Ida J. Spruill PhD, RN, LISWMay 13, 2010

The People (Overview of South Carolina and the Gullah population)

The Community (Community Engagement/Involvement )

Project SuGar & The Science (UCP 3 gene) (Linkage scan)

Outcomes & Results (GWAS)

Cultural and Historical Link

Funding: W.M.Keck Foundation, NIH:DK4761, ADA,GENNID

There are ethnic differences in the pathophysiology of the Metabolic Syndrome and Diabetes

The Increased risk of Diabetes in African Americans has a genetic basis.

SCIENCE Ascertain sib-pairs and pedigrees with T2DM, Obesity Phenotype: anthropometrics, glucose tolerance, lipids,

blood pressure, health beliefs/practices Study genes contributing to T2DM and Obesity in a

homogeneous African-derived population: whole genome scan, candidate genes

SERVICE Health education, disease screenings, health fairs,

referrals

COBRE, MUSC Dept of Medicine

Create a Diabetes Registry/DNA of 400 affected African American

families

Scientific Aims:

Isolate and Identify diabetes and obesity genes Linkage Analysis Genome-Wide Association Study (GWAS)

Community:

Use Community-Based Participatory Research (CBPR) principals to engage the community

Community-Based Research

Ida Spruill

Ann Smuniewski

Gloria Smith

Deborah Daniels

Andrea Collins

Pam Wilson

Susan Cromwell

Fredrika Joyner

Karen Small

Gwen Maine

Mattie Wideman

Genetics & Molecular

Kerry Lok

George Argyropoulos

Angela Brown

Pamela Binns

David McLean

Kerin McCormack

Kirby Smith

Yuchang Fu

Helliner Vestri

Julian Munoz

Human Physiology

Steve Willi

Lidia Maianu

Penny Wallace

Amy Hutto

Sara Shaughnessy

Soonho Kwon

Jyotika Fernandes

Statistical Genetics

Michele Sale (UVa)

Carl Langefeld (WFU)

Don Bowden (WFUStatistical Genetics

Lingyi Lu (WFU)

•PIs: W.T. Garvey

•Jtoyika Fernandes

•Citizen’s Advisory Committee Members

Affected biological sib pairs > 18 years of age

One living biological parent with T2DM

Born or raised on the Sea Islands

Biological parents born or raised on Sea Islands

Charleston

Minimal genetic admixture (Pollitzer 1999,

Garvey,2001) (<3.5%)

Geographical isolation and cultural identity

Large stable multi-generational families

Population Admixture Estimate (%±SE)

Gullah Sea Islanders 3.5 ± 0.8Charleston 9.8 ± 1.2

Mississippi delta 13.3 ± 1.9

Chicago 18.8 ± 1.4

New York 19.8 ± 2.1

Pittsburgh 25.2 ± 2.7

Baltimore 15.5 ± 2.6

New Orleans 22.5 ± 1.6

Jamaica 6.8 ± 1.3

Parra et al, Am J Physical Anthropol, 114:18, 2001Parra et al, Am J Hum Genet, 63:1839, 1998

High prevalence and relative risk for T2DM, obesity, hypertension, lupus, prostate cancer

Uniform diet and lifestyle (maximize expression of disease in patients with susceptibility genes) (Garvey,1996)

•Non-Hispanic Blacks : 13.1%

•Non Hispanic Whites: 8% BRRSS,2006

Most of the newly-

identified diabetes genes do not play a major role

in diabetes risk in African Americans

Community

17

Our Approach to the Community

Plan a socio-cultural assessment of the community

Study the culture and strengths of the community

Identify gaps in services

Acknowledge the different subcultures

Involve community in initial research plan

Match research staff to study population

Organize a citizen advisory committee

.

COMMUNITY SProject SuGar Mobile

Project Sugar

mobile unit

Community Services

650 Families recruitedFemaleMarriedAttended High SchoolHave InsurancePreferred learning in Groups

21

Diabetes is Inherited: 61.1% Diabetes is prevented: 66.6%

11.8% use Home RemediesMost Common Remedies

◦ Garlic *◦ Ho-hung tea◦ Vinegar and water◦ Cinnamon *◦ Goldenseal tea

*Cited in literature as effective

Referral to Ancillary Services◦ Diabetes class & dietician : 41.1%◦ Ophthalmologist : 32.8%◦ Dentist : 22.3%◦ Podiatrist :12.8%

Self Management Behaviors◦ Reported Exercising : 55.6%◦ Monitored blood glucose daily: 27.7%

Communication patterns reflect social customs of the South (wear mask, no eye contact)

Language patterns ,I ain’t claiming it", falling off for losing weight

Practice patterns, “ If you on the needle, your sugar is bad”,

“Make do with what you have”,

“You need to know which roots, herbs to use for sugar and pressure”

Has the potential to play an important role in energy balance and determination of body weight. Allele frequencies were determined and found to be similar in Gullah-speaking African Americans and the Mende tribe of Sierra Leone, but absent in Caucasians.

Manuscript: Effects of Mutations in the Human Uncoupling Protein 3 Gene on the Respiratory Quotient and Fat Oxidation in Severe Obesity and Type 2 Diabetes

George Angelopoulos,*et,al. (1998) J.Clin Invest,102,(7)

Helps store metabolic fuel more efficiently.

Increased stored fuel (i.e., fat) is advantageous in environment where intermittent access to food

Can lead to weight gain and obesity in an environment where food is plentiful

Frayling TM. Nat Rev Genet 2007 Sep; 8:657-62 2007: A breakthrough year in diabetes genetics,T2DM genes found :C3,(2000)C1, (2003)C10,(2006)

Genetic linkage analysis is a statistical method that is used to associate functionality of genes to their location on chromosomes.

DNA submitted toThe Center for Inherited Disease Research

426 families (2-7 members)

Sib-pair study design with (834 Affected ), (194 Unaffected )

Analysis: MERLIN (computer program)

Chromosomes: 14q and C7 in the Gullah population. (Implication for personalized medicine)

Key phenotypes: Type 2 Diabetes, BMI, NMR

Statistical Genetics: Michele Sale (Univ of Va) and Carl Langefeld (WFU)

C 7 C 14

Saxena, R. et al. Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science 316, 1331–1336 (2007).

Broad Institute, Lund U, Novartis

Scott, L. J. et al. A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science 316, 1341–1345 (2007).

U of Helsinki, CIDR UCLA, NHGRI, U Michigan

Sladek, R. et al. A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature 445, 881–885 (2007).

McGill U, INSERM,

Genome Wide Gene Association Studies (GWAS) Can Identify Complex Disease

Genes

GENE Chromo-

some

Mode of ID Previous Evidence

Evidence from Human Physiology

PPARG 3 Candidate Drug target Insulin sensitivity

KCNJ11 12 Candidate Drug target Insulin secretion

TCF217

Candidate/

linkage

Monogenic diabetes

MODY, Insulin secretion

WFS14

Candidate/

Linkage

Monogenic diabetes

Wolfram Syndrome

TCF7L210

Linkage then

region-wide AS

none Insulin secretion

HHEX-IDE10

GWAS Pancreas development

Insulin secretion

SLC30A8 8 GWAS none Insulin secretion

CDKAL1 6 GWAS none Insulin secretion

CDKN2A-2B9

GWAS Reduced islet mass in mice

(Coronary Artery Disease)

IGF2BP2 3 GWAS Binds IGF2

FTO 16 GWAS none BMI/obesity

Type 2 Diabetes Genes

Identified as a major new diabetes gene on C-10 byGrant et al. Nat Genet 2006 March; 38: 320-323

Shown to have a role in impairment of insulin secretion (rather than a defect in insulin action in peripheral tissues)

Play a major role in T2DM risks in African Americans (Lyssenko et al. J Clin Invest. 2007 Aug; 117:2155-63) (Diabetes,2009,UNC)

Do Not play a major role in T2DM risks in the Gullah population (Seale,2008)

Powerful research tools for identifying genetic variants that contribute to health and disease.

To identify common genetic factors that influence health and disease.

The study of genetic variation across the entire human genome that is designed to identify genetic associations with observable traits (such as blood pressure or weight), or the presence or absence of a disease or condition.

Potential for increased understanding of basic biological processes affecting human health, and the promise of personalized medicine.

Genotyping phase using the Affymetrix 6.0 product is scheduled to commence very soon, and anticipated to take 6-8 weeks.

Currently harmonizing the phenotypic datasets from the different studies. (PS/SIGNET) (Jackson Heart,) (Wake Forest)

Actual relevance for health outcomes is yet to be seen. (M.Sale)

The classic Metabolic Syndrome trait cluster is not operative in a population of African Americans with little European genetic admixture,

Different criteria for identifying metabolic risk should be developed as a function of race/ethnicity, perhaps based on ancestral genetic admixture,

Susceptibility genes can be unique or exert differential effects on metabolic traits as a function of race/ethnicity

Exercise and diet are good for everyone!!!!!!!!!!

1. M. Sale /(Molecular Geneticist) PI/ R01 Genetic contributors to Diabetes and Dyspipdemia in African Americans

2. I. Spruill Minority Supplement/ Qualitative component:

What is the likelihood that an individual will change his or her health behaviors if they have knowledge of a genetic susceptibility?

What is the best format and source for presenting genetic information?

3. J. Fernandes ( Re contact to obtain estimates of the prevalence of diabetes complications and co morbidities in Project Sugar participants

Community: Staffing, engagement

Plan: Flexible protocol,direct,active recruitment

Rewards: Services to the Community

Non-traditional family styles

Blood relatives vs fictive kin

Ask the Right questions

Birth parents vs who raise you

“What you tell me is in private”

Flexible Protocol

Recruit extended family members Compensation Weekend after hours Inform consent read to participants Direct and active recruitment

Always provide a tangible service to the community, (SuGar Bus)

Find ways to keep the community engaged

(attend a local church) Cultural events, Speaking engagements

Share results/finding with community (quarterly newsletter)

•You must have patience,

•Acknowledge Altruism within the culture

• “(I am doing this so my grand kids don’t have to suffer)”

•Identify the gatekeeper in the family