Pharmacogenomics in Diabetes Mellitus - PowerPoint Presentation

Slide1

Pharmacogenomics in Diabetes Mellitus

Toni I. Pollin, MS, PhD, CGC

Associate Professor

Departments of Medicine and Epidemiology & Public Health

September 22, 2018

Slide2

Disclosures

I, Dr. Toni Pollin, have nothing to disclose.

Slide3

Learning Objectives

Pharmacists: At the completion of this activity, the participant should be able to

Explain the use of common genetic markers to predict treatment response in Type 2 Diabetes

Explain how diagnosis of specific and highly penetrant forms of diabetes informs the selection of appropriate treatment

Describe

pharmocogenetic

approaches used to identify novel drug target treatments for type 2 diabetes

Pharmacy Technicians: At the completion of this activity, the participant should be able to

Define pharmacogenomics

Define a genetic marker

List examples of genetic markers

Explain how genetic markers are used in the treatment of diabetes

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Pharmacogenomics

NHGRI: Pharmacogenomics is a branch of pharmacology concerned with using DNA and amino acid sequence data to inform drug development and testing.

Includes:

Study of how individual genetic variation informs differential drug response (efficacy and adverse events)

Study of how the genome reveals novel drug targets

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Quick DNA/Genetics Review

(Not to scale!)

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DNA is a Blueprint for Protein

www.genome.gov

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The Genetic Code

www.genome.gov

Slide8

Gene Regulation

www.accessexcellence.org

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Genetic Variant/Genetic Marker

Genetic Marker

NHGRI: DNA sequence with a known physical location on a chromosome…The genetic marker itself may be a part of a gene or may have no known function

Genetic Variant

Location in the DNA sequence that varies among individuals

May be rare or common

May impact protein sequence, regulatory or other sequence, or be a marker for a variant that does

Slide10

Diabetes Classification

(ADA/WHO*)

Type 1 Diabetes (T1DM)

Type 2 Diabetes (T2DM)

Specific types of diabetes due to other causes

Gestational diabetes mellitus (GDM, ~4% of pregnancies)

*ADA = American Diabetes Association

WHO = World Health Organization

Type 2

Type 1

Specific

types due to

other causes

Slide11

Relevant to Type 2 Diabetes:

Metformin Pharmacokinetics

Adapted from Todd and

Florez

, Pharmacogenomics 15:529, 2014

SLC29A4

SLC22A3

SLC22A1

SLC47A1

SLC22A2

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SLC22A1 coding variants reduce metformin response in stably transfected HEK293 cells

Shu et al, JCI 117:1422, 2007

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SLC22A1 coding variants associated with reduced metformin glycemic response in healthy volunteers

Shu et al, JCI 117:1422, 2007

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Diabetes Prevention Program (DPP)

Multi-ethnic, multicenter clinical trial randomizing individuals with pre-diabetes to three treatment arms and followed for diabetes incidence for mean follow-up time of 3.2 years

Placebo

850 mg metformin 2x/day

Intensive lifestyle intervention: Goal of 150 minutes/week moderate exercise and 7% weight loss through dietary fat intake reduction

Troglitazone

(ended prematurely due to drug recall)

DPP Research Group, NEJM 346:393, 2002

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Diabetes Prevention Program (DPP):

Main Results

(n = 1082)

(n = 1073)

(n = 1079)

DPP Research Group, NEJM 346:393, 2002

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SLC22A1 (OCT1) Coding SNPs Associated with Metformin Response

* p < 0.05

** p < 0.01

Pollin et al, in preparation

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Haplotype Analysis Reveals Specific OCT1 Isoform Associated with Reduced Response

* p < 0.05

*** p < 0.001

Pollin et al, in preparation

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Diabetes Free Survival: All

Pollin et al, in preparation

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Diabetes-Free Survival by OCT1 Haplotype

Pollin et al, in preparation

Slide20

GoDarts Study

Patients: Scottish observational cohort of individuals with T2DM of Scottish Ancestry

Outcome: Ability of metformin or sulfonylurea to reduce %HBA1c to 7% within first 18 months of therapy

Zhou et al, Nature Genetics 43:117, 2011

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Zhou et al, Nature Genetics 43:117, 2011

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CYP2C9 loss of function variants reduce risk of sulfonylurea monotherapy failure

Zhou et al (2009) Clinical Pharmacology & Therapeutics 87:52.

Slide23

Metformin Response GWAS in

GoDarts

Study: Results in 1024 patients

Zhou et al, Nature Genetics 43:117, 2011

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Metformin Response GWAS in GoDarts Study: Results

Zhou et al, Nature Genetics 43:117, 2011

Slide25

Metformin Response GWAS in

GoDarts

Study:

ATM

Variant

Zhou et al, Nature Genetics 43:117, 2011

Slide26

Replication of ATM

Association with Metformin Response

HBA1c ≤ 7%

HBA1c

van Leeuwen et al,

Diabetologia

55:1971, 2012

Slide27

No Association of ATM Variant with Metformin Response in the DPP

Florez et al, Diabetes Care 35:1864, 2012

Slide28

Fajans et al,

NEJM

2001

Slide29

Shepherd et al,

Diabetic Medicine

2009

Slide30

Monogenic Diabetes is Underdiagnosed in the U.S.:

The SEARCH Study

Pihoker

et al (2013),

JCEM

98:4055

Slide31

SEARCH Participants with MODY Mutations

Pihoker

et al (2013),

JCEM

98:4055

Slide32

Components of the

Personalized Diabetes Medicine Program

Diagnosed before 1 year?

Diagnosed before 30 years?

Age of diagnosis ____

Hearing or visual impairment/birth defects/ kidney disease?

Extremely overweight at diagnosis?

Type 1 diabetes?

Parent or child with type 1 diabetes?

2 or more people related by blood with diabetes?

Patient completes questionnaire

C-peptide Positive?

IA-2 Antibody negative?Consistent family/ medical history elicited by genetic counselor

Further workup as indicated

Sequence 40 monogenic diabetes genes for mutations

If indicated…Segregation in familyFunctional studies

If pathogenic or likely pathogenic variant found:

If variant of unknown

Significance found:

Confirm, disclose and add to electronic health record and customize treatment

Make genetic counseling and testing available to family members

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Next Generation Sequencing Panel

HNF4A

HNF1A

PDX1/IPF1/STF1

HNF1B

NEUROD1

KLF11

CEL

PAX4

BLK

ABCC8

GCK

INS

KCNJ11

ZFP57

AGPAT2

BSCL2

CAV1

LMNA

PLIN1

PPARG

PPP1R3A

PTRF

MODY

Neonatal Diabetes

Lipodystrophy

MC4R

LEP

LEPR

SIM1

Severe Obesity

ALMS1

CISD2/WFS2

EIF2AK3

FOXP3

GATA6

GLIS3

INSR

PTF1A

RFX6

SLC19A2

SLC2A2

WFS1

GLUD1

HADH

Syndromes

Hyperinsulinemia

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IGNITE Network

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2,190 patients screened with questionnaire at 4 sites

532 patients enrolled

507

patients sequenced and analyzed (includes 311 suspected monogenic diabetes cases plus 196 controls)

36/311 (11.6%) hit rate in cases

Individuals identified with monogenic diabetes

Gene

Disease

Number

GCK

MODY2/

GCK

-MODY

19

HNF1A

MODY3/

HNF1A-MODY

7

HNF4A

MODY1/

HNF4A

-MODY

2

INS

MODY10

2

LMNA

Familial partial lipodystrophy

2

HNF1B

MODY5/

Renal Cysts & Diabetes

1

KCNJ11

MODY13/

K

ATP

diabetes

1

WFS1

Wolfram syndrome

1

MC4R

Monogenic obesity

1

PDMP Current Results by the Numbers

Slide36

Case Example

9 y/o female dx T1DM at 15mth

No DKA

Neg GAD*, IA2

Treated with insulin

Family

hx

significant for T1DM in mother (dx.5) and first cousin once removed

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Diagnosis

KCNJ11

: c.697C>T p.(Leu233Phe); (heterozygous):

Likely pathogenic

MODY13

Slide38

KCNJ11

p.Leu233Phe mutation was previously reported only once—in a sulfonylurea-responsive child dx DM at 5 weeks with polyuria since 3 days and showed

in vitro

response to

sulfyonylureas

Joshi and

Phatarpekar

(2011) World J Pediatrics 7:371

Babiker

et al (2016)

Diabetologia

59:1162

Slide39

Follow-up on Case

9-year old

proband

successfully transitioned from insulin to glyburide in 13 days

42-year old mother diagnosed with T1DM at 5 years confirmed to have same mutation and has transitioned from insulin to glyburide

Mother’s endocrinologist now convinced of importance of antibody testing for all T1DM dx

6 year old brother with normoglycemia confirmed not to have the mutation

Mother’s cousin with diabetes also confirmed not to have the mutation

Mother’s parents do not have the mutation (de novo in

proband’s mother)

Slide40

High dose sulfonylureas are efficacious and safe in KCNJ11

diabetes in the long term (n = 81)

Bowman et al (2018) Lancet Diabetes & Endocrinology 6:637

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At least 4.5% (22/488) of overweight/obese youth diagnosed with T2DM have MODY:

The TODAY Study

Kleinberger, et al., Genetics in Medicine 2017

Slide42

Patients with HNF4A

-MODY diagnosed with T2DM fail treatment with metformin:

The TODAY Study

Kleinberger, et al., Genetics in Medicine 2017

Slide43

Zinc Transporter Null Variants Appear to

Protect Against Diabetes

Flannick

et al (2014) Nature Genetics

Slide44

Concluding Remarks

Some promising research suggests potential

pharmacogenetic

targets for type 2 diabetes

Replication needed

Pharmacogenetic

targets already exist for monogenic diabetes (~2% of diabetes)

Future diabetes treatments may be informed by novel type 2 diabetes genetic discoveries

Slide45

Acknowledgments

Jose C. Florez

Sook-Wah

Yee

Kathleen A. Jablonski

Jarred B. McAteer

Andrew Taylor

Kieren

Mather

Edward HortonNeil H. WhiteElizabeth Barrett-ConnorWilliam C. Knowler WC Kathleen M. GiacominiAlan R. ShuldinerDiabetes Prevention Program Research GroupNIH R01 DK72041

Slide46

Alan

Shuldiner

Kathleen Palmer

Mickaela

Nicholson

Tom Fitzgerald

Tameka

Alestock

Devon NwabaMary PavlovichKristin Maloney

Casey OverbyDaniel MullinsDaisuke Goto

Kate TracyDeborah GreenbergStephanie Stein

Kristi SilverRana MalekKatie BisordiNanette SteinleMelanie Leu

Richard HorensteinElizabeth LamosKashif MunirIlias Spanakis

Elizabeth StreetenYasaman MohtasebiLinda JengColeen DamcottNicholas Ambulos

Jeff KleinbergerTrevor MatthiasDanielle SewellHaichen ZhangKeith TannerYue GuanUM CDE Staff and Patients

PPGM/ UMB MODY Fund

Slide47

Partners and Funding

David Carey

John Kennedy

Ying Hu

Kristina Blessing

Misha

Rashkin

Jessica

Goehringer

Natacha

AntunesMallory SnyderPhilip LevinKaren KleinLee BrombergerHarvey Institute

Amy KimballChristie NewsomeChristy HaakonsenMarcia FergusonJennifer Billiet

NHGRI U01 HG00775ignite-genomics.orgNICHD U24 HD093486UMB Program for Personalized and Genomic MedicineUMB Foundation MODY Fund

Slide48

References

www.genome.gov

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Hardie

DG,

Peltonen

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Zhou K, Donnelly L, Burch L,

Tavendale

R,

Doney

AS,

Leese

G, Hattersley AT, McCarthy MI, Morris AD, Lang CC, Palmer CN, Pearson ER. Loss-of-function CYP2C9 variants improve therapeutic response to sulfonylureas in type 2 diabetes: a Go-DARTS study.

Clin

Pharmacol

Ther

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Epub

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Leeuwen

N,

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G, Becker ML,

Deshmukh

H, Zhou K,

Stricker

BH,

Uitterlinden

AG,

Hofman

A, van 't

Riet

E, Palmer CN,

Guigas

B,

Slagboom

PE,

Durrington

P,

Calle

RA, Neil A, Hitman G, Livingstone SJ, Colhoun H, Holman RR, McCarthy MI, Dekker JM, 't Hart LM, Pearson ER. A gene variant near ATM is significantly associated with metformin treatment response in type 2 diabetes: a replication and meta-analysis of five cohorts.

Diabetologia

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Florez JC, Jablonski KA, Taylor A, Mather K, Horton E, White NH, Barrett-Connor E, Knowler WC, Shuldiner AR, Pollin TI; Diabetes Prevention Program Research Group. The C allele of ATM rs11212617 does not associate with metformin response in the Diabetes Prevention Program. Diabetes Care. 2012 Sep;35(9):1864-7.

Epub

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Slide49

References, continued

Shepherd M, Shields B,

Ellard

S, Rubio-

Cabezas

O, Hattersley AT. A genetic diagnosis of HNF1A diabetes alters treatment and improves

glycaemic

control in the majority of insulin-treated patients.

Diabet

Med. 2009 Apr;26(4):437-41.

doi

: 10.1111/j.1464-5491.2009.02690.x. PubMed PMID: 19388975.

Pihoker C, Gilliam LK, Ellard S,

Dabelea D, Davis C, Dolan LM, Greenbaum CJ, Imperatore

G, Lawrence JM, Marcovina SM, Mayer-Davis E, Rodriguez BL, Steck AK, Williams DE, Hattersley AT; SEARCH for Diabetes in Youth Study Group. Prevalence, characteristics and clinical diagnosis of maturity onset diabetes of the young due to mutations in HNF1A, HNF4A, and glucokinase: results from the SEARCH for Diabetes in Youth. J

Clin Endocrinol Metab. 2013 Oct;98(10):4055-62.

doi: 10.1210/jc.2013-1279. Epub

2013 Jun 14. PubMed PMID: 23771925; PubMed Central PMCID: PMC3790621.

Joshi R,

Phatarpekar

A. Neonatal diabetes mellitus due to L233F mutation in the KCNJ11 gene. World J

Pediatr

. 2011 Nov;7(4):371-2.

doi

: 10.1007/s12519-011-0254-z.

Epub

2011 Jan 5. PubMed PMID: 21210267.

Babiker

T,

Vedovato

N, Patel K, Thomas N, Finn R,

Männikkö

R,

Chakera

AJ, Flanagan SE, Shepherd MH,

Ellard

S, Ashcroft FM, Hattersley AT. Successful transfer to sulfonylureas in KCNJ11 neonatal diabetes is determined by the mutation and duration of diabetes.

Diabetologia

. 2016 Jun;59(6):1162-6.

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: 10.1007/s00125-016-3921-8.

Epub

2016 Mar 31. PubMed PMID: 27033559; PubMed Central PMCID: PMC4869695.

Bowman P,

Sulen

Å,

Barbetti

F,

Beltrand

J,

Svalastoga

P,

Codner

E,

Tessmann

EH,

Juliusson

PB,

Skrivarhaug

T, Pearson ER, Flanagan SE,

Babiker

T, Thomas NJ, Shepherd MH,

Ellard

S,

Klimes

I,

Szopa

M,

Polak

M,

Iafusco

D, Hattersley AT,

Njølstad

PR; Neonatal Diabetes International Collaborative Group. Effectiveness and safety of long-term treatment with sulfonylureas in patients with neonatal diabetes due to KCNJ11 mutations: an international cohort study. Lancet Diabetes

Endocrinol

. 2018 Aug;6(8):637-646.

doi

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Epub

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Endocrinol

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Kleinberger JW, Copeland KC, Gandica RG,

Haymond

MW, Levitsky LL, Linder B, Shuldiner AR,

Tollefsen

S, White NH, Pollin TI. Monogenic diabetes in overweight and obese youth diagnosed with type 2 diabetes: the TODAY clinical trial. Genet Med. 2018 Jun;20(6):583-590.

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Epub

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Flannick J,

Thorleifsson

G, Beer NL, Jacobs SB,

Grarup

N,

Burtt

NP, Mahajan A, Fuchsberger C,

Atzmon

G,

Benediktsson

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F, Chambers J, Cho YS, Christensen C, Douglas DA,

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Dymek

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Farjoun

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P,

Forsén

T, Gabriel S, Glaser B,

Gudbjartsson

DF,

Hanis

C, Hansen T,

Hreidarsson

AB,

Hveem

K,

Ingelsson

E,

Isomaa

B, Johansson S,

Jørgensen

T,

Jørgensen

ME,

Kathiresan

S, Kong A,

Kooner

J,

Kravic

J,

Laakso

M, Lee JY, Lind L, Lindgren CM,

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A, Masson G,

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T,

Mohlke

KL,

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S,

Rauramaa

R,

Ribel

-Madsen R, Richard AM,

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T,

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V,

Segrè

AV,

Skärstrand

H,

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V,

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HM,

Sulem

P, Tai ES,

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YY,

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T,

Thorsteinsdottir U, Trimmer JK, Tuomi T, Tuomilehto J, Vaziri-Sani F, Voight BF, Wilson JG, Boehnke M, McCarthy MI, Njølstad PR, Pedersen O; Go-T2D Consortium; T2D-GENES Consortium, Groop L, Cox DR, Stefansson K, Altshuler D. Loss-of-function mutations in SLC30A8 protect against type 2 diabetes. Nat Genet. 2014 Apr;46(4):357-63. doi: 10.1038/ng.2915. Epub 2014 Mar 2. PubMed PMID: 24584071; PubMed Central PMCID: PMC4051628.

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CE Access Code and Instructions

pharmacogenomicsDM