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Leveraging an Electronic Health Record-Linked Biorepository to Generate a Metformin Pharmacogenomics Hypothesis.

Breitenstein MK, Wang L, Simon G, Ryu E, Armasu SM, Ray B, Weinshilboum RM, Pathak J - AMIA Jt Summits Transl Sci Proc (2015)

Bottom Line: Using a cohort of 258 T2DM patients who had new metformin exposure, existing genetic data, and longitudinal electronic health records, we compared genetic variation within FMO5 to change in glycemic response.Gene-level and SNP-level analysis identified marginally significant associations for FMO5 variation, representing an EHR-driven pharmacogenetics hypothesis for a potential novel mechanism for metformin biotransformation.However, functional validation of this EHR-based hypothesis is necessary to ascertain its clinical and biological significance.

View Article: PubMed Central - PubMed

Affiliation: Mayo Clinic, Rochester, MN ; University of Minnesota, Minneapolis, MN.

ABSTRACT
Metformin is a first-line antihyperglycemic agent commonly prescribed in type 2 diabetes mellitus (T2DM), but whose pharmacogenomics are not clearly understood. Further, due to accumulating evidence highlighting the potential for metformin in cancer prevention and treatment efforts it is imperative to understand molecular mechanisms of metformin. In this electronic health record(EHR)-based study we explore the potential association of the flavin-containing monooxygenase(FMO)-5 gene, a biologically plausible biotransformer of metformin, and modifying glycemic response to metformin treatment. Using a cohort of 258 T2DM patients who had new metformin exposure, existing genetic data, and longitudinal electronic health records, we compared genetic variation within FMO5 to change in glycemic response. Gene-level and SNP-level analysis identified marginally significant associations for FMO5 variation, representing an EHR-driven pharmacogenetics hypothesis for a potential novel mechanism for metformin biotransformation. However, functional validation of this EHR-based hypothesis is necessary to ascertain its clinical and biological significance.

No MeSH data available.


Related in: MedlinePlus

Locus Zoom Plot for FMO5 association with glycemic response to metformin
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f2-2091597: Locus Zoom Plot for FMO5 association with glycemic response to metformin

Mentions: Of the 5 candidate genes, only FMO5 had SNPs that demonstrated a potentially significant association (Table 2). After adjusting for multiple testing rs7541245, the top SNP in FMO5, was marginally significant, but since this signal is very close to passing correction (0.00188-observed vs. 0.00161-Bonferonni threshold) it was deemed appropriate for consideration. None of the SNPs in FMO1-FMO4 gene cluster were found to be significant. Among 31 genotyped SNPs within FMO5 gene (Figure 2), 4 SNPs had p-values less than 0.05 for the association with a decrease in glycemic response during metformin exposure, with rs7541245 having the most significant signal. The FMO5 linkage disequilibrium (LD) plot (not shown due to space constraints) contained 4 LD blocks and appeared to show 9 independent SNPs. The conditional analysis that adjusted for the top most significant SNP in each gene and clinical covariates was performed. FMO5 rs7541245 was the main signal on FMO5 gene as no SNPs reached p-values less than 0.05 which pointed to the remaining SNPs within FMO5 being in high LD with rs7541245 and hence, not independent.


Leveraging an Electronic Health Record-Linked Biorepository to Generate a Metformin Pharmacogenomics Hypothesis.

Breitenstein MK, Wang L, Simon G, Ryu E, Armasu SM, Ray B, Weinshilboum RM, Pathak J - AMIA Jt Summits Transl Sci Proc (2015)

Locus Zoom Plot for FMO5 association with glycemic response to metformin
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4525256&req=5

f2-2091597: Locus Zoom Plot for FMO5 association with glycemic response to metformin
Mentions: Of the 5 candidate genes, only FMO5 had SNPs that demonstrated a potentially significant association (Table 2). After adjusting for multiple testing rs7541245, the top SNP in FMO5, was marginally significant, but since this signal is very close to passing correction (0.00188-observed vs. 0.00161-Bonferonni threshold) it was deemed appropriate for consideration. None of the SNPs in FMO1-FMO4 gene cluster were found to be significant. Among 31 genotyped SNPs within FMO5 gene (Figure 2), 4 SNPs had p-values less than 0.05 for the association with a decrease in glycemic response during metformin exposure, with rs7541245 having the most significant signal. The FMO5 linkage disequilibrium (LD) plot (not shown due to space constraints) contained 4 LD blocks and appeared to show 9 independent SNPs. The conditional analysis that adjusted for the top most significant SNP in each gene and clinical covariates was performed. FMO5 rs7541245 was the main signal on FMO5 gene as no SNPs reached p-values less than 0.05 which pointed to the remaining SNPs within FMO5 being in high LD with rs7541245 and hence, not independent.

Bottom Line: Using a cohort of 258 T2DM patients who had new metformin exposure, existing genetic data, and longitudinal electronic health records, we compared genetic variation within FMO5 to change in glycemic response.Gene-level and SNP-level analysis identified marginally significant associations for FMO5 variation, representing an EHR-driven pharmacogenetics hypothesis for a potential novel mechanism for metformin biotransformation.However, functional validation of this EHR-based hypothesis is necessary to ascertain its clinical and biological significance.

View Article: PubMed Central - PubMed

Affiliation: Mayo Clinic, Rochester, MN ; University of Minnesota, Minneapolis, MN.

ABSTRACT
Metformin is a first-line antihyperglycemic agent commonly prescribed in type 2 diabetes mellitus (T2DM), but whose pharmacogenomics are not clearly understood. Further, due to accumulating evidence highlighting the potential for metformin in cancer prevention and treatment efforts it is imperative to understand molecular mechanisms of metformin. In this electronic health record(EHR)-based study we explore the potential association of the flavin-containing monooxygenase(FMO)-5 gene, a biologically plausible biotransformer of metformin, and modifying glycemic response to metformin treatment. Using a cohort of 258 T2DM patients who had new metformin exposure, existing genetic data, and longitudinal electronic health records, we compared genetic variation within FMO5 to change in glycemic response. Gene-level and SNP-level analysis identified marginally significant associations for FMO5 variation, representing an EHR-driven pharmacogenetics hypothesis for a potential novel mechanism for metformin biotransformation. However, functional validation of this EHR-based hypothesis is necessary to ascertain its clinical and biological significance.

No MeSH data available.


Related in: MedlinePlus