Genome-Wide Meta-analysis Identifies Genetic Variants Associated With Glycemic Response to Sulfonylureas.

Abstract

Sulfonylureas, the first available drugs for the management of type 2 diabetes, remain widely prescribed today. However, there exists significant variability in glycemic response to treatment. We aimed to establish heritability of sulfonylurea response and identify genetic variants and interacting treatments associated with HbA_1c reduction. As an initiative of the Metformin Genetics Plus Consortium (MetGen Plus) and the DIabetes REsearCh on patient straTification (DIRECT) consortium, 5,485 White Europeans with type 2 diabetes treated with sulfonylureas were recruited from six referral centers in Europe and North America. We first estimated heritability using the generalized restricted maximum likelihood approach and then undertook genome-wide association studies of glycemic response to sulfonylureas measured as HbA_1c reduction after 12 months of therapy followed by meta-analysis. These results were supported by acute glipizide challenge in humans who were naïve to type 2 diabetes medications, <i>cis</i> expression quantitative trait loci (eQTL), and functional validation in cellular models. Finally, we examined for possible drug-drug-gene interactions. After establishing that sulfonylurea response is heritable (mean ± SEM 37 ± 11%), we identified two independent loci near the <i>GXYLT1</i> and <i>SLCO1B1</i> genes associated with HbA_1c reduction at a genome-wide scale (<i>P</i> < 5 × 10^-8). The C allele at rs1234032, near <i>GXYLT1</i>, was associated with 0.14% (1.5 mmol/mol), <i>P</i> = 2.39 × 10^-8), lower reduction in HbA_1c. Similarly, the C allele was associated with higher glucose trough levels (β = 1.61, <i>P</i> = 0.005) in healthy volunteers in the SUGAR-MGH given glipizide (<i>N</i> = 857). In 3,029 human whole blood samples, the C allele is a <i>cis</i> eQTL for increased expression of <i>GXYLT1</i> (β = 0.21, <i>P</i> = 2.04 × 10^-58). The C allele of rs10770791, in an intronic region of <i>SLCO1B1</i>, was associated with 0.11% (1.2 mmol/mol) greater reduction in HbA_1c (<i>P</i> = 4.80 × 10^-8). In 1,183 human liver samples, the C allele at rs10770791 is a <i>cis</i> eQTL for reduced <i>SLCO1B1</i> expression (<i>P</i> = 1.61 × 10^-7), which, together with functional studies in cells expressing <i>SLCO1B1</i>, supports a key role for hepatic <i>SLCO1B1</i> (encoding OATP1B1) in regulation of sulfonylurea transport. Further, a significant interaction between statin use and SLCO1B1 genotype was observed (<i>P</i> = 0.001). In statin nonusers, C allele homozygotes at rs10770791 had a large absolute reduction in HbA_1c (0.48 ± 0.12% [5.2 ± 1.26 mmol/mol]), equivalent to that associated with initiation of a dipeptidyl peptidase 4 inhibitor. We have identified clinically important genetic effects at genome-wide levels of significance, and important drug-drug-gene interactions, which include commonly prescribed statins. With increasing availability of genetic data embedded in clinical records these findings will be important in prescribing glucose-lowering drugs.