Genetically predicted high IGF-1 levels showed protective effects on COVID-19 susceptibility and hospitalization: a Mendelian randomisation study with data from 60 studies across 25 countries

  1. Xinxuan Li
  2. Yajing Zhou
  3. Shuai Yuan
  4. Xuan Zhou
  5. Lijuan Wang
  6. Jing Sun
  7. Lili Yu
  8. Jinghan Zhu
  9. Han Zhang
  10. Nan Yang
  11. Shuhui Dai
  12. Peige Song
  13. Susanna C Larsson
  14. Evropi Theodoratou
  15. Yiming Zhu
  16. Xue Li  Is a corresponding author
  1. Department of Big Data in Health Science School of Public Health, Center of Clinical Big Data and Analytics of The Second Affiliated Hospital, Zhejiang University School of Medicine, China
  2. Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Sweden
  3. The Second School of Clinical Medicine, Southern Medical University, China
  4. School of Public Health and Women's Hospital, Zhejiang University School of Medicine, China
  5. Unit of Medical Epidemiology, Department of Surgical Sciences, Uppsala University, Sweden
  6. Centre for Global Health, Usher Institute, University of Edinburgh, United Kingdom
  7. Cancer Research UK Edinburgh Centre, Medical Research Council Institute of Genetics and Cancer, University of Edinburgh, United Kingdom
2 figures, 6 tables and 3 additional files

Figures

Overall study design.

Abbreviation: IGF-1, insulin-like growth factor-1; GWAS, genome-wide association study; SNP, single-nucleotide polymorphism; LD, linkage disequilibrium; IVW, inverse variance weighting; MR, Mendelian randomization.

Figure 2 with 2 supplements
IGF-1 and COVID-19 outcomes in Mendelian randomization (MR) analyses.

Abbreviation: IGF-1, insulin-like growth factor-1; SNP, single-nucleotide polymorphism; IVW, inverse variance weighting; OR, odds ratio; CI, confidence interval.

Figure 2—figure supplement 1
Leave-one-out plot for IGF-1 and COVID-19 susceptibility, hospitalization and severity in Mendelian randomization analysis.
Figure 2—figure supplement 2
Funnel plot for IGF-1 and COVID-19 susceptibility, hospitalization and severity in Mendelian randomization analysis.

Tables

Table 1
Sources of data for Mendelian randomization analysis in COVID-19 HGI.
PhenotypeParticipants
SusceptibilityMeta-analysis of 35 GWAS performed in individuals of European ancestry
Cases: 32,494 individuals with COVID-19 by laboratory confirmation, chart review, or self-report
Controls: 1,316,207 individuals without confirmation or history of COVID-19
HospitalizationMeta-analysis of 23 GWAS performed in individuals of European ancestry
Cases: 8316 hospitalized individuals with COVID-19
Controls: 1,549,095 individuals without confirmation or history of COVID-19
SeverityMeta-analysis of 14 GWAS performed in individuals of European ancestry
Cases: 4792 SARS-CoV-2 infected hospitalized individuals who died or required respiratory support (intubation, CPAP, BiPAP, continuous external negative pressure, high flow nasal cannula).
Controls:1,054,664 individuals without confirmation or history of COVID-19
  1. Notes: COVID-19 outcomes are taken from the COVID-19 HGI.

  2. HGI, Host Genetics Initiative; GWAS, genome-wide association study; UKB, UK Biobank; CPAP, continuous positive airway pressure ventilation; BiPAP, bilevel positive airway pressure ventilation.

Table 2
Sex hormones, SHBG, IGF-1, and COVID-19 outcomes in Mendelian randomization (MR) analyses.
ExposureMethodSusceptibilityHospitalizationSeverity
SNPsOR (95% CI)p Effectp Heterogeneityp InterceptSNPsOR (95% CI)p Effectp Heterogeneityp InterceptSNPsOR (95% CI)p Effectp Heterogeneityp Intercept
TestosteroneIVW3150.94 (0.83, 1.06)0.3090.0063030.82 (0.64, 1.04)0.1030.0553160.83 (0.60, 1.15)0.2560.041
MR-Egger0.93 (0.76, 1.12)0.4300.0050.8600.79 (0.55, 1.15)0.2170.0510.8190.78 (0.48, 1.27)0.3130.0380.732
Weighted median0.89 (0.71, 1.12)0.3290.81 (0.52, 1.28)0.3700.71 (0.40, 1.26)0.246
Simple mode1.13 (0.73, 1.77)0.5840.77 (0.27, 2.20)0.6230.44 (0.09, 2.18)0.316
Weighted mode0.91 (0.77, 1.08)0.3000.77 (0.52, 1.13)0.1800.65 (0.40, 1.05)0.081
MR-PRESSO0.94 (1.06, 0.84)0.82 (1.04, 0.65)0.83 (1.15, 0.59)
SHBGIVW3190.91 (0.80, 1.04)0.1820.0023090.86 (0.66, 1.11)0.2550.0873200.92 (0.65, 1.29)0.6180.096
MR-Egger0.96 (0.78, 1.18)0.7080.0020.4940.83 (0.57, 1.22)0.3520.0810.8180.92 (0.56, 1.51)0.7300.0900.994
Weighted median0.90 (0.72, 1.13)0.3600.82 (0.52, 1.29)0.3910.72 (0.41, 1.27)0.255
Simple mode1.09 (0.66, 1.81)0.7351.18 (0.40, 3.44)0.7671.16 (0.25, 5.41)0.850
Weighted mode0.94 (0.78, 1.14)0.5470.81 (0.56, 1.18)0.2790.79 (0.47, 1.33)0.376
MR-PRESSO0.91 (1.05, 0.80)0.86 (1.11, 0.67)0.91 (1.28, 0.65)
EstradiolIVW70.54 (0.15, 1.94)0.3460.18870.87 (0.11, 6.70)0.8950.76970.50 (0.03, 7.64)0.6200.987
MR-Egger0.73 (0.04, 14.11)0.8450.1230.8300.34 (0.00, 29.54)0.6570.6850.6620.04 (0.00, 17.04)0.3451.0000.401
Weighted median0.36 (0.10, 1.35)0.1300.35 (0.03, 4.21)0.4070.30 (0.01, 7.26)0.458
Simple mode0.29 (0.03, 2.60)0.3130.71 (0.01, 44.94)0.8750.33 (0.00, 43.56)0.673--
Weighted mode0.34 (0.07, 1.73)0.2410.38 (0.03, 4.81)0.4820.29 (0.01, 9.43)0.511--
MR-PRESSO0.54 (1.94, 0.15)0.87 (3.93, 0.19)0.51 (1.52, 0.17)---
IGF-1IVW160.77 (0.61, 0.97)0.0270.175160.62 (0.25, 0.51)0.0180.715180.85 (0.52, 1.38)0.5130.601-
MR-Egger0.84 (0.56, 1.26)0.4080.1450.6140.72 (0.37, 1.38)0.3360.6680.5951.45 (0.67, 3.10)0.3580.7580.096
Weighted median0.76 (0.57, 1.02)0.0710.75 (0.44, 1.28)0.2940.76 (0.38, 1.53)0.446--
Simple mode0.64 (0.39, 1.05)0.0970.66 (0.30, 1.45)0.3180.82 (0.27, 2.47)0.730--
Weighted mode0.77 (0.58, 1.02)0.0840.71 (0.44, 1.17)0.1990.70 (0.35, 1.38)0.319--
MR-PRESSO0.77 (0.98, 0.61)0.62 (0.88, 0.43)0.85 (1.34, 0.54)---
  1. SNP, single-nucleotide polymorphism; OR, odds ratio; CI, confidence interval; IVW, inverse variance weighting; SHBG, sex hormones-binding globulin; IGF-1, insulin-like growth factor-1.

Table 3
Sensitive analysis between serum IGF-1 levels instrumented by 10 SNPs in the IGF-1 gene region and COVID-19 outcomes.
MethodSusceptibilityHospitalizationSeverity
OR (95% CI)p Effectp Heterogeneityp InterceptOR (95% CI)p Effectp Heterogeneityp InterceptOR (95% CI)p Effectp Heterogeneityp Intercept
IVW0.99 (0.91, 1.07)0.7770.5960.90 (0.74, 1.10)0.6450.1041.01 (0.82, 1.24)0.4150.437
MR-Egger0.99 (0.93, 1.05)0.7320.5410.5270.97 (0.84, 1.11)0.3380.1080.3751.09 (0.92, 1.30)0.9530.3720.590
Weighted median1.01 (0.96, 1.06)0.7390.97 (0.86, 1.10)0.6201.05 (0.93, 1.20)0.310
Simple mode0.98 (0.89, 1.08)0.6851.12 (0.88, 1.43)0.3951.16 (0.88, 1.51)0.316
Weighted mode0.98 (0.92, 1.05)0.5960.94 (0.82, 1.09)0.4391.12 (0.92, 1.37)0.279
  1. IGF-1, insulin-like growth factor-1; SNP, single-nucleotide polymorphism; IVW, inverse variance weighting; OR, odds ratio; CI, confidence interval.

Table 4
Sex-specific associations of genetically testosterone and estradiol levels with COVID-19 risk.
ExposureMethodSusceptibilityHospitalizationSeverity
MaleFemaleMaleFemaleMaleFemale
OR (95% CI)pOR (95% CI)pOR (95% CI)pOR (95% CI)pOR (95% CI)pOR (95% CI)p
TestosteroneIVW0.96 (0.90, 1.05)0.4631.06 (0.97, 1.15)0.2140.96 (0.83, 1.10)0.5471.03 (0.87, 1.22)0.7311.07 (0.89, 1.27)0.4790.88 (0.69, 1.11)0.269
MR-Egger0.97 (0.86, 1.09)0.6441.04 (0.85, 1.26)0.7130.88 (0.71, 1.10)0.2701.13 (0.76, 1.69)0.5490.81 (0.62, 1.08)0.1520.68 (0.39, 1.18)0.169
Weighted median0.93 (0.83, 1.04)0.1841.06 (0.94, 1.19)0.3700.89 (0.72, 1.10)0.2771.08 (0.84, 1.39)0.5230.89 (0.67, 1.19)0.4380.81 (0.57, 1.14)0.227
p for intercept1.00 (1.00, 1.00)0.9981.00 (0.99, 1.01)0.8541.00 (1.00, 1.01)0.3481.00 (0.99, 1.01)0.6151.01 (1.00, 1.02)0.0171.01 (0.99, 1.03)0.314
MR-PRESSO0.97 (0.90, 1.05)0.4641.06 (0.97, 1.15)0.2160.96 (0.83, 1.10)0.5491.03 (0.87, 1.22)0.7321.07 (0.89, 1.27)0.4780.88 (0.69, 1.11)0.270
EstradiolIVW0.99 (0.89, 1.11)0.9230.95 (0.71, 1.26)0.7240.98 (0.81, 1.18)0.8261.04 (0.63, 1.73)0.8730.90 (0.71, 1.15)0.4031.39 (0.74, 7.15)0.310
MR-Egger1.00 (0.73, 1.36)0.9930.89 (0.59, 1.34)0.5980.93 (0.52, 1.67)0.8121.15 (0.56, 2.34)0.7190.61 (0.29, 6.15)0.2331.76 (0.74, 3.15)0.234
Weighted median1.05 (0.92, 1.20)0.4320.95 (0.68, 1.32)0.7450.93 (0.74, 1.16)0.5081.32 (0.67, 2.57)0.4220.88 (0.65, 1.15)0.4111.96 (0.81, 5.15)0.135
p for intercept1.00 (0.96, 1.04)0.9801.00 (0.99, 1.02)0.6691.01 (0.94, 1.08)0.8560.99 (0.96, 1.02)0.7071.05 (0.96, 0.15)0.3120.99 (0.95, 0.15)0.441
MR-PRESSO0.99 (0.89, 1.11)0.9250.95 (0.71, 1.26)0.7320.98 (0.81, 1.18)0.8311.04 (0.63, 1.73)0.8770.90 (0.71, 1.15)0.4251.39 (0.74, 2.63)0.335
  1. OR, odds ratio; CI, confidence interval; IVW, inverse variance weighting.

Table 5
Associations of serum E2 levels instrumented by rs7173595 in the CYP19A1 gene region with COVID-19 outcomes.
SexPhenotypebetaSEOR (95% CI)p Effect
FemaleSusceptibility–1.140.880.32 (0.06, 1.80)0.195
Hospitalization–1.271.600.28 (0.01, 6.46)0.426
Severity–1.492.060.22 (0.00, 12.73)0.469
MaleSusceptibility–1.000.770.37 (0.08, 1.67)0.195
Hospitalization–1.111.400.33 (0.02, 5.11)0.426
Severity–1.311.800.27 (0.01, 9.26)0.469
  1. E2, estradiol; OR, odds ratio; CI, confidence interval.

Table 6
Testosterone, SHBG, IGF-1, and COVID-19 outcomes in Mendelian randomization (MR) analyses adjusting BMI.
ExposureMethodSusceptibilityHospitalizationSeverity
SNPsOR (95% CI)p Effectp Heterogeneityp InterceptSNPsOR (95% CI)p Effectp Heterogeneityp InterceptSNPsOR (95% CI)p Effectp Heterogeneityp Intercept
TestosteroneIVW3060.95 (0.83,1.07)0.3860.0062940.83 (0.64,1.06)0.1340.0413070.84 (0.60,1.17)0.3040.030
MR-Egger0.93 (0.77,1.13)0.4840.0060.8550.83 (0.56,1.21)0.3240.0380.9910.83 (0.50,1.37)0.4660.0270.949
Weighted median0.90 (0.72,1.12)0.3310.82 (0.52,1.28)0.3750.71 (0.42,1.21)0.214
Simple mode1.13 (0.70,1.82)0.6100.68 (0.24,1.91)0.4650.37 (0.07,1.88)0.229
Weighted mode0.95 (0.79,1.13)0.5400.81 (0.56,1.17)0.2730.65 (0.40,1.06)0.085
MR-PRESSO0.94 (0.83,1.07)0.83 (0.64,1.06)0.83 (0.64,1.06)
SHBGIVW3080.90 (0.79,1.04)0.1600.0021980.84 (0.64,1.10)0.2090.0473090.89 (0.62,1.26)0.5110.058
MR-Egger0.94 (0.76,1.15)0.5380.0010.6630.81 (0.54,1.21)0.2990.0430.7940.89 (0.53,1.49)0.6660.0540.978
Weighted median0.90 (0.71,1.13)0.3560.81 (0.52,1.28)0.3770.72 (0.42,1.23)0.230
Simple mode1.05 (0.60,1.84)0.8601.25 (0.42,3.78)0.6890.97 (0.22,4.22)0.967
Weighted mode0.94 (0.77,1.15)0.5700.81 (0.55,1.20)0.2950.72 (0.43,1.22)0.224
MR-PRESSO0.90 (0.79,1.04)0.84 (0.64,1.10)0.89 (0.62,1.26)
IGF-1IVW150.76 (0.60,0.96)0.0210.172150.61 (0.41,0.90)0.0140.688170.84 (0.52,1.38)0.4970.534
MR-
Egger
0.88 (0.58,1.33)0.5540.1680.3900.77 (0.39,1.50)0.4580.6760.4031.55 (0.71,3.39)0.2840.757
Weighted median0.75 (0.57,0.99)0.0460.75 (0.45,1.24)0.2600.75 (0.38,1.48)0.410
Simple mode0.65 (0.38,1.11)0.1350.64 (0.30,1.37)0.2650.75 (0.25,2.31)0.629
Weighted mode0.76 (0.56,1.03)0.0960.71 (0.44,1.15)0.1850.72 (0.36,1.47)0.383
MR-PRESSO0.76 (0.60,0.96)0.61 (0.43,0.86)0.84 (0.53,1.35)
  1. SNP, single-nucleotide polymorphism; OR, odds ratio; CI, confidence interval; IVW, inverse variance weighting; SHBG, sex hormones-binding globulin; IGF-1, insulin-like growth factor-1.

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  1. Xinxuan Li
  2. Yajing Zhou
  3. Shuai Yuan
  4. Xuan Zhou
  5. Lijuan Wang
  6. Jing Sun
  7. Lili Yu
  8. Jinghan Zhu
  9. Han Zhang
  10. Nan Yang
  11. Shuhui Dai
  12. Peige Song
  13. Susanna C Larsson
  14. Evropi Theodoratou
  15. Yiming Zhu
  16. Xue Li
(2022)
Genetically predicted high IGF-1 levels showed protective effects on COVID-19 susceptibility and hospitalization: a Mendelian randomisation study with data from 60 studies across 25 countries
eLife 11:e79720.
https://doi.org/10.7554/eLife.79720