Genome-Wide Meta-analysis Identifies Genetic Variants Associated With Glycemic Response to Sulfonylureas
Authors: Dawed Adem Y , Yee Sook Wah , Zhou Kaixin , Leeuwen Nienke van , Zhang Yanfei , Siddiqui Moneeza K , Etheridge Amy , Innocenti Federico , Xu Fei , Li Josephine H. , Beulens Joline W , Heijden Amber A van der , Slieker Roderick C , Chang Yu-Chuan , Mercader Josep M. , Kaur Varinderpal , Witte John S. , Lee Ming Ta Michael , Kamatani Yoichiro , Momozawa Yukihide , Kubo Michiaki , Palmer Colin N A , Florez Jose C. , Hedderson Monique M. , Hart Leen M. ‘t , Giacomini Kathleen M. , Pearson Ewan R , Consortium the MetGen Plus , Consortium the DIRECT 
Published: October 2021

Objective:
Sulfonylureas, the first available drugs for the management of type 2 diabetes,
remain widely prescribed today. However there exists significant variability in glycaemic response to
treatment. We aimed to establish heritability of
sulfonylurea response and identify genetic variants and interacting treatments
associated with HbA1c reduction.

<p>Research
design and methods: As an initiative of the Metformin Genetics Plus (MetGen
Plus) and the DIabetes REsearCh on patient straTification (DIRECT) consortia,
5,485 white Europeans with type 2 diabetes treated with sulfonylurea were
recruited from 6 referral centres in Europe and North America. We first
estimated heritability using generalized restricted
maximum likelihood (REML) and then undertook GWAS of glycemic response to sulfonylureas
measured as HbA1c 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, cis-eQTLs
and functional validation in cellular models. Finally, we examined for a
possible drug-drug-gene interactions. </p>

<p>Results: After establishing that
sulfonylurea response is heritable (37±11%), we identified two independent loci
near the <i>GXYLT1</i> and <i>SLCO1B1</i> genes associated with HbA1c reduction
at a genome-wide scale (p < 5×10<sup>-8</sup>). The C-allele at <a>rs1234032</a>, near <i>GXYLT1</i>, was associated with
0.14% (1.5 mmol/mol), p=2.39×10<sup>−8</sup>)
lower reduction in HbA1c. Similarly, the C-allele was associated with higher
glucose trough levels (β=1.61, p=0.005) in healthy volunteers in the SUGAR-MGH
given glipizide (N = 857). In 3, 029 human whole blood samples, the C-allele is
a cis-eQTL for increased expression of <i>GXYLT1</i> (β=0.21, p=2.04<a>×10<sup>-58</sup></a>). The C-allele of rs10770791, in an
intronic region of <i>SLCO1B1</i>, was associated with <a>0.11%
(1.2 mmol/mol) </a>greater reduction in HbA1c (p=4.80×10<sup>−8</sup>). In
1,183 human liver samples, the C-allele at rs10770791 is a cis-eQTL for reduced
<i>SLCO1B1</i> expression (p=1.61×10<sup>−7</sup>) 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, sulfonylurea
response and <i>SCLO1B1</i> genotype was observed (p=0.001). In statin
non-users, C-allele homozygotes at rs10770791 had a large absolute reduction in HbA1c
(0.48±0.12% (5.2±1.26 mmol/mol)), equivalent to initiating a DPP4 inhibitor.</p>

<p>Conclusion:
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 when prescribing glucose-lowering drugs. </p>