GeneEnvironmentInteracons, …...Three major pathways via which intestinal microbiota can alter human cardio-metabolism. Vinjé S et al. Eur Heart J 2013;eurheartj.eht467 Published

Gene-‐Environment Interac0ons, Metabolomics, and Racial Dispari0es

in CardioMetabolic Diseases

Frank Hu, MD, PhD Professor of Nutri5on and Epidemiology

Harvard School of Public Health Professor of Medicine Harvard Medical School

• Racial Disparity in Diseases

• Gene-‐Environment Interac5ons

• Metabolomics

• Personalized Preven5on

2

The Change of US Popula5on

Asian

Hispanic

Black Non-‐Hispanic white

1980 1990 2000 2010 2020

Percen

t, %

Year

Modified from US Census Bureau

Percentage Surviving by Race and Sex, U.S. 2008

0

0.1

0.2

0.3

0.4

0.5

Total CVD

HBP CHD MI Stroke HF

Prevalen

ce Mexican

Americans

Whites

Blacks

Prevalence of Diseases across Races

Data source: Heart Disease and Stroke Sta5s5cs—2011 AHA Update

Why racial disparity on complex disease?

Type 2 Diabetes Coronary artery disease

Hypertension

Gene5c vs. Non Gene5c on Complex Disease

Body Mass Index

T2D and related complica5ons

Murea et al. Rev Diabet Stud, 2012

Gene5c effects

Published Genome-‐wide Associa5ons (~June 2013)

hap://www.ebi.ac.uk/fgpt/gwas/#

Waters et al. PLoS Genet. 2010

19 loci were tested

5 ethnic groups were compared

Waters et al. PLoS Genet. 2010

Direction in association (null=50%) All ethnic groups >63%; 100% in Japanese

Heterogeneity in ORs 5 of the 19 risk variants showed nominal evidence for heterogeneity; Only one remained significant after correction of multiple comparison; CDKAL1

European Americans, 1.11, 1.06–1.17 African Americans: 1.09, 1.05–1.12 Native Hawaiians, 1.10, 1.06–1.15 Latinos, 1.12, 1.09–1.14 Japanese, 1.20, 1.17–1.24

Combined genetic effect, per allele of genetic risk score

Difference among African origin popula5ons

Type 2 Diabetes

Hypertension 0

5

10

15

20

25

30

35

rural Cameroon Urban Cameroon

Jamaica Caribbean migrants to Britain

Age-‐ad

justed

prevalence of disease

Cruickshank et al. 2001

•  Life style •  Socioeconomic status •  Educa5on, income, Residen5al segrega5on

• Health prac5ces •  Racial discrimina5on

Environmental factors on racial disparity

Prevalence of regular leisure-‐5me physical ac5vity among adults by race/ethnicity and sex (NHIS: 2009)

0

5

10

15

20

25

30

35

40

45

Men Women

Perc

ent o

f Pop

ulat

ion

NH White NH Black Hispanic Roger VL et al. Circulation. 2010

Source: CDC/NCHS, Health Data Interac5ve. All percentages are age-‐adjusted. NH indicates non-‐Hispanic. * Includes both Hispanics and non-‐Hispanics.

Prevalence of current smoking for adults by race/ethnicity and sex (NHIS: 2006-‐2008)

0

5

10

15

20

25

30

35

Men Women

Percen

t of P

opula0

on

NH White NH Black Hispanic Asian* American Indian/Alaska Na5ve* Source: CDC/NCHS, Health Data Interac5ve. All percentages are age-‐adjusted. NH indicates non-‐Hispanic. * Includes both Hispanics and non-‐Hispanics. Roger VL et al. Circulation. 2010

Educa5on Effects on Hypertension by Races

Anderson et al. 2004

JAMA. 2005;294(8):937-946."

Racial difference in drug response "(the same environmental effect)

Causes of Human Disease

Who took my piece of pizza?

• Disparity in Diabetes

• Gene-‐Environment Interac5ons

• Metabolomics

• Personalized medicine

20

Missing Heritability of Complex Disease

Sabah et al. 2009

Manolio et al. 2009

Sources of missing heritability

1.  Other gene5c determinants, such as common copy number varia5ons, and rare variants;

2.  Interplay of different factors, such as epistasis, and gene-‐environment interac0on

Manolio et al. Nat Rev Gen.2006

An illustra5on of gene-‐diet interac5on

A Classic GXE Example

Phenylketonuria

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

NHS HPFS WGHS Pooled

Diffe

rence in BMI p

er 10 risk alleles, kg/m

2 Sugar-‐sweetened Beverage consump0on

<1 serving/mo 1-‐4 servings/mo 2-‐6 servings/wk ≥1 servings/day

P for interac5on =0.008



P for interac5on <0.001

Sugar-‐Sweetened Beverages & Gene0c Effect

Qi Q et al. N Engl J Med 2012

(n=6,934) (n=4,423) (n=21,740)

The Effects of SSB Intake (1 serving/day) on BMI According to quar5les of gene5c risk score

Beta=-0.07 P=0.36

Beta=0.44 P=0.003

Quartiles of Obesity Genetic Risk Score

Physical Ac0vity, Television Watching and Gene0c Predisposi0on in rela0on to Body Mass Index in

Women and Men

Gene0c Predisposi0on Score and BMI by Physical Ac0vity

Gene0c Predisposi0on Score and BMI by TV Watching

IP: Intermediate Phenotype Suhre K, et al. Nat Rev Genet, 2012

GENETICS & METABOTYPES

the Human Metabolome

• Disparity in Diabetes

• Gene-‐environment interac5ons

• Metabolomics


32

3000+ metabolites

•  Metabolome: the complete set of small-‐molecule metabolites to be found within a biological sample (cell, 5ssue, or organism).

•  Metabolomics: the systema5c study of small-‐molecule metabolites in a biological sample under a given set of condi5ons.

Metabolome

Metabolome GXE

BCAAs

*Among 2,422 normoglycemic individuals followed for 12 years, 201 developed diabetes.

Wang et al., Nature Medicine 17, 448–453 (2011).

In Caucasians

Dietary BCAA intake and plasma BCAA levels

Age-‐adjusted Age-‐ and BMI-‐adjusted

Qi et al. unpublished data

Metabolomics in African Americans

Metabolomic profiles were measured in ~2000 African-‐Americans at baseline examina5on

•  The Atherosclerosis Risk in Communi5es (ARIC) Study is a popula5on-‐based prospec5ve biracial cohort study to inves5gate the causes of atherosclerosis and its clinical outcomes.

characteris0cs Total popula0on (N=1977)

Females (N=1275)

Males (N=702)

Age, y 52.9 ± 5.7 52.8 ± 5.7 53.0 ± 5.8 Current smoker, n (%) 498 (28.8) 308 (24.2) 261 (37.2) Physical ac5vity 6.6 ± 1.4 6.4 ± 1.5 6.6 ± 1.4 BMI, kg/m2 29.5 ± 6.0 30.8 ± 6.4 27.6 ± 4.5 Prevalent hypertension, n (%) 1050 (53.1) 694 (54.4) 356 (50.7) Prevalent diabetes, n (%) 319 (16.2) 218 (17.1) 101 (14.4) Prevalent heart failure, n (%) 97 (4.9) 76 (6.0) 21 (3.0)

Characteris5cs of study popula5on at baseline examina5on in 1987-‐89.

GWAS Metabolomics

bilirubin (E,E) UGT1A

biliverdin UGT1A

bilirubin (Z,Z)

UGT1A

[H]HWESASLLR[OH] ACE

aspartyl phenyl alanine ACE

threonylphenyl alanine ACE

HXGXA KLKB1

crea5ne GATM

glycine CPS1

N-‐acetyl ornithine NAT8

N-‐acetyl phenyl alanine ACY3

phenyl acetate ACSM2B

3-‐hydroxy decanoate THEM4

acetyl carni5ne SIAE

deoxy carni5ne SLC6A13

hexade canedioate

ADH4

palmitoleate (16:1n7) PKD2L1

LEU-‐PHE KLKB1

trehalose TREH

Cofactors and vitamins Pep5de

Lipid

Amino acid

Carbohydrate

Common variants with p-‐value < 1.6Í10-‐10

Metabolite

gene

Yu, et al. PLoS GeneIcs. 2014

bilirubin (E,E) UGT1A

biliverdin UGT1A

bilirubin (Z,Z)

UGT1A

[H]HWESASLLR[OH] ACE

aspartyl phenyl alanine ACE

threonylphenyl alanine ACE

HXGXA KLKB1

crea5ne GATM

glycine CPS1

N-‐acetyl ornithine NAT8

N-‐acetyl phenyl alanine ACY3

phenyl acetate ACSM2B

3-‐hydroxy decanoate THEM4

acetyl carni5ne SIAE

deoxy carni5ne SLC6A13

hexade canedioate

ADH4

palmitoleate (16:1n7) PKD2L1

LEU-‐PHE KLKB1

trehalose TREH

Cofactors and vitamins Pep5de

Lipid

Amino acid

Carbohydrate

Common variants with p-‐value < 1.6Í10-‐10 Yu, et al. PLoS GeneIcs. 2014.

GWAS Metabolomics

Gene-‐Metabolite-‐Disease Pathway

Yu, et al. PLoS GeneIcs. 2014

0

5

10

15

20

25

30

35

40

# related metabolite

s

cofactors and vitamins

carbohydrate

xenobio5cs

energy

pep5de

lipid

amino acid

Super pathway of metabolites

42 Zheng, et al. Am J Epidemiol. In press.

Zheng, et al. In submission.

Nutri5onal Metabolomics

Metabolomics in Diseases Research

Reliability of human metabolome

Metabolomics in incident heart failure

Metabolomics in incident hypertension

4-‐hydroxyhippurate

Oxida5ve break-‐down of benzenoid substances in guts

Zheng, et al. Am J Epidemiol. 2013. Zheng, et al. Hypertension. 2013.

204 metabolites

Meta-‐analysis of red meat intake and T2 diabetes

Pan et al., AJCN 2011

Three major pathways via which intestinal microbiota can alter human cardio-metabolism.

Vinjé S et al. Eur Heart J 2013;eurheartj.eht467

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2013. For permissions please email: [email protected]

Gut Microbiota as a Cardiometabolic Target

•  Gut bacteria play a critical role in metabolism of nutritional factors in the pathogenesis of diabetes: –  Components in red meat –  Plant-based foods: soluble fiber, polyphenols from fruits,

vegetables, coffee, etc.

•  Emerging evidence indicates that gut flora metabolites in development of complex metabolic phenotypes including obesity, diabetes, and CVD.

•  This research can provide novel prevention and therapeutic strategies for metabolic diseases (including diet/lifestyle, probiotic, and prebiotic approaches).

Franks PW et al. Diabetes Care 2013;36:1413-1421 Franks et al. Diabetes Care 2013

• Racial Disparity in diseases

• Gene-‐environment interac5ons

• Metabolomics


50

Personalized preven0on and racial disparity

•  NOT racialized BUT personalized medicine

•  Race and Pharmacogene5cs

•  Advance in GXE research and systems epidemiology approach

•  Applica5on of Metabolomics in clinical sehng

Acknowledgement •  Yan Zheng •  Qibin Qi •  Lu Qi •  Marilyn Cornelis •  Peter Kra| •  Brian Wolpert •  Mike Pan •  Rob van Dam •  Qi Sun

Documents

GeneEnvironmentInteracons, …...Three major pathways via which intestinal microbiota can alter human cardio-metabolism. Vinjé S et al. Eur Heart J 2013;eurheartj.eht467 Published