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Does the Common Type 2 Diabetes-Susceptibility Variant in the MTNR1B Gene Matter for Glycemic Control Among Patients on Antidiabetic Pharmacotherapy?

      To The Editor:
      The variant rs10830963 (G risk allele) in the melatonin receptor 1B (MTNR1B) gene increases the risk of type 2 diabetes.
      • Lyssenko V.
      • Nagorny C.L.
      • Erdos M.R.
      • et al.
      Common variant in MTNR1B associated with increased risk of type 2 diabetes and impaired early insulin secretion.
      Here, we investigated whether the G risk allele is associated with poorer glycemic control among patients with type 2 diabetes on antidiabetic pharmacotherapy.
      Type 2 diabetes was confirmed either by a validated algorithm based on self-reported disease, medication, and diagnosis of diabetes in medical history
      • Eastwood S.V.
      • Mathur R.
      • Atkinson M.
      • et al.
      Algorithms for the capture and adjudication of prevalent and incident diabetes in UK Biobank.
      or hemoglobin (Hb) A1c level ≥6.5%.
      • Nathan D.M.
      • Balkau B.
      • Bonora E.
      • et al.
      International Expert Committee
      International Expert Committee report on the role of the A1c assay in the diagnosis of diabetes.
      Following exclusion (missing data on HbA1c and covariates, HbA1c z-values > 3 and < –3, and genetically related participants), 8979 White patients with type 2 diabetes were available for analysis. Data on subjects' antidiabetic pharmacotherapy was taken from the UK Biobank verbal interview.
      The MTNR1B rs10830963 genotype (chromosome 11, intron variant) was directly genotyped by the Affymetrix UK Biobank Lung Exome Evaluation Axiom array (Thermo Fisher Scientific, Santa Clara, California) or the Applied Biosystems UK Biobank Axiom array (Thermo Scientific). Quality control and imputation using the Haplotype Reference Consortium, UK10K, and 1000 Genomes phase 3 reference panels were conducted centrally. Testing for Hardy-Weinberg equilibrium revealed that the single nucleotide polymorphism did not deviate from the expected genotype proportion.
      HbA1C values, measured by Bio-Rad VARIANT II TURBO HbA1c analyzer (Bio-Rad, Hercules, California), were naturally log transformed before analysis. We assumed additive genetic effects for all analyses. All analyses were performed with SPSS 24.0 (SPSS Statistics, IBM, Chicago, Illinois) and, if not otherwise specified, adjusted for participants’ age at UK Biobank investigation, sex, Townsend index reflecting socioeconomic status, body mass index, hypertension status, smoking status, level of physical activity, sleep duration, age at diagnosis of type 2 diabetes, number of prescribed antidiabetic drugs, the region of the assessment center, and principal genetic components (first 10 columns).
      Cohort characteristics are given in the Table. HbA1C values did not differ between carriers and noncarriers of the MTNR1B risk variant. The American Diabetes Association recommends an HbA1C target <7.0% for patients with diabetes on antidiabetic treatment.
      American Diabetes Association
      Standards of medical care in diabetes: 2009.
      As suggested by logistic regression, the odds of having an HbA1C less than 7%—observed among 52.4%—did not differ between noncarriers (reference group) and carriers of the G risk allele (fully-adjusted odds ratio [OR]; 95% CI: CG/GC, 1.03 [0.94,1.12]; and GG, 1.04 [0.89,1.22]). Insulin treatment is recommended in patients with type 2 diabetes exhibiting a secondary failure to oral antidiabetic treatment.
      • Efendic S.
      • Alvarsson M.
      • Brismar K.
      • Wagner H.
      Pathophysiology and treatment of patients with type 2 diabetes exhibiting failure to oral drugs.
      Given the association of the MTNR1B risk variant with type 2 diabetes,
      • Lyssenko V.
      • Nagorny C.L.
      • Erdos M.R.
      • et al.
      Common variant in MTNR1B associated with increased risk of type 2 diabetes and impaired early insulin secretion.
      it could also be hypothesized that carriers may exhibit a higher risk of requiring insulin treatment. However, in the current study, type 2 diabetes carriers of the G risk allele did not exhibit higher odds of being treated with insulin compared with noncarriers (fully adjusted OR [95%]: CG/GC, 0.91 [0.82,1.02]; and GG, 0.91[0.75,1.10]).
      TableCohort Characteristics
      CharacteristicMTNR1B genotype (G=type 2 diabetes risk allele)P
      CCCG/GCGG
      Number of subjects, % full cohort4564 (50.8)3681 (41.0)734 (8.2)--
      HbA1c, %7.13 (1.10)7.12 (1.06)7.14 (1.10)0.989
      P value derived from Kruskal-Wallis.
      ln HbA1c, %1.953 (0.002)1.952 (0.002)1.955 (0.005)0.852
      P value and estimated marginal means derived from univariate analysis of variance (ANOVA).
      ln HbA1c, %1.953 (0.002)1.952 (0.002)1.956 (0.005)0.789
      P value and estimated marginal means derived from analysis of covariance (ANCOVA) adjusted for participants’ age at UK Biobank investigation, sex, Townsend index reflecting socioeconomic status, body mass index (<25 vs ≥25 and <30 vs ≥30 kg/m2), hypertension status, smoking status (current/previous vs never), level of physical activity (divided into low to moderate vs high level of physical activity), sleep duration (<7 hours per day vs 7 to 8 hours per day vs >8 hours per day), age at diagnosis of type 2 diabetes, number of prescribed antidiabetic drugs (1 vs 2 vs 3 or more), the region of the assessment center, and principal genetic components (first 10 columns).
      Age at investigation, years60.7 (6.4)60.7 (6.5)60.9 (6.2)0.873
      P value derived from Kruskal-Wallis.
      Age at diabetes diagnosis, years52.8 (9.2)52.5 (9.7)52.9 (9.3)0.552
      P value derived from Kruskal-Wallis.
      Male/female, %34.0/66.034.1/65.932.6/67.30.721
      P value derived from χ2.
      Region of UKB assessment center0.129
      P value derived from χ2.
       England, %88.388.988.8
       Scotland, %4.44.95.7
       Wales, %7.36.25.4
       Townsend index–0.83 (3.29)–0.69 (3.29)–0.63 (3.26)0.045
      P value derived from Kruskal-Wallis.
      BMI, kg/m2
       <25, %8.39.47.40.192
      P value derived from χ2.
       ≥25 and <30, %31.432.232.3
       ≥30, %60.358.460.4
       Hypertension, %59.560.962.90.135
      P value derived from χ2.
      Smoking status
       Never, %39.942.842.60.021
      P value derived from χ2.
       Previous/current, %60.157.257.4
      Level of physical activity
       Low/moderate, %73.471.871.00.152
      P value derived from χ2.
       High, %26.628.229.0
      Habitual sleep duration per day
       ≤6 hours, %26.426.728.60.404
      P value derived from χ2.
       7 to 8 hours, %59.858.458.3
       ≥9 hours, %13.814.813.1
      Antidiabetic administrations
       Metformin, %83.784.084.20.881
      P value derived from χ2.
       Sulfonylurea, %32.333.131.60.640
      P value derived from χ2.
       Glitazone, %12.511.611.60.429
      P value derived from χ2.
       Meglitinide, %0.60.71.20.187
      P value derived from χ2.
       Other oral antidiabetics, %0.30.30.10.673
      P value derived from χ2.
       Insulin, %21.319.919.80.223
      P value derived from χ2.
      Number of prescribed antidiabetic drugs
       1, %56.557.158.00.830
      P value derived from χ2.
       2, %36.536.535.6
       3 or more, %6.86.46.3
      Mean (standard deviation [SD]) is shown unless otherwise stated.
      a P value derived from Kruskal-Wallis.
      b P value and estimated marginal means derived from univariate analysis of variance (ANOVA).
      c P value and estimated marginal means derived from analysis of covariance (ANCOVA) adjusted for participants’ age at UK Biobank investigation, sex, Townsend index reflecting socioeconomic status, body mass index (<25 vs ≥25 and <30 vs ≥30 kg/m2), hypertension status, smoking status (current/previous vs never), level of physical activity (divided into low to moderate vs high level of physical activity), sleep duration (<7 hours per day vs 7 to 8 hours per day vs >8 hours per day), age at diagnosis of type 2 diabetes, number of prescribed antidiabetic drugs (1 vs 2 vs 3 or more), the region of the assessment center, and principal genetic components (first 10 columns).
      d P value derived from χ2.
      Patients with type 2 diabetes carrying a common type 2 diabetes susceptibility variant in the MTNR1B gene (rs10830963) did not exhibit clinically relevant signs of more inadequate long-term glycemic control than noncarriers, as measured by HbA1C. Indeed, the observed descriptive difference in HbA1C between carriers and noncarriers appears negligible from a clinical perspective (Table). By comparison, the glucose-lowering drug metformin lowers HbA1C by 1.5% to 2.0% among patients with type 2 diabetes.
      Metformin: some background information.
      Our results should be seen as hypothesis-generating associations only, considering its sample size.

      Acknowledgment

      This research has been conducted using the UK Biobank Resource under Project Number 43015.

      References

        • Lyssenko V.
        • Nagorny C.L.
        • Erdos M.R.
        • et al.
        Common variant in MTNR1B associated with increased risk of type 2 diabetes and impaired early insulin secretion.
        Nat Genet. 2009; 41: 82-88
        • Eastwood S.V.
        • Mathur R.
        • Atkinson M.
        • et al.
        Algorithms for the capture and adjudication of prevalent and incident diabetes in UK Biobank.
        PLoS One. 2016; 11: e0162388
        • Nathan D.M.
        • Balkau B.
        • Bonora E.
        • et al.
        • International Expert Committee
        International Expert Committee report on the role of the A1c assay in the diagnosis of diabetes.
        Diabetes Care. 2009; 32: 1327-1334
        • American Diabetes Association
        Standards of medical care in diabetes: 2009.
        Diabetes Care. 2009; 32: S13-S61
        • Efendic S.
        • Alvarsson M.
        • Brismar K.
        • Wagner H.
        Pathophysiology and treatment of patients with type 2 diabetes exhibiting failure to oral drugs.
        Acta Physiol (Oxf). 2008; 192: 117-125
      1. Metformin: some background information.
        (Available at:)