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A Genetic Investigation of the Ectonucleotide Pyrophosphatase/Phosphodiesterase 1 (ENPP1) Variants with Diabetes and Glycemia Traits in Afro-Caribbean Men

Leak, Tennille S (2011) A Genetic Investigation of the Ectonucleotide Pyrophosphatase/Phosphodiesterase 1 (ENPP1) Variants with Diabetes and Glycemia Traits in Afro-Caribbean Men. Master's Thesis, University of Pittsburgh.

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    Abstract

    Ectonucleotide pyrophosphatase/phosphodiesterase 1, which downregulates insulin signaling by inhibiting insulin-receptor tyrosine kinase activity, is encoded by the ENPP1 gene. Common variants in ENPP1 have been associated with body mass index (BMI), diabetes and glycemia related traits in populations of European Ancestry, but data in African ancestry populations are sparse. Our objective was to evaluate common ENPP1 variants for association with diabetes and glycemia related traits in a high risk Afro-Caribbean population. Thirty-four single nucleotide polymorphisms (SNPs) based on pair-wise tagging (r2 > 0.80; MAF > 0.05) were successfully genotyped in 380 cases and 1,455 controls without diabetes. Associations with BMI, fasting glucose, fasting insulin and HOMA-IR were also analyzed in non-diabetic controls. The most interesting association was observed between rs1044498 K121 allele and lower BMI (age-adjusted P = 0.018). Nominal associations were observed with ENPP1 SNPs and fasting glucose (age-and BMI-adjusted P=0.001 to 0.020). Also, six SNPs showed nominal evidence for association (P < 0.05) with diabetes in one or more genotypic model. The most significant associations were observed with SNPs in intron 11 (rs17060836; OR=1.32 [1.04-1.67]; dominant P = 0.019), two SNPs in intron 1 (rs703184, rs7749493; OR= 0.78 to 1.39) and three SNPs in the 3' untranslated region (rs7754561, rs7769993 and rs9373000; OR = 0.69-1.38). In this population of Afro-Caribbean men, the ENPP1-rs1044498 the K121 allele and intronic variants may modulate BMI and glucose. Also, variants in the 3' UTR confer an increased risk of developing diabetes confirming and extending reports in European and African Americans. After accounting for multiple testing, we conclude that ENPP1 is not a major contributor to diabetes related traits; nevertheless, our results reveal that variants in the ENPP1 gene may modulate BMI and maintain glucose homeostasis in this population of Afro-Caribbean men. These studies are of public health relevance or importance because they contribute epidemiologic information to the genetic etiology of type 2 diabetes in men of African ancestry.


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    Item Type: University of Pittsburgh ETD
    ETD Committee:
    ETD Committee TypeCommittee MemberEmail
    Committee ChairZmuda, Joseph MZmudaJ@edc.pitt.edu
    Committee MemberNewman, Anne Bnewmana@edc.pitt.edu
    Committee MemberKammerer, Candace Mcmk3@pitt.edu
    Title: A Genetic Investigation of the Ectonucleotide Pyrophosphatase/Phosphodiesterase 1 (ENPP1) Variants with Diabetes and Glycemia Traits in Afro-Caribbean Men
    Status: Unpublished
    Abstract: Ectonucleotide pyrophosphatase/phosphodiesterase 1, which downregulates insulin signaling by inhibiting insulin-receptor tyrosine kinase activity, is encoded by the ENPP1 gene. Common variants in ENPP1 have been associated with body mass index (BMI), diabetes and glycemia related traits in populations of European Ancestry, but data in African ancestry populations are sparse. Our objective was to evaluate common ENPP1 variants for association with diabetes and glycemia related traits in a high risk Afro-Caribbean population. Thirty-four single nucleotide polymorphisms (SNPs) based on pair-wise tagging (r2 > 0.80; MAF > 0.05) were successfully genotyped in 380 cases and 1,455 controls without diabetes. Associations with BMI, fasting glucose, fasting insulin and HOMA-IR were also analyzed in non-diabetic controls. The most interesting association was observed between rs1044498 K121 allele and lower BMI (age-adjusted P = 0.018). Nominal associations were observed with ENPP1 SNPs and fasting glucose (age-and BMI-adjusted P=0.001 to 0.020). Also, six SNPs showed nominal evidence for association (P < 0.05) with diabetes in one or more genotypic model. The most significant associations were observed with SNPs in intron 11 (rs17060836; OR=1.32 [1.04-1.67]; dominant P = 0.019), two SNPs in intron 1 (rs703184, rs7749493; OR= 0.78 to 1.39) and three SNPs in the 3' untranslated region (rs7754561, rs7769993 and rs9373000; OR = 0.69-1.38). In this population of Afro-Caribbean men, the ENPP1-rs1044498 the K121 allele and intronic variants may modulate BMI and glucose. Also, variants in the 3' UTR confer an increased risk of developing diabetes confirming and extending reports in European and African Americans. After accounting for multiple testing, we conclude that ENPP1 is not a major contributor to diabetes related traits; nevertheless, our results reveal that variants in the ENPP1 gene may modulate BMI and maintain glucose homeostasis in this population of Afro-Caribbean men. These studies are of public health relevance or importance because they contribute epidemiologic information to the genetic etiology of type 2 diabetes in men of African ancestry.
    Date: 31 January 2011
    Date Type: Completion
    Defense Date: 11 November 2010
    Approval Date: 31 January 2011
    Submission Date: 30 November 2010
    Access Restriction: No restriction; The work is available for access worldwide immediately.
    Patent pending: No
    Institution: University of Pittsburgh
    Thesis Type: Master's Thesis
    Refereed: Yes
    Degree: MS - Master of Science
    URN: etd-11302010-111743
    Uncontrolled Keywords: Afro-Caribbean; Ancestry; Association; ENPP1; Genetics
    Schools and Programs: Graduate School of Public Health > Epidemiology
    Date Deposited: 10 Nov 2011 15:07
    Last Modified: 15 May 2012 14:05
    Other ID: http://etd.library.pitt.edu/ETD/available/etd-11302010-111743/, etd-11302010-111743

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