prospective evaluation of b-type natriuretic peptide concentrations and the risk of type 2 diabetes...
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Prospective Evaluation of B-type Natriuretic Peptide Concentrations and the Risk of Type 2 Diabetes in Women
B.M. Everett, N. Cook, D.I. Chasman, M.C. Magnone, M. Bobadilla, N. Rifai, P.M. Ridker, and A.D. Pradhan
March 2013
www.clinchem.org/content/59/3/557.full
© Copyright 2013 by the American Association for Clinical Chemistry
© Copyright 2009 by the American Association for Clinical Chemistry
IntroductionIntroduction
Natriuretic Peptides in Heart Failure Promote vasodilation, natriuresis and diuresis in
normal physiology Assays for the active form of the B-type natriuretic
peptide (BNP) and the inactive amino-terminal fragment of the peptide (NT-proBNP) are commercially available
Commonly used to diagnosis of heart failure in acute-care settings
© Copyright 2009 by the American Association for Clinical Chemistry
Natriuretic Peptides in Metabolism Natriuretic peptides play an important role in regulating
lipolysis in both humans and animals Several cross-sectional studies in humans have
reported inverse associations between natriuretic peptide levels and features of the metabolic syndrome, including
Body mass index Glucose concentrations Measures of insulin resistance Blood pressure
However, prospective studies of natriuretic peptides and incident type 2 diabetes (T2DM) are scarce and results have been inconsistent
IntroductionIntroduction
© Copyright 2009 by the American Association for Clinical Chemistry
To determine the correlations between plasma concentrations of natriuretic peptides and other circulating markers of metabolism and inflammation
To determine whether baseline concentrations of B-type natriuretic peptides associate with incident T2DM in a cohort of women followed prospectively for T2DM
To determine whether common genetic variants in the natriuretic peptide promoter region (NPPA-NPPB), which are known to affect B-type natriuretic peptide concentrations, also associate with incident T2DM
AimsAims
© Copyright 2009 by the American Association for Clinical Chemistry
Describe the strengths and weaknesses of evaluating the relationship between B-type natriuretic peptide concentrations and T2DM in a prospective as compared to a cross-sectional study.
Are these strengths and weaknesses more or less important when studying diabetes?
QuestionQuestion
© Copyright 2009 by the American Association for Clinical Chemistry
Laboratory Analysis
• Plasma NT-proBNP was measured using an electrochemiluminescent immunassay from Roche Diagnostics
• Plasma concentrations of a variety of metabolic, lipid, and inflammatory biomarkers were also measured
• DNA was genotyped using Illumina Infinium II platform. Included samples were successfully genotyped for 98% of assayed single nucleotide polymorphisms (SNPs) and did not deviate from Hardy-Weinberg
• 4 SNPs in natriuretic peptide A and B (NPPA-NPPB) region previously associated with natriuretic peptide levels, type 2 diabetes, and/or metabolic syndrome were identified from the literature: rs198358, rs5068, rs632793, rs198389
• rs198358 was directly genotyped, and estimated allele dose for remaining SNPs calculated using MACH (http://www.sph.umich.edu/csg/abecasis/mach/index.html)
Materials and Methods: Laboratory StudiesMaterials and Methods: Laboratory Studies
© Copyright 2009 by the American Association for Clinical Chemistry
Prospective association of NT-proBNP and T2DM 491 women with incident T2DM 561 women selected as the reference subcohort Correlations between NT-proBNP and other biomarkers were
analyzed in the reference subcohort of 561 women Cross-sectional association of genotype and NT-proBNP levels
Subset (n=458) of the 561 women selected as the reference subcohort who had genotyping information available
Correlations between NT-proBNP and other biomarkers were analyzed in the reference subcohort of 561 women
Prospective association of genotype and incident T2DM 1372 cases of incident T2DM in 22,607 women at risk
Materials and Methods: Study ParticipantsMaterials and Methods: Study Participants
© Copyright 2009 by the American Association for Clinical Chemistry
How do you determine which covariates to include in a statistical model testing the relationship between an exposure (e.g., NT-proBNP concentrations) and an outcome (e.g., T2DM)?
The minor allele frequency at each of the tested SNPs varies from approximately 6% to 40%.
At which SNP are you likely to have the most power to detect an association with either NT-proBNP concentrations or incident T2DM?
How should a null result at the lower frequency SNPs be interpreted?
QuestionsQuestions
© Copyright 2009 by the American Association for Clinical Chemistry
Correlations between NT-proBNP and other Correlations between NT-proBNP and other metabolic biomarkersmetabolic biomarkers
© Copyright 2009 by the American Association for Clinical Chemistry
Risk of incident T2DM by NT-proBNP Risk of incident T2DM by NT-proBNP concentration at baselineconcentration at baseline
© Copyright 2009 by the American Association for Clinical Chemistry
Genetic variants in Genetic variants in NPPA-NPPB NPPA-NPPB and NT-and NT-proBNP concentrationsproBNP concentrations
© Copyright 2009 by the American Association for Clinical Chemistry© Copyright 2009 by the American Association for Clinical Chemistry
Association between variants in Association between variants in NPPA-NPPA-NPPB NPPB and incident T2DMand incident T2DM
Table 4. Each of the four SNPs previously noted to be associated with either natriuretic peptide levels, metabolic syndrome traits, and/or type 2 diabetes were tested for association with incident type 2 diabetes in the Women’s Genome Health Study. For this analysis, 22,607 women of European ancestry without type 2 diabetes at baseline who had available genotyping information were followed for the development of incident type 2 diabetes. In total, 1372 women developed type 2 diabetes during follow up.
SNPPer-Allele Relative Risk (95% CI)
P-value
rs198359 0.94 (0.86-1.03) 0.18
rs5068 0.98 (0.83-1.16) 0.84
rs632793 0.91 (0.84-0.989) 0.026
rs198389 0.92 (0.85-0.995) 0.036
© Copyright 2009 by the American Association for Clinical Chemistry
What aspects of this study support a causal link between natriuretic peptide concentrations and type 2 diabetes?
What aspects of this study do not support such a link?
QuestionsQuestions
© Copyright 2009 by the American Association for Clinical Chemistry
NT-proBNP concentrations that are high, but still within the reference interval, associate with incident T2DM in a prospective study of initially healthy women
Authors observed a nearly 50% reduction in the risk of incident type 2 diabetes among women with NT-proBNP concentrations >117 ng/L, a concentration that is both within the reference interval and routinely observed in clinical practice
NT-proBNP concentrations correlate with fasting insulin levels in healthy women, even after adjusting for age and body mass index
Conclusions (1)Conclusions (1)
© Copyright 2009 by the American Association for Clinical Chemistry
Common variants in the NPPA-NPPB promoter region associate with a lower risk of T2DM
These same variants associate with increased plasma concentrations of NT-proBNP
The direction of their effect on the risk of T2DM is consistent with their direction of effect on NT-proBNP concentrations, and with the observation that increased NT-proBNP concentrations associate with lower T2DM risk
These prospective data, in combination with other studies in both humans and animals, support a causal role for the natriuretic peptide system in the development of type 2 diabetes
Conclusions (2)Conclusions (2)
© Copyright 2009 by the American Association for Clinical Chemistry
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