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Ida J. Spruill PhD, RN, LISW May 13, 2010 The People The Community Project SuGar & The Science Outcomes & Results (Overview of South Carolina and the Gullah population) (Community Engagement/Involvement ) scan) (GWAS) (UCP 3 gene) (Linkage 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 •PIs: W.T. Garvey •Jtoyika Fernandes Human Physiology •Citizen’s Advisory Committee Members Steve Willi Lidia Maianu Penny Wallace Genetics & Molecular Amy Hutto Kerry Lok George Argyropoulos Sara Shaughnessy Angela Brown Community-Based Research Soonho Kwon Pamela Binns Ida Spruill Jyotika Fernandes David McLean Ann Smuniewski Kerin McCormack Gloria Smith Kirby Smith Yuchang Fu Helliner Vestri Julian Munoz Deborah Daniels Statistical Genetics Andrea Collins Michele Sale (UVa) Pam Wilson Carl Langefeld (WFU) Susan Cromwell Don Bowden (WFUStatistical Genetics Fredrika Joyner Karen Small Gwen Maine Mattie Wideman Lingyi Lu (WFU) 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 Admixture Estimate Population (%±SE) Gullah Sea Islanders 3.5 ± 0.8 Charleston Mississippi delta 9.8 ± 1.2 13.3 ± 1.9 Chicago 18.8 ± 1.4 New York 19.8 ± 2.1 Pittsburgh Baltimore New Orleans Jamaica 25.2 ± 2.7 15.5 ± 2.6 22.5 ± 1.6 6.8 ± 1.3 Parra et al, Am J Physical Anthropol, 114:18, 2001 Parra 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% Most of the newly-identified diabetes genes do not play a major role in diabetes risk in African Americans BRRSS,2006 Project SuGar / CPR (Spruill,I.2005) Community 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 17 . Community Services Free Screening COMMUNITY SProject SuGar Mobile Project Sugar mobile unit 650 Families recruited Female Married Attended High School Have Insurance Preferred learning in Groups 21 Diabetes is Inherited: 61.1% Diabetes is prevented: 66.6% 11.8% use Home Remedies Most 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 2007: A breakthrough year in diabetes genetics, Frayling TM. Nat Rev Genet 2007 Sep; 8:657-62 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) C7 C 14 Genome Wide Gene Association Studies (GWAS) Can Identify Complex Disease Genes 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, Type 2 Diabetes Genes GENE Chromo- Mode of ID some Previous Evidence Evidence from Human Physiology PPARG 3 Candidate Drug target Insulin sensitivity KCNJ11 12 Candidate Drug target Insulin secretion 17 Candidate/ linkage Monogenic diabetes MODY, Insulin secretion 4 Candidate/ Linkage Monogenic diabetes Wolfram Syndrome 10 Linkage then region-wide AS none Insulin secretion GWAS Pancreas development Insulin secretion TCF2 WFS1 TCF7L2 HHEX-IDE 10 SLC30A8 8 GWAS none Insulin secretion CDKAL1 6 GWAS none Insulin secretion GWAS Reduced islet mass in mice (Coronary Artery Disease) CDKN2A-2B 9 IGF2BP2 3 GWAS Binds IGF2 FTO 16 GWAS none BMI/obesity Identified as a major new diabetes gene on C-10 by Grant 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. 2. M. Sale /(Molecular Geneticist) PI/ R01 Genetic contributors to Diabetes and Dyspipdemia in African Americans 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