Background
Methods
Study design and participants
Data collection and measurements
Questionnaire interview and physical examination
SCA measurements and outcome definition
Genotyping and quality control
Genome-wide association (GWA) analyses
Genome-wide interaction analyses
Statistical analyses
Functional annotation, gene mapping and gene set analysis
Results
Demographic characteristics and risk factors of SCA
Characteristics | PWH (n = 2583) | HIV-negative counterparts (n = 5321) | P valuec | ||||
---|---|---|---|---|---|---|---|
SCA+ | SCA− | P valuea | SCA+ | SCA− | P valueb | ||
Overall | 940 (36.4) | 1643 (63.6) | 1516 (28.5) | 3805 (71.5) | < 0.001d | ||
Age (years) | < 0.001 | < 0.001 | < 0.001 | ||||
18–29 | 71 (14.1) | 431 (85.9) | 36 (3.6) | 971 (96.4) | |||
30–44 | 195 (23.1) | 651 (76.9) | 238 (13.3) | 1546 (86.7) | |||
45–59 | 332 (43.9) | 424 (56.1) | 557 (36.2) | 980 (63.8) | |||
60–89 | 342 (71.4) | 137 (28.6) | 685 (69.0) | 308 (31.0) | |||
Male | 748 (37.1) | 1269 (62.9) | 0.167 | 1214 (31.5) | 2636 (68.5) | < 0.001 | 0.762 |
BMI (kg/m3) (n = 7900) | 0.017 | < 0.001 | < 0.001 | ||||
< 18.5 | 87 (33.7) | 171 (66.3) | 41 (14.2) | 247 (85.8) | |||
18.5–24.0 | 594 (35.0) | 1104 (65.0) | 573 (23.8) | 1830 (76.2) | |||
> 24 | 256 (41.1) | 367 (58.9) | 902 (34.3) | 1728 (65.7) | |||
Smoking status | < 0.001 | < 0.001 | < 0.001 | ||||
Never | 513 (32.8) | 1049 (67.2) | 688 (22.9) | 2316 (77.1) | |||
Previous | 144 (46.3) | 167 (53.7) | 272 (52.2) | 249 (47.8) | |||
Current | 283 (39.9) | 427 (60.1) | 556 (31.0) | 1240 (69.0) | |||
Regular alcohol use (n = 7888) | < 0.001 | < 0.001 | < 0.001 | ||||
Yes | 66 (55.0) | 54 (45.0) | 316 (44.1) | 400 (55.9) | |||
No | 874 (35.5) | 1589 (64.5) | 1196 (26.2) | 3393 (73.9) | |||
Dyslipidemia | 0.095 | < 0.001 | 0.487 | ||||
Yes | 565 (37.8) | 931 (62.2) | 894 (32.6) | 1846 (67.4) | |||
No | 370 (34.6) | 701 (65.4) | 621 (24.1) | 1958 (75.9) | |||
Total cholesterol (mmol/L, mean ± SD) | 4.80 ± 1.10 | 4.65 ± 1.00 | < 0.001 | 5.19 ± 1.03 | 5.03 ± 0.98 | < 0.001 | < 0.001 |
LDL cholesterol (mmol/L, mean ± SD) | 2.52 ± 0.81 | 2.44 ± 0.71 | 0.018 | 3.00 ± 0.86 | 2.86 ± 0.81 | < 0.001 | < 0.001 |
HDL cholesterol (mmol/L, median, IQR) | 1.0 (0.9, 1.3) | 1.0 (0.9, 1.2) | 0.905 | 1.1 (0.9, 1.3) | 1.1 (1.0, 1.4) | < 0.001 | < 0.001 |
Triglycerides (mmol/L, median, IQR) | 1.7 (1.2, 2.5) | 1.6 (1.1, 2.4) | 0.004 | 2.0 (1.3, 2.9) | 1.7 (1.1, 2.6) | < 0.001 | < 0.001 |
Abdominal obesity, measured as WHR (n = 7900) | 439 (41.7) | 614 (58.3) | < 0.001 | 974 (38.0) | 1589 (62.0) | < 0.001 | < 0.001 |
Hypertension | < 0.001 | < 0.001 | < 0.001 | ||||
Yes | 307 (53.9) | 262 (46.1) | 821 (46.8) | 934 (53.2) | |||
No | 633 (31.4) | 1381 (68.6) | 695 (19.5) | 2871 (80.5) | |||
Diabetes | < 0.001 | < 0.001 | < 0.001 | ||||
Yes | 109 (56.5) | 84 (43.5) | 307 (53.7) | 265 (46.3) | |||
No | 831 (34.8) | 1559 (65.2) | 1209 (25.5) | 3540 (74.5) | |||
Metabolic syndrome | < 0.001 | < 0.001 | < 0.001 | ||||
Yes | 337 (45.5) | 403 (54.5) | 796 (41.0) | 1147 (59.0) | |||
No | 600 (32.6) | 1239 (67.4) | 716 (21.3) | 2646 (78.7) | |||
Baseline CD4 (cells/μl) (n = 2563) | 0.024 | ||||||
≤ 200 | 177 (38.2) | 286 (61.8) | |||||
201–350 | 255 (40.0) | 382 (60.0) | |||||
> 350 | 500 (34.2) | 963 (65.8) | |||||
Nadir CD4 < 200 (cells/μl) (n = 2578) | 436 (37.8) | 719 (62.2) | 0.182 | ||||
Years since HIV diagnosis (median, IQR) | 1.2 (0.2, 4.4) | 1.6 (0.3, 4.5) | 0.059 |
Genetic variants associated with SCA
SNP | CHR | Position (GRCh37) | Gene | Location | MAF | Minor allele | Major allele | β valuea | Adjusted P valuea |
---|---|---|---|---|---|---|---|---|---|
All PWH | |||||||||
rs6772280 | 3 | 156,162,567 | KCNAB1 | Intronic | 0.109 | G | A | 0.07 | 3.66E−06 |
rs77741796 | 12 | 80,815,650 | PTPRQ | Intergenic | 0.054 | T | C | 0.09 | 5.83E−06 |
rs77595573 | 7 | 32,927,011 | KBTBD2 | Intronic | 0.115 | A | C | 0.07 | 6.19E−06 |
rs78012168 | 3 | 156,150,321 | KCNAB1 | Intronic | 0.094 | A | G | 0.07 | 7.98E−06 |
PWH under 45 years old | |||||||||
rs77741796 | 12 | 80,815,650 | PTPRQ | Intergenic | 0.054 | T | C | 0.14 | 2.20E−09 |
rs111815403 | 11 | 2,553,341 | KCNQ1 | Intronic | 0.061 | A | G | 0.11 | 1.50E−07 |
rs35812497 | 5 | 108,563,812 | FER;PJA2 | Intergenic | 0.089 | A | G | 0.09 | 3.27E−07 |
rs2507941 | 3 | 37,536,056 | ITGA9 | Synonymous | 0.064 | T | C | 0.11 | 3.85E−07 |
rs148420952 | 4 | 171,482,271 | LINC01612 | Intergenic | 0.051 | T | C | 0.12 | 3.94E−07 |
rs6762348 | 3 | 96,683,649 | EPHA6 | Intronic | 0.058 | G | A | 0.11 | 4.42E−07 |
rs62263680 | 3 | 96,627,491 | EPHA6 | Intronic | 0.057 | C | T | 0.12 | 4.50E−07 |
rs62262941 | 3 | 96,570,987 | EPHA6 | Intronic | 0.057 | C | T | 0.11 | 4.80E−07 |
rs10847321 | 12 | 127,782,099 | LINC02376 | Intergenic | 0.056 | A | C | 0.11 | 8.91E−07 |
PWH above 45 years old | |||||||||
rs11948504 | 5 | 166,997,147 | TENM2 | intronic | 0.068 | G | T | 0.16 | 1.11E−06 |
rs9851984 | 3 | 193,090,806 | ATP13A5 | intronic | 0.382 | G | A | − 0.07 | 6.51E−06 |
rs36130341 | 7 | 343,194 | FAM20C | Intergenic | 0.273 | A | G | 0.07 | 7.70E−06 |
rs35129955 | 4 | 181,960,818 | LINC00290 | Intergenic | 0.054 | C | T | 0.15 | 7.90E−06 |
rs2430722 | 12 | 15,122,111 | PDE6H | Intergenic | 0.255 | C | T | − 0.08 | 1.14E−05 |
rs6858162 | 4 | 40,555,674 | RBM47 | Intronic | 0.050 | T | C | 0.15 | 1.35E−05 |
Age-specific genetic variants associated with SCA
HIV-Gene interaction on SCA
SNP | CHR | Position (GRCh37) | MAF | Gene | Location | Minor allele | SNP × HIV | SNP | HIV | |||
---|---|---|---|---|---|---|---|---|---|---|---|---|
β valuea | Adjusted P valuea | β valuea | Adjusted P valuea | β valuea | Adjusted P valuea | |||||||
Among all participants | ||||||||||||
rs78012168 | 3 | 156,150,321 | 0.098 | KCNAB1 | Intronic | A | 0.09 | 7.49E−06 | − 0.1 | 1.69E−04 | 0.04 | 3.48E−05 |
rs1194716 | 10 | 54,196,773 | 0.199 | DKK1 | Intergenic | T | 0.06 | 1.17E−05 | − 0.08 | 4.74E−05 | 0.03 | 4.10E−03 |
rs4814734 | 20 | 1,889,477 | 0.333 | SIRPA | Intronic | T | 0.05 | 1.33E−05 | − 0.06 | 1.98E−04 | 0.02 | 8.50E−02 |
rs13096737 | 3 | 10,016,911 | 0.073 | EMC3 | Intronic | C | − 0.07 | 9.95E−04 | 0.14 | 5.38E−06 | 0.07 | 5.58E−13 |
rs2302786 | 3 | 9,979,660 | 0.199 | CRELD1 | Intronic | G | − 0.05 | 1.26E−03 | 0.09 | 8.71E−06 | 0.07 | 9.41E−13 |
rs3774207 | 3 | 9,985,656 | 0.200 | CRELD1 | Synonymous | T | − 0.04 | 2.20E−03 | 0.08 | 2.45E−05 | 0.07 | 1.91E−12 |
rs3755783 | 3 | 10,029,289 | 0.167 | EMC3 | Intronic | G | − 0.04 | 5.90E−03 | 0.09 | 6.36E−05 | 0.07 | 3.60E−12 |
rs6786636 | 3 | 10,045,703 | 0.170 | EMC3 | 3′-UTR | C | − 0.04 | 6.44E−03 | 0.09 | 4.89E−05 | 0.07 | 2.67E−12 |
rs3732968 | 3 | 10,013,273 | 0.149 | EMC3 | Intronic | G | − 0.04 | 1.72E−02 | 0.09 | 2.35E−04 | 0.06 | 1.63E−11 |
rs13146599 | 4 | 92,348,857 | 0.114 | CCSER1 | Intronic | A | − 0.04 | 2.21E−02 | 0.09 | 2.35E−04 | 0.06 | 1.63E−11 |
rs8058808 | 16 | 87,839,943 | 0.052 | SLC7A5 | Intergenic | A | − 0.05 | 3.45E−02 | 0.12 | 4.17E−04 | 0.06 | 1.94E−11 |
rs10856885 | 4 | 92,309,543 | 0.130 | CCSER1 | Intronic | C | − 0.03 | 4.29E−02 | 0.08 | 1.06E−03 | 0.06 | 5.64E−11 |
Among participants under 45 years old | ||||||||||||
rs9932976 | 16 | 6,505,665 | 0.119 | RBFOX1 | Intronic | C | − 0.09 | 3.47E−07 | 0.14 | 1.20E−08 | 0.1 | 1.38E−27 |
rs9938274 | 16 | 6,505,208 | 0.118 | RBFOX1 | Intronic | T | − 0.09 | 4.00E−07 | 0.14 | 1.67E−08 | 0.1 | 9.96E−28 |
rs1345439 | 16 | 48,751,012 | 0.133 | CBLN1 | Intergenic | A | 0.08 | 6.33E−07 | − 0.1 | 1.94E−05 | 0.06 | 6.29E−10 |
rs2507941 | 3 | 37,536,056 | 0.064 | ITGA9 | Synonymous | T | 0.12 | 8.42E−07 | − 0.14 | 7.37E−05 | 0.07 | 7.07E−15 |
rs6762348 | 3 | 96,683,649 | 0.058 | EPHA6 | Intronic | G | 0.12 | 1.93E−06 | − 0.12 | 2.80E−04 | 0.07 | 3.48E−15 |
rs62263680 | 3 | 96,627,491 | 0.057 | EPHA6 | Intronic | C | 0.12 | 2.45E−06 | − 0.12 | 3.71E−04 | 0.07 | 2.98E−15 |
rs62262941 | 3 | 96,570,987 | 0.057 | EPHA6 | Intronic | C | 0.12 | 3.13E−06 | − 0.12 | 4.77E−04 | 0.07 | 2.15E−15 |
rs77741796 | 12 | 80,815,650 | 0.054 | PTPRQ | Intergenic | T | 0.11 | 8.89E−06 | − 0.09 | 1.18E−02 | 0.07 | 2.67E−16 |
rs148420952 | 4 | 171,482,271 | 0.051 | LINC01612 | Intergenic | T | 0.11 | 4.05E−05 | − 0.09 | 1.21E−02 | 0.07 | 1.53E−16 |
rs35812497 | 5 | 108,563,812 | 0.089 | FER, PJA2 | Intergenic | A | 0.08 | 1.14E−04 | − 0.07 | 1.53E−02 | 0.07 | 1.04E−13 |
rs10847321 | 12 | 127,782,099 | 0.056 | LINC02376 | Intergenic | A | 0.09 | 1.69E−04 | − 0.07 | 3.06E−02 | 0.07 | 4.96E−16 |
rs111815403 | 11 | 2,553,341 | 0.061 | KCNQ1 | Intronic | A | 0.07 | 2.11E−03 | − 0.04 | 2.65E−01 | 0.07 | 1.65E−16 |
Among participants above 45 years old | ||||||||||||
rs11948504 | 5 | 166,997,147 | 0.068 | TENM2 | Intronic | G | 0.19 | 7.16E−06 | − 0.21 | 2.72E−04 | − 0.01 | 9.34E−01 |
rs2430722 | 12 | 15,122,111 | 0.255 | PDE6H | Intergenic | C | − 0.07 | 3.53E−03 | 0.08 | 1.37E−02 | 0.06 | 4.32E−03 |
rs35129955 | 4 | 181,960,818 | 0.054 | LINC00290 | Intergenic | C | 0.12 | 6.55E−03 | − 0.11 | 6.05E−02 | 0.01 | 6.22E−01 |
rs36130341 | 7 | 343,194 | 0.273 | FAM20C | Intergenic | A | 0.05 | 1.60E−02 | − 0.06 | 6.79E−02 | − 0.01 | 6.80E−01 |
rs6858162 | 4 | 40,555,674 | 0.050 | RBM47 | Intronic | T | 0.11 | 1.76E−02 | − 0.09 | 1.72E−01 | 0.01 | 5.00E−01 |
rs9851984 | 3 | 193,090,806 | 0.382 | ATP13A5 | Intronic | G | − 0.04 | 5.62E−02 | 0.03 | 3.18E−01 | 0.05 | 2.23E−02 |
Age-specific HIV-gene interactions on SCA
Gene interaction with potential risk factors of SCA among PWH
CHR | SNP | Position (GRCh37) | MAF | Gene | Location | Minor allele | SNP × covariate | SNP | Covariate | |||
---|---|---|---|---|---|---|---|---|---|---|---|---|
β valuea | P interaction | β valuea | P value | β valuea | P value | |||||||
SNP × alcohol interaction | ||||||||||||
6 | rs9375288 | 124,194,087 | 0.123 | NKAIN2 | Intronic | G | 0.09 | 2.31E−08 | 0.03 | 8.10E−02 | 0.01 | 7.70E−01 |
12 | rs77741796 | 80,815,650 | 0.054 | PTPRQ | Intergenic | T | 0.10 | 6.45E−06 | 0.03 | 2.31E−01 | − 0.01 | 7.68E−01 |
3 | rs6762348 | 96,683,649 | 0.058 | EPHA6 | Intronic | G | 0.10 | 2.23E−05 | − 0.01 | 7.37E−01 | − 0.01 | 8.61E–01 |
3 | rs62262941 | 96,570,987 | 0.057 | EPHA6 | Intronic | C | 0.10 | 3.40E−05 | − 0.01 | 8.26E−01 | − 0.01 | 8.90E−01 |
3 | rs62263680 | 96,627,491 | 0.057 | EPHA6 | Intronic | C | 0.10 | 3.83E−05 | − 0.01 | 8.22E−01 | − 0.01 | 8.81E−01 |
4 | rs148420952 | 171,482,271 | 0.051 | LINC01612 | Intergenic | T | 0.09 | 1.74E−04 | 0.01 | 9.23E−01 | − 0.01 | 8.86E−01 |
12 | rs10847321 | 127,782,099 | 0.056 | LINC02376 | Intergenic | A | 0.05 | 1.97E−02 | 0.01 | 9.53E−01 | 0.01 | 8.51E−01 |
SNP × tobacco interaction | ||||||||||||
9 | rs817856 | 110,118,754 | 0.115 | RAD23B | Intergenic | G | 0.39 | 1.03E−09 | − 0.02 | 2.15E−01 | − 0.04 | 1.81E−01 |
8 | rs78096022 | 132,359,092 | 0.107 | ADCY8 | Intergenic | T | 0.41 | 3.70E−09 | − 0.03 | 4.55E−02 | − 0.04 | 2.58E−01 |
20 | rs6513469 | 58,588,895 | 0.059 | CDH26 | 3′-UTR | C | 0.50 | 9.53E−09 | 0.01 | 7.63E−01 | − 0.03 | 3.73E−01 |
1 | rs17392147 | 9,060,210 | 0.054 | SLC2A7 | Intronic | C | 0.83 | 1.89E−08 | 0.02 | 4.43E−01 | 0.01 | 9.39E−01 |
5 | rs186333 | 23,202,461 | 0.074 | CDH12 | Intergenic | G | 0.43 | 2.70E−08 | − 0.01 | 6.68E−01 | − 0.02 | 5.47E−01 |
5 | rs78752139 | 103,593,227 | 0.092 | NUDT12 | Intergenic | T | 0.40 | 4.28E−08 | − 0.01 | 9.25E−01 | − 0.04 | 2.88E−01 |
11 | rs111815403 | 2,553,341 | 0.061 | KCNQ1 | Intronic | A | 0.22 | 3.67E−03 | 0.04 | 2.64E−02 | 0.01 | 8.74E−01 |
4 | rs148420952 | 171,482,271 | 0.051 | LINC01612 | Intergenic | T | − 0.24 | 1.39E−02 | 0.08 | 1.64E−04 | 0.06 | 4.87E−02 |
3 | rs2507941 | 37,536,056 | 0.064 | ITGA9 | Synonymous | T | 0.30 | 1.79E−02 | 0.05 | 7.73E−03 | 0.03 | 4.29E−01 |
SNP × BMI category interaction | ||||||||||||
3 | rs2507941 | 37,536,056 | 0.064 | ITGA9 | Synonymous | T | 0.12 | 1.87E−04 | − 0.21 | 5.03E−03 | 0.01 | 5.19E−01 |
12 | rs10847321 | 127,782,099 | 0.056 | LINC02376 | Intergenic | A | 0.11 | 1.48E−03 | − 0.20 | 1.01E−02 | 0.01 | 3.62E−01 |
11 | rs111815403 | 2,553,341 | 0.061 | KCNQ1 | Intronic | A | 0.10 | 2.91E−03 | − 0.16 | 3.41E−02 | 0.01 | 3.77E−01 |
4 | rs148420952 | 171,482,271 | 0.051 | LINC01612 | Intergenic | T | 0.08 | 1.69E−02 | − 0.11 | 1.50E−01 | 0.01 | 2.86E−01 |
5 | rs35812497 | 108,563,812 | 0.089 | FER, PJA2 | Intergenic | A | 0.06 | 3.58E−02 | − 0.09 | 1.46E−01 | 0.01 | 3.63E−01 |
3 | rs6762348 | 96,683,649 | 0.058 | EPHA6 | Intronic | G | 0.06 | 4.18E−02 | − 0.09 | 2.20E−01 | 0.01 | 2.24E−01 |
Association of GRS with SCA
Functional annotation, gene mapping and gene set analysis
Category | GeneSet | N | n | P-value | Adjusted P | Genes |
---|---|---|---|---|---|---|
PWH under 45 years old | ||||||
GO_bp | regulation of atrial cardiac muscle cell membrane repolarization | 8 | 2 | 4.75E−06 | 0.034 | KCNQ1, SCN5A |
GO_bp | atrial cardiac muscle cell membrane repolarization | 11 | 2 | 9.33E−06 | 0.034 | KCNQ1, SCN5A |
GO_mf | protein kinase A catalytic subunit binding | 13 | 2 | 1.32E−05 | 0.018 | KCNQ1, PJA2 |
GO_mf | protein kinase A regulatory subunit binding | 20 | 2 | 3.22E−05 | 0.018 | KCNQ1, PJA2 |
GO_mf | protein phosphatase 1 binding | 20 | 2 | 3.22E−05 | 0.018 | KCNQ1, FER |
GO_mf | protein kinase activity | 588 | 4 | 9.15E−05 | 0.038 | DCLK3, ACVR2B, EPHA6, FER |
HIV-negative participants under 45 years old | ||||||
GWAS catalog reported genes | Hyperopia | 6 | 2 | 1.09E−06 | 1.98E−03 | RBFOX1, LAMA2 |
GWAS catalog reported genes | Urinary albumin-to-creatinine ratio in non-diabetics | 19 | 2 | 1.24E−05 | 6.44E−03 | SOGA3, SOGA3, C6orf58 |
GWAS catalog reported genes | Spherical equivalent (joint analysis main effects and education interaction) | 20 | 2 | 1.38E−05 | 6.44E−03 | RBFOX1, LAMA2 |
GWAS catalog reported genes | Spherical equivalent or myopia (age of diagnosis) | 175 | 3 | 1.42E−05 | 6.44E−03 | RBFOX1, LAMA2, DPP6 |
GWAS catalog reported genes | Refractive error | 29 | 2 | 2.95E−05 | 1.07E−02 | RBFOX1, LAMA2 |
GWAS catalog reported genes | Waist-to-hip ratio adjusted for BMI | 403 | 3 | 1.69E−04 | 4.30E−02 | ECHDC1, SOGA3, SOGA3, C6orf58 |
GWAS catalog reported genes | Intracranial aneurysm | 72 | 2 | 1.84E−04 | 4.30E−02 | RBFOX1, CARHSP1 |
GWAS catalog reported genes | Myopia | 73 | 2 | 1.89E−04 | 4.30E−02 | RBFOX1, LAMA2 |