The basic characteristics of insulin, insulin resistance, and TG were lower in the highest quintile than in the lowest quintile, whereas HDL-C, LDL-C, APOA, and APOA/APOB were higher (all P < 0.05; Table S1). As expected, TC, APOB, and LDL-C levels were higher in the highest quintile than in the lowest quintile (all P < 0.05, Table S2).
Associations between common APOA-I and APOB genotypes and serum APOA-I and APOB levels
All SNPs of APOA-I and APOB were in Hardy-Weinberg equilibrium (P > 0.05). The associations of SNPs with APOA-I and APOB levels are summarized in Table 2. APOA-I rs964184 and rs9804646 were associated with APOA-I (β = −0.013, P = 0.021; β = 0.015, P = 0.006). APOB SNP rs2854725 was significantly associated with APOB (β = −0.03, P < 0.001). APOB SNPs rs1367117 and rs12713956 were moderately associated with increased APOB levels (β = 0.012, P = 0.008; β = −0.03, P = 0.004, respectively) (Table 2).
Associations of APOA-I and APOB and their GRS with insulin resistance and MetS risks
The associations between each SNP of APOA-I and APOB with insulin resistance and MetS are listed in Table S3. APOA-I SNPs rs9804646 and rs888246 were associated with insulin resistance (OR = 0.856, 95% confidence interval [CI]: 0.756–0.968, P = 0.013; OR = 1.340, 95% CI: 1.069–1.680, P = 0.011) after adjustment. APOA-I SNPs rs964184, rs9804646, and rs888246 were significantly associated with MetS (OR = 1.353, 95% CI: 1.201–1.523, P < 0.01; OR = 0.777, 95% CI: 0.69–0.874, P < 0.01; OR = 1.274, 95% CI: 1.024–1.586, P = 0.03, respectively) after adjustment. For APOB, only rs2854725 was associated with MetS (OR = 0.829, 95% CI: 0.718–0.956, P = 0.01) after adjusting for age, gender, and BMI.
Patients with insulin resistance had a lower APOA-I GRS and higher APOB/ APOA-I and APOB levels (Table 3) (OR = 0.923, 95% CI: 0.880–0.968, P < 0.001; OR = 4.551, 95% CI: 3.379–6.129, P < 0.001; OR = 6.677, 95% CI: 4.654–9.579, P < 0.001), which remained after adjusting for age, gender, and BMI (all P < 0.01). Similar associations were not seen for APOB GRS (P > 0.05). Patients with MetS had a lower APOA-I GRS and APOA-I levels and higher APOB/APOA-I and APOB levels (OR = 0.886, 95% CI: 0.845–0.929, P < 0.001; OR = 0.131, 95% CI: 0.093–0.184, P < 0.001; OR = 19.021, 95% CI: 13.629–26.545, P < 0.001; OR = 12.095, 95% CI: 8.349–17.522, P < 0.001, respectively), even after adjustments (all P < 0.01). Subjects with OSA had higher APOB/APOA-I and APOB levels (OR = 7.610, 95% CI: 4.886–11.852, P < 0.001; OR = 31.683, 95% CI: 18.231–55.059, P < 0.001, respectively), even after adjusting for age, gender, and BMI.
Table 3
Association of risk of APOA-I, APOB level and their GRS with risks of insulin resistance and MetS
| non-HOMA-IR vs HOMA-IR | | non-MetS vs MetS | | non-OSA vs moderate to severe OSA |
| OR | 95%CI | P | | OR | 95%CI | P | | OR | 95%CI | P |
APOA-I GRS | 0.923 | 0.880–0.968 | < 0.001 | | 0.886 | 0.845–0.929 | < 0.001 | | 0.983 | 0.920–1.049 | 0.600 |
APOA-I GRS* | 0.917 | 0.869–0.967 | 0.001 | | 0.870 | 0.827–0.916 | < 0.001 | | 0.994 | 0.924–1.070 | 0.874 |
APOB GRS | 1.011 | 0.950–1.076 | 0.734 | | 1.060 | 0.997–1.128 | 0.063 | | 1.011 | 0.927–1.101 | 0.811 |
APOB GRS* | 1.364 | 1.330–1.339 | 0.610 | | 1.072 | 1.003–1.147 | 0.042 | | 1.000 | 0.907–1.104 | 0.993 |
APOB/ APOA-I | 4.551 | 3.379–6.129 | < 0.001 | | 19.021 | 13.629–26.545 | < 0.001 | | 7.610 | 4.886–11.852 | < 0.001 |
APOB/ APOA-I * | 2.285 | 1.657–3.150 | < 0.001 | | 14.488 | 10.093–20.797 | < 0.001 | | 3.237 | 1.993–5.258 | < 0.001 |
APOA-I | 0.573 | 0.414–0.792 | < 0.001 | | 0.131 | 0.093–0.184 | < 0.001 | | 1.307 | 0.828–2.063 | 0.250 |
APOA-I * | 0.823 | 0.566–1.196 | 0.308 | | 0.09 | 0.061–0.132 | < 0.001 | | 1.336 | 0.788–2.267 | 0.282 |
APOB | 6.677 | 4.654–9.578 | < 0.001 | | 12.095 | 8.349–17.522 | < 0.001 | | 31.683 | 18.231–55.059 | < 0.001 |
APOB* | 3.168 | 2.139–4.691 | < 0.001 | | 6.098 | 4.109–9.051 | < 0.001 | | 8.582 | 4.653–45.830 | < 0.001 |
HOMA-IR, homeostasis model assessment of insulin resistance; GRS: genetic risk score; Met S, metabolic syndrome; Apolipoprotein A-I, APOA-I; Apolipoprotein B, APOB. |
*adjust for age, gender, BMI |
We also stratified APOA-I and APOB GRS into quintiles. When compared with the bottom quintile, subjects in the top quintile of the APOA-I GRS group had a lower risk of insulin resistance and MetS (Table 4) [OR = 0.753 (0.63–0.90), P = 0.002; OR = 0.651 (0.546–0.777), P < 0.001], even after adjusting for age, gender, and BMI [OR = 0.761 (0.623–0.929), P = 0.007; OR = 0.637 (0.526–0.773), P < 0.001]. Such a relationship was not found between APOB GRS and insulin resistance and MetS (all P > 0.05). Linear regression analysis revealed that APOA-I GRS was associated with decreased insulin, TG, HOMA-IR, APOB/APOA-I, and elevated HDL-C, LDL-C, and APOA-I levels (all P < 0.05, Table S4), even after adjustment, whereas APOB GRS was associated with elevated TC, LDL-C, APOB, and APOB/APOA-I levels (all P < 0.001, Table S5).
Table 4
Risk of OSA, insulin resistance and MetS according to quintile of APOA-I GRS and APOB GRS
| | Top vs. bottom quintile unadjusted analysis | | Top vs. bottom quintile adjusted analysis* |
OR | 95%CI | P | | OR* | 95%CI* | P* |
APOAGRS | Non-OSA vs moderate to severe OSA | 0.812 | 0.635–1.039 | 0.098 | | 0.855 | 0.654–1.118 | 0.252 |
non-insulin resistance vs insulin resistance | 0.753 | 0.630–0.899 | 0.002 | | 0.761 | 0.623–0.929 | 0.007 |
non- MetS vs MetS | 0.651 | 0.546–0.777 | < 0.001 | | 0.637 | 0.526–0.773 | < 0.001 |
APOBGRS | Non-OSA vs moderate to severe OSA | 0.997 | 0.768–1.295 | 0.984 | | 0.98 | 0.738–1.301 | 0.889 |
non-insulin resistance vs insulin resistance | 1.019 | 0.848–1.225 | 0.839 | | 1.032 | 0.841–1.267 | 0.761 |
non- MetS vs MetS | 1.154 | 0.962–1.384 | 0.123 | | 1.182 | 0.971–1.439 | 0.096 |
OSA, obstructive sleep apnea; HOMA-IR, homeostasis model assessment of insulin resistance; GRS: genetic risk score; MetS, metabolic syndrome; AHI, apnoea–hypopnea index; Apolipoprotein A-I, APOA-I; Apolipoprotein B, APOB. |
*adjust for age, gender, BMI |
Percentages of independent contributors of HOMA-IR
To reveal the percentages of independent contributors of HOMA-IR, stepwise multivariate linear regression analysis was performed. APOA-I GRS, age, gender, and BMI were included in model 1. APOA GRS, gender, and BMI explained 0.099%, 0.14%, and 18% of HOMA-IR, respectively (Table S6). As AHI was identified as an important marker of OSA, we included AHI in model 2. APOA-I GRS, gender, BMI, and AHI explained 0.1%, 0.14%, 18%, and 0.94% of HOMA-IR, respectively (all P < 0.05, Table S6).