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Complications

A Genetic Locus on Chromosome 2q24 Predicting Peripheral Neuropathy Risk in Type 2 Diabetes: Results From the ACCORD and BARI 2D Studies

  1. Yaling Tang1,2,
  2. Petra A. Lenzini3,
  3. Rodica Pop-Busui4,
  4. Pradipta R. Ray5,
  5. Hannah Campbell3,6,
  6. Bruce A. Perkins7,
  7. Brian Callaghan8,
  8. Michael J. Wagner9,
  9. Alison A. Motsinger-Reif10,
  10. John B. Buse11,
  11. Theodore J. Price5,
  12. Josyf C. Mychaleckyj12,
  13. Sharon Cresci3,6,
  14. Hetal Shah1,2⇑ and
  15. Alessandro Doria1,2⇑
  1. 1Research Division, Joslin Diabetes Center, Boston, MA
  2. 2Department of Medicine, Harvard Medical School, Boston, MA
  3. 3Department of Genetics, Washington University School of Medicine, St. Louis, MO
  4. 4Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, MI
  5. 5School of Behavioral and Brain Sciences and Center for Advanced Pain Studies, The University of Texas at Dallas, Richardson, TX
  6. 6Department of Medicine, Washington University School of Medicine, St. Louis, MO
  7. 7Leadership Sinai Centre for Diabetes, Sinai Health System, and Division of Endocrinology and Metabolism, University of Toronto, Toronto, Ontario, Canada
  8. 8Department of Neurology, University of Michigan, Ann Arbor, MI
  9. 9Center for Pharmacogenomics and Individualized Therapy, University of North Carolina at Chapel Hill, Chapel Hill, NC
  10. 10Bioinformatics Research Center, and Department of Statistics, North Carolina State University, Raleigh, NC
  11. 11Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC
  12. 12Center for Public Health Genomics, University of Virginia, Charlottesville, VA
  1. Corresponding authors: Hetal Shah, hetal.shah{at}joslin.harvard.edu, and Alessandro Doria, alessandro.doria{at}joslin.harvard.edu
  1. H.S. and A.D. contributed equally to this work and are co-senior authors.

Diabetes 2019 Aug; 68(8): 1649-1662. https://doi.org/10.2337/db19-0109
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  • Figure 1
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    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
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    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

  • Figures
  • Table 1

    Characteristics of DPN case and control subjects

    Baseline characteristicDiscovery set (ACCORD)Validation set (BARI 2D)
    DPN case subjects
(n = 4,384)DPN control subjects
(n = 784)P valueDPN case subjects
(n = 791)DPN control subjects
(n = 158)P value
    Female1,538 (35.1)289 (36.9)0.34204 (25.8)51 (32.3)0.09
    Age (years)63.2 ± 6.561.6 ± 6.4<0.000163.33 ± 8.4762.09 ± 9.290.10
    T2D duration (years)10.9 ± 7.59.1 ± 6.9<0.000110.5 ± 8.389.06 ± 8.710.05
    BMI (kg/m2)33.2 ± 5.231.9 ± 4.8<0.000131.8 ± 5.4132.33 ± 5.970.27
    Waist circumference (cm)110.0 ± 12.9105.3 ± 12.0<0.0001108.99 ± 13.08108.42 ± 13.970.62
    Height (cm)171.7 ± 9.5170.0 ± 9.4<0.0001NANANA
    HbA1c (%)8.22 ± 0.938.11 ± 0.900.027.54 ± 1.547.66 ± 1.630.40
    Fasting glucose (mmol/L)9.93 ± 2.829.75 ± 2.760.09NANANA
    SBP (mmHg)135.2 ± 16.7134.7 ± 16.40.42131.65 ± 20.6128.75 ± 16.320.05
    DBP (mmHg)74.1 ± 10.475.0 ± 10.70.0373.82 ± 11.9273.54 ± 11.220.78
    LDL (mmol/L)2.67 ± 0.842.68 ± 0.830.522.43 ± 0.832.59 ± 0.850.03
    HDL (mmol/L)1.04 ± 0.271.06 ± 0.290.00470.95 ± 0.230.98 ± 0.230.13
     Women1.16 ± 0.291.22 ± 0.290.00091.06 ± 0.241.02 ± 0.220.19
     Men0.97 ± 0.230.98 ± 0.230.540.91 ± 0.210.96 ± 0.240.02
    Total cholesterol (mmol/L)4.74 ± 1.054.76 ± 1.040.334.35 ± 1.054.56 ± 1.160.03
    Triglycerides (mmol/L)†1.95 (1.37–2.81)1.91 (1.29–2.76)0.141.76 (1.24–2.58)1.90 (1.28–2.7)0.46
    eGFR (mL/min/1.73 m2)87.8 ± 21.790.4 ± 20.40.0016NANANA
    UACR (mg/mmol)†1.4 (0.7–4.2)1.1 (0.6–2.8)<0.0001NANANA
    Previous CV event*1,556 (35.5)264 (33.7)0.33318 (40.2)69 (43.7)0.42
    Report of retinopathy439 (11.3)40 (5.6)<0.0001NANANA
    Current smoker496 (11.3)84 (10.7)0.863 (8)19 (12.1)0.09
    Previous smoker2,194 (57.0)390 (56.2)0.8456 (57.8)88 (56.1)0.69
    Insulin therapy1,598 (36.5)220 (28.1)<0.0001212 (26.8)27 (17.1)0.01
    ACCORD Glycemia trial
     Standard2,227 (50.8)371 (47.3)0.07———
     Intensive2,157 (49.2)413 (52.7)———
    ACCORD BP trial1,862 (42.5)361 (46.1)0.06———
     Standard926 (21.1)182 (23.2)0.81———
     Intensive936 (21.4)179 (22.8)———
    ACCORD Lipid trial2,522 (57.5)423 (54.0)0.06———
     Fibrate1,294 (29.5)219 (27.9)0.86———
     Placebo1,228 (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

    SNPPosition‡Closest geneMA**Discovery set (ACCORD)Validation set (BARI 2D)ACCORD + BARI 2D*
    MAF¶ 1000GMAF§ case subjectsMAF§ control subjectsOR (95% CI)PMAF case subjectsMAF control subjectsOR (95% CI)POR (95% CI)P
    rs134177832:167629849XIRP2T0.140.140.200.64 (0.55–0.74)1.9 × 10−90.140.200.57 (0.41–0.80)0.00090.63 (0.55–0.72)7.9 × 10−12
    rs129886692:240275570HDAC4C0.150.160.200.71 (0.62–0.82)2.7 × 10−60.160.131.22 (0.83–1.78)0.320.76 (0.66–0.87)5.1 × 10−5
    rs607708803:8037416LOC101–927394A0.210.210.260.75 (0.66–0.84)5.0 × 10−60.200.210.93 (0.68–1.26)0.620.77 (0.68–0.86)1.0 × 10−5
    rs119329464:45140214GUF1G0.120.120.160.69 (0.59–0.82)9.6 × 10−60.130.111.01 (0.68–1.49)0.980.73 (0.63–0.85)4.5 × 10−5
    rs12026607:70658177WBSCR17T0.220.200.250.74 (0.65–0.84)6.2 × 10−60.230.260.81 (0.60–1.09)0.160.75 (0.67–0.85)2.5 × 10−6
    rs132654308:4165607CSMD1A0.090.090.130.64 (0.52–0.76)1.0 × 10−60.110.091.35 (0.84–2.15)0.210.70 (0.59–0.83)4.3 × 10−5
    rs249101910:70776987KIAA1279A0.450.470.401.31 (1.17–1.47)4.4 × 10−60.450.461.02 (0.79–1.32)0.861.25 (1.13–1.39)2.0 × 10−5
    rs7749407411:132794801OPCMLT0.080.070.100.61 (0.50–0.74)1.0 × 10−60.070.061.28 (0.71–2.29)0.410.66 (0.54–0.79)1.3 × 10−5
    rs20165591814:76791306ESRRBC0.280.260.320.75 (0.66–0.85)6.9 × 10−60.300.241.41 (1.02–1.96)0.040.81 (0.72–0.91)5.3 × 10−4
    rs1107375215:88423051NTRK3C0.330.320.380.76 (0.67–0.85)2.1 × 10−60.330.360.80 (0.61–1.05)0.110.76 (0.68–0.85)6.5 × 10−7
    rs994809518:12018665IMPA2C0.140.150.200.71 (0.61–0.82)3.6 × 10−60.140.160.88 (0.63–1.24)0.460.73 (0.64–0.84)5.4 × 10−6
    rs10555080 (aka rs72397229)19:32043170THEG5ANA0.360.301.32 (1.17–1.49)6.9 × 10−60.380.321.46 (1.10–1.94)0.00981.34 (1.20–1.50)2.6 × 10−7
    rs3494855821:42825856MX1A0.280.270.320.76 (0.67–0.85)4.7 × 10−60.300.311.01 (0.77–1.33)0.950.79 (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

    ACCORDBARI 2D
    N case/N control subjectsOR (95% CI)HR (95% CI)N case/N control subjectsOR (95% CI)HR (95% CI)
    Case vs. control subjects
     Prevalent 2,547/7840.64 (0.55–0.75)—518/1580.59 (0.42–0.83)—
     Incident 1,837/7840.65 (0.56–0.77)0.80 (0.73–0.88)271/1580.59 (0.40–0.87)0.69 (0.55–0.88)
  • Table 4

    Association between low-frequency variants at 2q24 and DPN

    Low-frequency variantPositionAlleles*MAFr2‡UnivariableMultivariable†
    Low-frequency variantrs13417783Low-frequency variantrs13417783
    ORPORPORPORP
    rs168524652:167524744G/A0.0360.0091.943.8E–040.641.9E–091.801.7E–030.662.1E–08
    rs15096522:167589745C/T0.0380.011.761.1E–030.641.9E–091.635.3E–030.662.0E–08
    rs118849052:167611786C/T0.0370.0091.846.7E–040.641.9E–091.703.1E–030.662.1E–08
    rs67216692:167636784T/C0.0350.0091.982.9E–040.641.9E–091.841.3E–030.662.2E–08
    rs67550152:167666021T/C0.0400.0081.682.5E–030.641.9E–091.561.0E–020.661.6E–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

    TissueFraction of samples with detectable (TPM >0) SCN2A expressionMean SCN2A TPM (± SD) among coding genes in samples with TPM >0Mean SCN2A percentile (± SD) among coding genes in samples with TPM >0
    Hippocampus123 of 12318.8 ± 15.871.7 ± 14.9
    DRG21 of 2118.1 ± 6.049.0 ± 6.6
    Tibial nerve413 of 4142.0 ± 1.830.8 ± 5.7
    Skeletal muscle112 of 5640.13 ± 0.0822.8 ± 3.3
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A Genetic Locus on Chromosome 2q24 Predicting Peripheral Neuropathy Risk in Type 2 Diabetes: Results From the ACCORD and BARI 2D Studies
Yaling Tang, Petra A. Lenzini, Rodica Pop-Busui, Pradipta R. Ray, Hannah Campbell, Bruce A. Perkins, Brian Callaghan, Michael J. Wagner, Alison A. Motsinger-Reif, John B. Buse, Theodore J. Price, Josyf C. Mychaleckyj, Sharon Cresci, Hetal Shah, Alessandro Doria
Diabetes Aug 2019, 68 (8) 1649-1662; DOI: 10.2337/db19-0109

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A Genetic Locus on Chromosome 2q24 Predicting Peripheral Neuropathy Risk in Type 2 Diabetes: Results From the ACCORD and BARI 2D Studies
Yaling Tang, Petra A. Lenzini, Rodica Pop-Busui, Pradipta R. Ray, Hannah Campbell, Bruce A. Perkins, Brian Callaghan, Michael J. Wagner, Alison A. Motsinger-Reif, John B. Buse, Theodore J. Price, Josyf C. Mychaleckyj, Sharon Cresci, Hetal Shah, Alessandro Doria
Diabetes Aug 2019, 68 (8) 1649-1662; DOI: 10.2337/db19-0109
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