A Genetic Locus on Chromosome 2q24 Predicting Peripheral Neuropathy Risk in Type 2 Diabetes: Results From the ACCORD and BARI 2D Studies
Article Figures & Tables
Figures
- Figure 1
GWAS results. A: Manhattan plot. Each dot represents a polymorphism (SNP). The x-axis depicts each chromosome and the y-axis shows the negative log10 P value for association of each SNP with DPN. The red dotted line indicates the genome-wide significance threshold of P = 5 × 10−8; the gray dotted line indicates the notable genome-wide significance threshold of P = 1 × 10−6. B: QQ plot (inset). The black dashed line indicates the null hypothesis. The blue line represents the observed log10 P values corresponding to the expected P values. λ = 0.994.
- Figure 2
Characterization of locus 2q24. A: Regional association plot of locus 2q24. Variants are displayed ±2 Mbp upstream and downstream of the lead SNP (rs13417783). The x-axis depicts the chromosomal positions of the SNPs according to National Center for Biotechnology Information Build 37, and the y-axis depicts the −log10 P values for association of these SNPs with DPN in ACCORD. SNPs in strong LD with the lead SNP (purple) are marked in red (r2 > 0.8). The bottom panel depicts genes from the University of California, Santa Cruz (UCSC) Known Genes data set within the region. The locus zoom plot was generated using LocusZoom (Abecasis Laboratory, University of Michigan School of Public Health) through http://locuszoom.sph.umich.edu/genform.php?type=yourdata. The reference database was hg19/1000 Genomes Nov 2014 European. B: eQTL analysis of locus 2q24 showing the association between rs13417783 and tibial nerve–specific expression of neighboring genes. The eQTL analysis was conducted on data from the GTEx database (http://www.gtexportal.org/home/). Genes were those located within ±2 Mbp from the lead SNP rs13417783. *NES is the normalized effect size, i.e., the slope of the linear regression between minor (T) allele dosage and gene expression. This effect size is computed in a normalized space where magnitude has no direct biological interpretation. C: Tibial nerve–specific expression of AC019181.2 stratified by rs13417783 genotypes. D: Tibial nerve–specific expression of SCN2A stratified by rs13417783 genotypes. Box plots were generated in GTEx.
Tables
- Table 1
Characteristics of DPN case and control subjects
Baseline characteristic Discovery set (ACCORD) Validation set (BARI 2D) DPN case subjects (n = 4,384) DPN control subjects (n = 784) P value DPN case subjects (n = 791) DPN control subjects (n = 158) P value Female 1,538 (35.1) 289 (36.9) 0.34 204 (25.8) 51 (32.3) 0.09 Age (years) 63.2 ± 6.5 61.6 ± 6.4 <0.0001 63.33 ± 8.47 62.09 ± 9.29 0.10 T2D duration (years) 10.9 ± 7.5 9.1 ± 6.9 <0.0001 10.5 ± 8.38 9.06 ± 8.71 0.05 BMI (kg/m2) 33.2 ± 5.2 31.9 ± 4.8 <0.0001 31.8 ± 5.41 32.33 ± 5.97 0.27 Waist circumference (cm) 110.0 ± 12.9 105.3 ± 12.0 <0.0001 108.99 ± 13.08 108.42 ± 13.97 0.62 Height (cm) 171.7 ± 9.5 170.0 ± 9.4 <0.0001 NA NA NA HbA1c (%) 8.22 ± 0.93 8.11 ± 0.90 0.02 7.54 ± 1.54 7.66 ± 1.63 0.40 Fasting glucose (mmol/L) 9.93 ± 2.82 9.75 ± 2.76 0.09 NA NA NA SBP (mmHg) 135.2 ± 16.7 134.7 ± 16.4 0.42 131.65 ± 20.6 128.75 ± 16.32 0.05 DBP (mmHg) 74.1 ± 10.4 75.0 ± 10.7 0.03 73.82 ± 11.92 73.54 ± 11.22 0.78 LDL (mmol/L) 2.67 ± 0.84 2.68 ± 0.83 0.52 2.43 ± 0.83 2.59 ± 0.85 0.03 HDL (mmol/L) 1.04 ± 0.27 1.06 ± 0.29 0.0047 0.95 ± 0.23 0.98 ± 0.23 0.13 Women 1.16 ± 0.29 1.22 ± 0.29 0.0009 1.06 ± 0.24 1.02 ± 0.22 0.19 Men 0.97 ± 0.23 0.98 ± 0.23 0.54 0.91 ± 0.21 0.96 ± 0.24 0.02 Total cholesterol (mmol/L) 4.74 ± 1.05 4.76 ± 1.04 0.33 4.35 ± 1.05 4.56 ± 1.16 0.03 Triglycerides (mmol/L)† 1.95 (1.37–2.81) 1.91 (1.29–2.76) 0.14 1.76 (1.24–2.58) 1.90 (1.28–2.7) 0.46 eGFR (mL/min/1.73 m2) 87.8 ± 21.7 90.4 ± 20.4 0.0016 NA NA NA UACR (mg/mmol)† 1.4 (0.7–4.2) 1.1 (0.6–2.8) <0.0001 NA NA NA Previous CV event* 1,556 (35.5) 264 (33.7) 0.33 318 (40.2) 69 (43.7) 0.42 Report of retinopathy 439 (11.3) 40 (5.6) <0.0001 NA NA NA Current smoker 496 (11.3) 84 (10.7) 0.8 63 (8) 19 (12.1) 0.09 Previous smoker 2,194 (57.0) 390 (56.2) 0.8 456 (57.8) 88 (56.1) 0.69 Insulin therapy 1,598 (36.5) 220 (28.1) <0.0001 212 (26.8) 27 (17.1) 0.01 ACCORD Glycemia trial Standard 2,227 (50.8) 371 (47.3) 0.07 — — — Intensive 2,157 (49.2) 413 (52.7) — — — ACCORD BP trial 1,862 (42.5) 361 (46.1) 0.06 — — — Standard 926 (21.1) 182 (23.2) 0.81 — — — Intensive 936 (21.4) 179 (22.8) — — — ACCORD Lipid trial 2,522 (57.5) 423 (54.0) 0.06 — — — Fibrate 1,294 (29.5) 219 (27.9) 0.86 — — — Placebo 1,228 (28.0) 204 (26.0) — — — BARI 2D CV intervention Medical therapy — — — 398 (50.3) 67 (42.4) 0.07 Early revascularization — — — 393 (49.7) 91 (57.6) BARI 2D diabetic therapy Insulin provision — — — 394 (49.8) 71 (44.9) 0.26 Insulin sensitization — — — 397 (50.2) 87 (55.1) Except where noted, data are means ± SD for continuous variables and counts (%) for categorical data. BP, blood pressure; CV, cardiovascular; DBP, diastolic blood pressure; NA, not available; SBP, systolic blood pressure.
†Median (interquartile range). *Prior CV event: In ACCORD, this includes secondary prevention status or history of myocardial infarction, stroke, angina, and/or ischemic changes (electrocardiogram) on graded exercise tolerance test or positive imaging, coronary revascularization procedures, or other revascularization procedures at baseline; in BARI 2D, this includes history of myocardial infarction, congestive heart failure, stroke, or transient ischemic attack.
- Table 2
Top loci (P < 1 × 10−5) associated with DPN: effects in ACCORD and validation in BARI 2D
SNP Position‡ Closest gene MA** Discovery set (ACCORD) Validation set (BARI 2D) ACCORD + BARI 2D* MAF¶ 1000G MAF§ case subjects MAF§ control subjects OR (95% CI) P MAF case subjects MAF control subjects OR (95% CI) P OR (95% CI) P rs13417783 2:167629849 XIRP2 T 0.14 0.14 0.20 0.64 (0.55–0.74) 1.9 × 10−9 0.14 0.20 0.57 (0.41–0.80) 0.0009 0.63 (0.55–0.72) 7.9 × 10−12 rs12988669 2:240275570 HDAC4 C 0.15 0.16 0.20 0.71 (0.62–0.82) 2.7 × 10−6 0.16 0.13 1.22 (0.83–1.78) 0.32 0.76 (0.66–0.87) 5.1 × 10−5 rs60770880 3:8037416 LOC101–927394 A 0.21 0.21 0.26 0.75 (0.66–0.84) 5.0 × 10−6 0.20 0.21 0.93 (0.68–1.26) 0.62 0.77 (0.68–0.86) 1.0 × 10−5 rs11932946 4:45140214 GUF1 G 0.12 0.12 0.16 0.69 (0.59–0.82) 9.6 × 10−6 0.13 0.11 1.01 (0.68–1.49) 0.98 0.73 (0.63–0.85) 4.5 × 10−5 rs1202660 7:70658177 WBSCR17 T 0.22 0.20 0.25 0.74 (0.65–0.84) 6.2 × 10−6 0.23 0.26 0.81 (0.60–1.09) 0.16 0.75 (0.67–0.85) 2.5 × 10−6 rs13265430 8:4165607 CSMD1 A 0.09 0.09 0.13 0.64 (0.52–0.76) 1.0 × 10−6 0.11 0.09 1.35 (0.84–2.15) 0.21 0.70 (0.59–0.83) 4.3 × 10−5 rs2491019 10:70776987 KIAA1279 A 0.45 0.47 0.40 1.31 (1.17–1.47) 4.4 × 10−6 0.45 0.46 1.02 (0.79–1.32) 0.86 1.25 (1.13–1.39) 2.0 × 10−5 rs77494074 11:132794801 OPCML T 0.08 0.07 0.10 0.61 (0.50–0.74) 1.0 × 10−6 0.07 0.06 1.28 (0.71–2.29) 0.41 0.66 (0.54–0.79) 1.3 × 10−5 rs201655918 14:76791306 ESRRB C 0.28 0.26 0.32 0.75 (0.66–0.85) 6.9 × 10−6 0.30 0.24 1.41 (1.02–1.96) 0.04 0.81 (0.72–0.91) 5.3 × 10−4 rs11073752 15:88423051 NTRK3 C 0.33 0.32 0.38 0.76 (0.67–0.85) 2.1 × 10−6 0.33 0.36 0.80 (0.61–1.05) 0.11 0.76 (0.68–0.85) 6.5 × 10−7 rs9948095 18:12018665 IMPA2 C 0.14 0.15 0.20 0.71 (0.61–0.82) 3.6 × 10−6 0.14 0.16 0.88 (0.63–1.24) 0.46 0.73 (0.64–0.84) 5.4 × 10−6 rs10555080 (aka rs72397229) 19:32043170 THEG5 A NA 0.36 0.30 1.32 (1.17–1.49) 6.9 × 10−6 0.38 0.32 1.46 (1.10–1.94) 0.0098 1.34 (1.20–1.50) 2.6 × 10−7 rs34948558 21:42825856 MX1 A 0.28 0.27 0.32 0.76 (0.67–0.85) 4.7 × 10−6 0.30 0.31 1.01 (0.77–1.33) 0.95 0.79 (0.71–0.88) 3.0 × 10−5 In ACCORD, the primary model was adjusted by assignment to interventions, seven clinical center networks, and top three principal components. In BARI 2D, adjustments included assignment to interventions, country of origin, and top three principal components.
*Meta-analysis of results in the discovery and validation sets. ‡Position is chromosome:bp according to the National Center for Biotechnology Information assembly build GRCh37/hg19. **MA is minor or effect allele. §MAF in the discovery set is the average of minor allele frequencies in the two ACCORD genotyping sets (ANYSET and ACCSET). ¶MAF in 1000 Genomes Project Phase 3 European populations was derived from Ensembl GRCh37 Release 93 (http://grch37.ensembl.org/index.html).
- Table 3
Association between top loci and prevalent/incident DPN in ACCORD and BARI 2D
ACCORD BARI 2D N case/N control subjects OR (95% CI) HR (95% CI) N case/N control subjects OR (95% CI) HR (95% CI) Case vs. control subjects Prevalent 2,547/784 0.64 (0.55–0.75) — 518/158 0.59 (0.42–0.83) — Incident 1,837/784 0.65 (0.56–0.77) 0.80 (0.73–0.88) 271/158 0.59 (0.40–0.87) 0.69 (0.55–0.88) - Table 4
Association between low-frequency variants at 2q24 and DPN
Low-frequency variant Position Alleles* MAF r2‡ Univariable Multivariable† Low-frequency variant rs13417783 Low-frequency variant rs13417783 OR P OR P OR P OR P rs16852465 2:167524744 G/A 0.036 0.009 1.94 3.8E–04 0.64 1.9E–09 1.80 1.7E–03 0.66 2.1E–08 rs1509652 2:167589745 C/T 0.038 0.01 1.76 1.1E–03 0.64 1.9E–09 1.63 5.3E–03 0.66 2.0E–08 rs11884905 2:167611786 C/T 0.037 0.009 1.84 6.7E–04 0.64 1.9E–09 1.70 3.1E–03 0.66 2.1E–08 rs6721669 2:167636784 T/C 0.035 0.009 1.98 2.9E–04 0.64 1.9E–09 1.84 1.3E–03 0.66 2.2E–08 rs6755015 2:167666021 T/C 0.040 0.008 1.68 2.5E–03 0.64 1.9E–09 1.56 1.0E–02 0.66 1.6E–08 *Minor allele/major allele. †Results of regression models including one of the low-frequency variants along with rs13417783 as DPN predictors.
‡r2 with rs13417783.
- Table 5
Relative SCN2A abundance (in TPM) and corresponding percentiles across coding genes
Tissue Fraction of samples with detectable (TPM >0) SCN2A expression Mean SCN2A TPM (± SD) among coding genes in samples with TPM >0 Mean SCN2A percentile (± SD) among coding genes in samples with TPM >0 Hippocampus 123 of 123 18.8 ± 15.8 71.7 ± 14.9 DRG 21 of 21 18.1 ± 6.0 49.0 ± 6.6 Tibial nerve 413 of 414 2.0 ± 1.8 30.8 ± 5.7 Skeletal muscle 112 of 564 0.13 ± 0.08 22.8 ± 3.3
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