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Genetics/Genomes/Proteomics/Metabolomics

Phenotypic and Genetic Characterization of Lower LDL Cholesterol and Increased Type 2 Diabetes Risk in the UK Biobank

  1. Yann C. Klimentidis1,2⇑,
  2. Amit Arora1,
  3. Michelle Newell1,
  4. Jin Zhou1,
  5. Jose M. Ordovas3,4,
  6. Benjamin J. Renquist5 and
  7. Alexis C. Wood6
  1. 1Department of Epidemiology and Biostatistics, Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, AZ
  2. 2BIO5 Institute, University of Arizona, Tucson, AZ
  3. 3Nutrition and Genomics Laboratory, Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, MA
  4. 4Instituto Madrileño de Estudios Avanzados (IMDEA) Food Institute, Campus de Excelencia Internacional Universidad Autónoma de Madrid + Consejo Superior de Investigaciones Científicas, Madrid, Spain
  5. 5School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, AZ
  6. 6U.S. Department of Agriculture/Agricultural Research Service Children’s Nutrition Research Center, Baylor College of Medicine, Houston, TX
  1. Corresponding author: Yann C. Klimentidis, yann{at}email.arizona.edu
Diabetes 2020 Oct; 69(10): 2194-2205. https://doi.org/10.2337/db19-1134
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    Figure 1

    T2D prevalence, HbA1c, and BMI by circulating LDL-C deciles in the UK Biobank. T2D prevalence is shown as a percentage, with error bars corresponding to the Clopper-Pearson CI. Whisker plots show the median value (horizontal line in box), the 25th and 75th percentile delimited by the box, and the vertical lines extending to the 5th and 95th percentile.

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    Figure 2

    Plot of β-coefficients for circulating LDL-C vs. T2D for SNPs with opposite directions of effect on these two traits. β-Coefficients correspond to log-ORs for T2D, and SDs for circulating LDL-C. Shaded area corresponds to the 95% CI for the best fit regression line.

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    Figure 3

    Association of T2D-increasing allele at 31 identified SNPs with nine cardiometabolic traits, based on univariate analyses, and hierarchical clustering dendogram based on corresponding standardized effect sizes. WHR, waist-to-hip ratio.

Tables

  • Figures
  • Table 1

    List of replicated genetic loci in which all SNPs have P < 5E−5 for both circulating LDL-C and T2D and with opposite directions of effect, for UK Biobank LDL-C and DIAGRAM T2D

    UK Biobank LDL-C and DIAGRAM T2DGLGC
    Chrbp_minbp_maxNearest genesTop SNP-metaCCAmetaCCA-min PT2D βT2D PLDL βLDL PTop SNP-metaCCALDL PmetaCCA P
    1109,285,825109,285,825FNDC7-STXBP3rs121446586.7E−10−0.0958.3E−060.0287.0E−06rs121446581.7E−034.2E−07
    1109,843,746110,078,255SORT1-PSMA5rs562185862.0E−178−0.0598.1E−060.0952.6E−118rs176475436.3E−272.5E−32
    227,161,47628,246,841GCKRrs65476921.4E−194−0.0551.6E−170.0438.1E−113rs12603268.4E−101.3E−32
    243,452,18344,020,441THADArs1160970552.2E−150.181.5E−10−0.0341.7E−06rs558778051.1E−032.4E−29
    2121,306,440121,350,667LINC01101-GLI2rs170502722.0E−51−0.0313.5E−060.0266.4E−42rs8964998.9E−094.7E−12
    2234,508,963234,565,917UGT1A8rs27410388.5E−09−0.031.5E−050.0093.8E−05rs27410193.5E−062.5E−09
    312,058,24612,456,689PPARGrs170361701.8E−19−0.132.7E−060.0739.9E−15rs170363261.5E−081.2E−24
    3124,912,207129,301,874SLC12A8rs98735191.8E−16−0.0391.4E−090.0111.9E−08rs46793703.2E−042.7E−10
    3170,631,635170,743,747SLC2A2rs124967348.0E−180.052.5E−07−0.0204.5E−12rs74306724.2E−051.1E−15
    574,352,18075,042,913HMGCR-POC5rs343616.9E−322−0.058.7E−140.0543.3E−156rs77030513.0E−867.5E−118
    578,350,39078,385,845BHMT2rs5920521.7E−100.0311.1E−06−0.0081.3E−05rs5573023.0E−032.3E−07
    631,145,92031,372,569HLA-C/Brs360577351.4E−15−0.0376.7E−060.0162.3E−11rs77437612.5E−112.5E−10
    632,127,47733,514,567HLA-DQA1/B1rs31302761.8E−100.0313.8E−06−0.0094.4E−06rs92752213.6E−151.0E−23
    6126,629,425127,167,072CENPWrs93884903.2E−29−0.0494.5E−140.0153.2E−15rs93884903.8E−038.9E−15
    744,585,05244,709,372NPC1L1-DDX56rs20084282.9E−780.0314.8E−05−0.0384.5E−63rs2173866.3E−224.3E−23
    7100,266,081100,414,386GIGYF1-POP7-EPOrs2217932.5E−24−0.0471.9E−050.0296.7E−20rs5065974.8E−043.5E−08
    89,168,1469,740,317PPP1R3Brs99872891.6E−880.0663.9E−09−0.0571.1E−65rs99872891.4E−271.4E−36
    1064,988,93165,340,897REEP3rs38473268.4E−15−0.0281.3E−050.0129.2E−11rs127752311.1E−036.7E−06
    10101,900,579102,039,463ERLIN1-CWF19L1rs356147922.8E−150.0311.9E−06−0.0122.2E−10rs3691365331.8E−038.5E−08
    1165,422,85365,604,195OVOL1-SNX32rs343810091.2E−090.0372.3E−05−0.0122.8E−06rs38147074.3E−046.5E−08
    1250,881,14850,987,378DIP2Brs73168643.3E−11−0.0294.6E−050.0116.7E−08rs108760411.1E−061.2E−06
    12121,435,778123,891,209HNF1A-OASLrs122318068.5E−17−0.058.0E−080.0181.4E−10rs71316964.4E−061.4E−15
    1562,383,15563,314,519C2CD4A/Brs18814152.8E−170.0474.7E−13−0.0081.8E−05rs45021561.1E−045.0E−14
    1729,628,54929,749,444NF1-EVI2Ars75025569.7E−190.0325.3E−07−0.0142.8E−13rs11295065.8E−069.2E−08
    1746,044,03146,114,620COPZ2rs129358903.0E−17−0.0326.6E−060.0156.2E−13rs116512753.6E−032.4E−07
    1919,320,82519,793,545TM6SF2rs591487999.9E−324−0.0543.4E−080.0771.4E−162rs104019694.6E−611.6E−86
    1945,324,75645,428,234APOErs101194.9E−420.0433.5E−09−0.0243.1E−31rs20756500.0E+000.0E+00
    1946,123,92946,314,504GIPRrs22386892.0E−33−0.051.3E−140.0179.4E−19rs104226011.9E−093.4E−22
    2042,958,76843,042,364HNF4Ars18009615.3E−72−0.163.2E−200.0761.8E−42rs18009615.2E−117.1E−31
    2218,415,15818,486,514MICAL3rs59929283.6E−110.0353.1E−06−0.0117.9E−07rs72866073.4E−052.4E−08
    2244,324,73044,394,402PNPLA3rs7384084.6E−19−0.0491.8E−100.0147.1E−10rs7384082.9E−051.9E−11
    • β-Coefficients refer to the SNP with the lowest P value for each trait in the respective region. The minimum univariate P value for LDL-C in GLGC summary statistics as well as the top SNP and P value of the top metaCCA SNP for the region discovered in UK Biobank is also shown. bp_min and bp_max are the minimum and maximum base pair position for which all SNPs have P < 5E−5 for LDL-C and T2D, with opposite directions of effect, and with metaCCA P < 5E−8. Human build GRCh37/hg19; β-coefficients correspond to log-ORs for T2D and SDs for LDL-C. P values from GLGC LDL-C associations are for SNPs showing opposite direction of association with T2D (DIAGRAM). Chr, chromosome.

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Phenotypic and Genetic Characterization of Lower LDL Cholesterol and Increased Type 2 Diabetes Risk in the UK Biobank
Yann C. Klimentidis, Amit Arora, Michelle Newell, Jin Zhou, Jose M. Ordovas, Benjamin J. Renquist, Alexis C. Wood
Diabetes Oct 2020, 69 (10) 2194-2205; DOI: 10.2337/db19-1134

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Phenotypic and Genetic Characterization of Lower LDL Cholesterol and Increased Type 2 Diabetes Risk in the UK Biobank
Yann C. Klimentidis, Amit Arora, Michelle Newell, Jin Zhou, Jose M. Ordovas, Benjamin J. Renquist, Alexis C. Wood
Diabetes Oct 2020, 69 (10) 2194-2205; DOI: 10.2337/db19-1134
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