Figures
- FIGURE 1
Flowchart of subjects included in the analyses. MOS: Malmö Offspring Study.
Tables
- TABLE 1
Baseline characteristics for the EpiHealth and Malmö Offspring Study (MOS) cohorts
EpiHealth MOS Subjects n 2229 645 Age years 60.7±8.4 40.2±13.4 Sex (female) 1122 (50.3) 335 (51.9) Height cm 172±9 174±9 Weight kg 78.6±14.3 78.8±16.8 BMI kg·m−2 26.5±3.8 26.1±4.6 BMI category <18.5 (underweight) 8 (0.4) 6 (0.9) ≥18.5 to <25 (normal weight) 772 (34.6) 296 (45.9) ≥25 to <30 (overweight) 1083 (48.6) 227 (35.2) ≥30 (obesity) 366 (16.4) 116 (18) Central obesity cm (male ≥102, female ≥88) 879 (39.4) 206 (31.9) Physical activity Sedentary 907 (40.7) 281 (43.6) Moderate 934 (41.9) 163 (25.3) High 388 (17.4) 201 (31.1) Smoking history Never 1108 (49.7) 393 (60.9) Previous 946 (42.4) 173 (26.8) Current 175 (7.9) 79 (12.3) Pack-years# 14.6±13.1 11.7±10.8 Diabetes 77 (3.5) 21 (3.3) Hypertension 602 (27.0) 107 (16.6) Hyperlipidaemia 486 (21.8) 81 (12.6) Cardiovascular disease 165 (7.4) 80 (12.7) FEV1 L 3.1±0.8 3.5±0.8 FEV1 % pred GLI 100±16 94±12 FVC L 4.0±1.1 4.5±1.0 FVC % pred GLI 101±16 98±12 FEV1/FVC 0.77±0.07 0.78±0.07 FEV1/FVC % pred GLI 99±9 95±8 Normal spirometry 2002 (89.8) 506 (78.4) Obstructive spirometry 124 (5.6) 91 (14.1) Restrictive spirometry 26 (1.2) 5 (0.8) PRISm 77 (3.5) 43 (6.7) Data are presented as mean±sd for continuous variables and n (%) for dichotomous variables. BMI: body mass index; FEV1: forced expiratory volume in 1 s; GLI: Global Lung Function Initiative; FVC: forced vital capacity; LLN: lower limit of normal. Cardiovascular disease: a history of myocardial infarction, stroke, angina pectoris, heart failure or atrial fibrillation. Normal spirometry: FEV1/FVC ≥ LLN and FEV1 ≥ LLN and FVC ≥ LLN. Obstructive spirometry: FEV1/FVC < LLN. Restrictive spirometry: FEV1/FVC ≥ LLN and FVC < LLN and FEV1 ≥ LLN. Preserved ratio impaired spirometry (PRISm): FEV1/FVC ≥ LLN and FEV1 < LLN. #: calculated only for subjects with a history of smoking.
- TABLE 2
Cross-sectional associations between plasma proteins and FEV1 % predicted in EpiHealth (discovery cohort) and MOS (replication cohort)
Protein Abbreviation UniProtNo Discovery cohort (EpiHealth)# Replication cohort (MOS)¶ FEV1% predicted FEV1% predicted β-coefficient (95% CI) Adjusted p-value β-coefficient (95% CI) p-value Leptin LEP P41159 −4.80 (−5.87– −3.74) 4.9×10−16 −2.17 (−3.52– −0.81) 0.002 Interleukin-6 IL-6 P05231 −1.86 (−2.54– −1.18) 5.8×10−6 −1.49 (−2.48– −0.51) 0.003 Paraoxonase 3 PON3 Q15166 1.87 (1.12–2.61) 4.5×10−5 1.45 (0.47–2.44) 0.004 Interleukin-1 receptor antagonist IL-1RA P18510 −1.54 (−2.32– −0.77) 0.003 −1.50 (−2.57– −0.43) 0.006 Fatty acid-binding protein 4 FABP4 P15090 −2.61 (−3.51– −1.72) 1.4×10−6 −1.62 (−2.86– −0.38) 0.01 Agouti-related protein AGRP O00253 1.01 (0.35–1.67) 0.04 1.01 (−0.04–2.05) 0.06 Growth hormone GH P01241 1.15 (0.39–1.92) 0.04 1.12 (−0.08–2.32) 0.07 Plasminogen activator inhibitor KIM1 Q96D42 −1.30 (−2.00– −0.60) 0.007 −0.88 (−1.96–0.20) 0.11 C-C motif chemokine 16 CCL16 O15467 −1.23 (−1.91– −0.54) 0.01 −0.57 (−1.51–0.38) 0.24 Metalloproteinase inhibitor 4 TIMP4 Q99727 −1.20 (−1.89– −0.50) 0.01 −0.61 (−1.61–0.41) 0.24 Retinoic acid receptor responder 2 RARRES2 Q99969 −1.96 (−2.68– −1.24) 5.8×10−6 −0.59 (−1.60–0.41) 0.25 Receptor for advanced glycosylation and products RAGE Q15109 1.02 (0.36–1.68) 0.04 0.46 (−0.46–1.38) 0.33 Trefoil factor 3 TFF3 Q07654 −1.08 (−1.77– −0.39) 0.04 −0.43 (−1.38–0.53) 0.38 Matrix metalloproteinase 7 MMP7 P09237 −1.15 (−1.85– −0.45) 0.02 0.34 (−0.60–1.29) 0.48 Plasminogen activator inhibitor PAI P05121 −1.00 (−1.66– −0.34) 0.04 −0.26 (−1.24–0.72) 0.60 Adrenomedullin ADM P35318 −1.92 (−2.69– −1.15) 4.5×10−5 −0.22 (−1.20–0.75) 0.65 Growth/differentiation factor 15 GDF15 Q99988 −1.36 (−2.15– −0.57) 0.01 0.11 (−0.84–1.06) 0.82 Tissue-type plasminogen activator tPA P00750 −1.56 (−2.28– −0.58) 0.0006 0.09 (−0.95–1.12) 0.87 Adhesion G protein-coupled receptor G2 ADGRG2 Q8IZP9 1.64 (0.95–2.32) 4.5×10−5 −0.006 (−1.02–1.01) 0.99 Multivariable linear regression analysis for each protein. Sorted based on p-value in replication cohort. Data are presented as regression coefficients for proteins increased by at least 1 standard deviation. Adjusted for age, sex, cohort, body mass index, smoking, pack-years and physical activity. MOS: Malmö Offspring Study; FEV1: forced expiratory volume in 1 s; CI: confidence interval. #: n=2229; ¶: n=645.
- TABLE 3
Cross-sectional associations between plasma proteins and FVC % predicted in EpiHealth (discovery cohort) and MOS (replication cohort)
Protein Abbreviation UniProtNo Discovery cohort (EpiHealth)# Replication cohort (MOS)¶ FVC % predicted FVC % predicted β-coefficient (95% CI) Adjusted
p-valueβ-coefficient (95% CI) p-value Leptin LEP P41159 −5.31 (−6.40– −4.22) 6.8×10−19 −2.63 (−3.93– −1.32) 8.8×10−5 Paraoxonase 3 PON3 Q15166 2.17 (1.41–2.93) 3.4×10−6 1.69 (0.74–2.64) 0.0005 Fatty acid-binding protein 4 FABP4 P15090 −2.35 (−3.27– −1.43) 2.6×10−5 −2.09 (−3.29– −0.89) 0.0006 Interleukin-6 IL-6 P05231 −1.34 (−2.04– −0.64) 0.003 −1.77 (−2.72– −0.81) 0.0003 Insulin-like growth factor-binding protein 2 IGFBP2 P18065 1.66 (0.91–2.42) 0.001 1.42 (0.44–2.40) 0.004 Interleukin-1 receptor antagonist protein IL-1RA P18510 −1.55 (−2.35– −0.76) 0.003 −1.40 (−2.44– −0.36) 0.008 Receptor for advanced glycosylation and products RAGE Q15109 0.97 (0.30–1.65) 0.05 1.20 (0.31–2.09) 0.008 Agouti-related protein AGRP O00253 1.19 (0.51–1.87) 0.008 1.13 (0.12–2.14) 0.03 Fibroblast growth factor 21 FGF21 Q9NSA1 −1.02 (−1.71– −0.31) 0.05 −1.01 (−2.00– −0.03) 0.04 Kidney injury molecule KIM1 Q96D42 −1.40 (−2.11– −0.68) 0.0028 −1.01 (−2.06–0.03) 0.06 Retinoic acid receptor responder 2 RARRES2 Q99969 −1.96 (−2.70– −1.22) 1.2×10−5 −0.84 (−1.81–0.13) 0.09 Hydroxyacid oxidase 1 HAOX1 Q9UJM8 −1.41 (−2.08– −0.73) 0.001 −0.71 (−1.65–0.23) 0.14 C-C motif chemokine 16 CCL16 O15467 −1.46 (−2.16– −0.76) 0.001 −0.68 (−1.60–0.24) 0.15 Insulin-like growth factor-binding protein 1 IGFBP1 P08833 1.53 (0.75–2.30) 0.0027 0.76 (−0.32–1.83) 0.17 Plasminogen activator inhibitor PAI P05121 −1.28 (−1.95– −0.60) 0.0035 −0.62 (−1.57–0.33) 0.20 Tissue-type plasminogen activator tPA P00750 −1.41 (−2.15– −0.68) 0.003 −0.58 (−1.59–0.42) 0.25 Growth hormone GH P01241 1.24 (0.45–2.02) 0.025 0.61 (−0.56–1.78) 0.31 C-C motif chemokine 17 CCL17 Q92583 −1.03 (−1.70– −0.36) 0.03 0.44 (−0.46–1.33) 0.34 C-C motif chemokine 3 CCL3 P10147 −1.02 (−1.71– −0.33) 0.04 −0.34 (−1.27–0.59) 0.47 Matrix metalloproteinase 7 MMP7 P09237 −1.34 (−2.06– −0.62) 0.0043 0.33 (−0.58–1.25) 0.48 Adhesion G protein-coupled receptor G2 ADGRG2 Q8IZP9 1.89 (1.19–2.59) 1.0×10−5 0.31 (−0.67–1.30) 0.53 Thrombospondin-2 THBS2 P35442 −1.02 (−1.68– −0.36) 0.03 −0.27 (−1.19–0.64) 0.55 Spondin-2 SPON2 Q9BUD6 −1.15 (−1.83– −0.46) 0.013 −0.25 (−1.14–0.63) 0.57 Adrenomedullin ADM P35318 −1.91 (−2.70– −1.12) 9.5×10−5 −0.25 (−1.19–0.70) 0.61 Multivariable linear regression analysis for each protein. Data are regression coefficients for proteins increased by at least 1 standard deviation. Adjusted for age, sex, cohort, body mass index, smoking, pack-years and physical activity. MOS: Malmö Offspring Study; FVC: forced vital capacity; CI: confidence interval. #: n=2229; ¶: n=645.
- TABLE 4
Sensitivity analysis in EpiHealth
Protein Abbreviation UniProtNo EpiHealth# EpiHealth¶ FEV1 % predicted FEV1 % predicted β-coefficient (95% CI) Adjusted p-value β-coefficient (95% CI) Adjusted p-value Leptin LEP P41159 −4.80 (−5.87– −3.74) 4.9×10−16 −3.44 (−4.46– −2.41) 1.6×10−8 Interleukin-6 IL-6 P05231 −1.86 (−2.54– −1.18) 5.8×10−6 −1.78 (−2.54– −1.03) 0.0003 Paraoxonase 3 PON3 Q15166 1.87 (1.12–2.61) 4.5×10−5 0.91 (0.69–1.75) 0.27* Interleukin-1 receptor antagonist IL-1RA P18510 −1.54 (−2.32– −0.77) 0.003 −1.16 (−2.07–0.46) 0.17* Fatty acid-binding protein 4 FABP4 P15090 −2.61 (−3.51– −1.72) 1.4×10−6 −2.3 (−3.27– −1.33) 0.0003 Agouti-related protein AGRP O00253 1.01 (0.35–1.67) 0.04 0.7 (−0.07–1.46) 0.36* Growth hormone GH P01241 1.15 (0.39–1.92) 0.04 1.21 (0.33–2.08) 0.11* Plasminogen activator inhibitor KIM1 Q96D42 −1.30 (−2.00– −0.60) 0.007 −1.37 (−2.20– −0.55) 0.025 C-C motif chemokine 16 CCL16 O15467 −1.23 (−1.91– −0.54) 0.01 −0.90 (−1.66– −0.14) 0.22* Metalloproteinase inhibitor 4 TIMP4 Q99727 −1.20 (−1.89– −0.50) 0.01 −1.36 (−2.15– −0.57) 0.023 Retinoic acid receptor responder 2 RARRES2 Q99969 −1.96 (−2.68– −1.24) 5.8×10−6 −1.68 (−2.46–0.9) 0.001 Receptor for advanced glycosylation and products RAGE Q15109 1.02 (0.36–1.68) 0.04 0.92 (0.17–1.67) 0.2* Trefoil factor 3 TFF3 Q07654 −1.08 (−1.77– −0.39) 0.04 −1.30 (−2.08– −0.53) 0.025 Matrix metalloproteinase 7 MMP7 P09237 −1.15 (−1.85– −0.45) 0.02 −0.81 (−1.65–0.02) 0.31* Plasminogen activator inhibitor PAI P05121 −1.00 (−1.66– −0.34) 0.04 −0.76 (−1.50– −0.01) 0.31* Adrenomedullin ADM P35318 −1.92 (−2.69– −1.15) 4.5×10−5 −1.65 (−2.54– −0.76) 0.01 Growth/differentiation factor 15 GDF15 Q99988 −1.36 (−2.15– −0.57) 0.01 −1.58 (−2.54–0.63) 0.03 Tissue-type plasminogen activator tPA P00750 −1.56 (−2.28– −0.58) 0.0006 −1.52 (−2.32– −0.73) 0.009 Adhesion G protein-coupled receptor G2 ADGRG2 Q8IZP9 1.64 (0.95–2.32) 4.5×10−5 1.34 (0.56–2.11) 0.02 Cross-sectional associations between plasma proteins and FEV1% predicted in EpiHealth before and after exclusion of individuals with known CVD, diabetes or obesity. Multivariable linear regression analysis for each protein. Data are presented as regression coefficients for proteins increased by at least 1 standard deviation. Adjusted for age, sex, cohort, body mass index, smoking, pack-years and physical activity. For the sensitivity analysis this multivariable linear regression model was adjusted for hypertension, hyperlipidaemia and waist circumference (normal versus high) instead of BMI. FEV1: forced expiratory volume in 1 s; CI: confidence interval; CVD: cardiovascular disease. #: n=2229; ¶: n=1685; *: non-significant.
- TABLE 5
Sensitivity analysis in EpiHealth
Protein Abbreviation UniProtNo EpiHealth# EpiHealth¶ FVC % preicted FVC % predicted β-coefficient (95% CI) Adjusted
p-valueβ-coefficient (95% CI) Adjusted p-value Leptin LEP P41159 −5.31 (−6.40– −4.22) 6.8×10−19 −4.64 (−5.7– −3.58) 5.1×10−15 Paraoxonase 3 PON3 Q15166 2.17 (1.41–2.93) 3.4×10−06 1.52 (0.65–2.39) 0.013 Fatty acid-binding protein 4 FAB4 P15090 −2.35 (−3.27– −1.43) 2.6×10−05 −2.93 (−3.93– −1.93) 1.3×10−6 Interleukin-6 IL-6 P05231 −1.34 (−2.04– −0.64) 0.003 −1.35 (−2.14– −0.56) 0.015 Insulin-like growth factor-binding protein 2 IGFBP2 P18065 1.66 (0.91–2.42) 0.001 1.37 (0.51–2.23) 0.02 Interleukin-1 receptor antagonist protein IL-1RA P18510 −1.55 (−2.35– −0.76) 0.003 −1.78 (−2.73– −0.83) 0.007 Receptor for advanced glycosylation and products RAGE Q15109 0.97 (0.30–1.65) 0.05 0.95 (0.17–1.73) 0.1+ Agouti-related protein AGRP O00253 1.19 (0.51–1.87) 0.008 1.07 (0.27–1.86) 0.07+ Fibroblast growth factor 21 FGF21 Q9NSA1 −1.02 (−1.71– −0.31) 0.05 −1.27 (−2.08– −0.46) 0.03 Kidney injury molecule KIM1 Q96D42 −1.40 (−2.11– −0.68) 0.0028 −1.59 (−2.44– −0.73) 0.008 Retinoic acid receptor responder 2 RARRES2 Q99969 −1.96 (−2.70– −1.22) 1.2×10−5 −2.07 (−2.88–1.26) 4.4×10−5 Hydroxyacid oxidase 1 HAOX1 Q9UJM8 −1.41 (−2.08– −0.73) 0.001 −1.33 (−2.11– −0.55) 0.015 C-C motif chemokine 16 CCL16 O15467 −1.46 (−2.16– −0.76) 0.001 −1.31 (−2.09– −0.53) 0.02 Insulin-like growth factor-binding protein 1 IGFBP1 P08833 1.53 (0.75–2.30) 0.0027 1.59 (0.72–2.47) 0.008 Plasminogen activator inhibitor PAI P05121 −1.28 (−1.95– −0.60) 0.0035 −1.16 (−1.93– −0.39) 0.04 Tissue-type plasminogen activator tPA P00750 −1.41 (−2.15– −0.68) 0.003 −1.59 (−2.41– −0.76) 0.007 Growth hormone GH P01241 1.24 (0.45–2.02) 0.025 1.53 (0.62–2.45) 0.02 C-C motif chemokine 17 CCL17 Q92583 −1.03 (−1.70– −0.36) 0.03 −1.09 (−1.86– −0.33) 0.052+ C-C motif chemokine 3 CCL3 P10147 −1.02 (−1.71– −0.33) 0.04 −1.22 (−2.08– −0.35) 0.06+ Matrix metalloproteinase 7 MMP7 P09237 −1.34 (−2.06– −0.62) 0.0043 −1.18 (−2.05– −0.32) 0.06+ Adhesion G protein-coupled receptor G2 ADGRG2 Q8IZP9 1.89 (1.19–2.59) 1.0×10−5 1.79 (0.97–2.59) 0.0006 Thrombospondin-2 THBS2 P35442 −1.02 (−1.68– −0.36) 0.03 −1.0 (−1.8– −0.19) 0.1+ Spondin-2 SPON2 Q9BUD6 −1.15 (−1.83– −0.46) 0.013 −1.49 (−2.27– −0.7) 0.007 Adrenomedullin ADM P35318 −1.91 (−2.70– −1.12) 9.5×10−5 −2.14 (−3.07– −1.21) 0.0004 Angiopoietin Like 1 ANGPTL1 O95841 0.74 (0.07–1.4) 0.18+ 31 (0.54–2–08) 0.01 Tumour necrosis factor receptor 2 TNFR2 P20333 −0.87 (−1.59– −0.14) 0.13+ −1.25 (−2.04–−0.46) 0.03 Versican core protein VCAN P13611 0.93 (0.26–1.6) 0.06+ 1.21 (0.44–1.97) 0.03 Trefoil factor 3 TFF3 Q07654 −0.92 (−1.63– −0.21) 0.095+ −1.19 (−1.99– −0.39) 0.04 Low-density lipoprotein receptor LDLreceptor P01130 −0.88 (−1.58– −0.19) 0.1+ −1.19 (−1.99– −0.38) 0.04 Cross-sectional associations between plasma proteins and FVC % predicted in EpiHealth before and after exclusion of individuals with known CVD, diabetes or obesity. Multivariable linear regression analysis for each protein. Data are regression coefficients for proteins increased by at least 1 standard deviation. Adjusted for age, sex, cohort, body mass index, smoking, pack-years and physical activity. For the sensitivity analysis this multivariable linear regression model was adjusted for hypertension, hyperlipidaemia and waist circumference (normal versus high) instead of BMI. FVC: forced vital capacity; CI: confidence interval; CVD: cardiovascular disease. #: n=2229; ¶: n=1685; +: non-significant.
Supplementary Material
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Table S1a 00321-2022.tableS1a
Table S1b 00321-2022.tableS1b
