# Presentation: 572099

## PROJECT SUGARGenetic and Metabolic Basis of Diabetes and Obesity in Gullah-Speaking African Americans

- W. Timothy Garvey, MD
- Department of Nutrition Sciences
- University of Alabama at Birmingham

*National Advisory Research Resources Council *
*Bethesda MD         September 11, 2007*

## Causes of Hyperglycemia inType 2 Diabetes

***Peripheral tissues***
***(skeletal muscle)***

**Insulin**
**Resistance**

**Increased glucose**
**production**

**Impaired insulin secretion**

****** ****Glucose**

***Pancreas***

***Liver***

**X**

**X**

## Variation in Insulin Sensitivity

- (Insulin Sensitivity)

## Metabolic Syndrome Insulin Resistance Syndrome, Syndrome X

- Hyperinsulinemia
- Impaired glucose tolerance
- Obesity
- Increased visceral fat distribution
- Hypertriglyceridemia/Low HDL
- Small, dense LDL
- Hypertension

- Positive family history
- Disfibrinolysis (high PAI-1)
- Vascular reactivity/ endothelial dysfunction
- Inflammation
- Microalbuminuria
- Polycystic ovary syndrome
- NAFLD

## Secreted Adipocyte Factors

_**Insulin Resistance/Adipocyte Size**_
-   Free Fatty Acids
-   Leptin
-   Adiponectin
-   Resistin

_**Dysfibrinolysis**_
-   PAI-1

_**Vascular Reactivity**_
-   Free Fatty Acids
-   Angiotensinogen (RAAS)
-   Inflammation

_**Lipids/Lipoproteins**_
-   Acylation Stimulation Protein
-   Cholesterol Ester Transfer Protein
-   Phospholipid Transfer Protein

_**Inflammation**_
-   TNF alpha
-   IL-1, IL-6, IL-8, IL-10
-   MCP-1
-   MIF

## Common Soil Hypothesis

**Metabolic Syndrome**
**“****Common Soil”**

**Environment**

**Genes**

**Type 2 Diabetes **

**Atherosclerosis**

## Multiple Criteria for Metabolic Syndrome

| RISK FACTOR | ATPIII | WHO | IDF |
| --- | --- | --- | --- |
|  | 3 out of 5 | IGT/IFG + 2 | Waist + 2 |
| I.	Waist  |  |  |  |
| 	men	 |  >102 cm (40 in) | W/H > .90
BMI > 30 |  94 cm (Europid) |
| 	women               | >88 cm (35 in) | W/H > .85
BMI > 30 |  80 cm (Europid) |
| II.	Triglycerides | ≥150 mg/dL | ≥ 1.7 mM | ≥150 mg/dL |
| III.	HDL Cholesterol |  | and/or |  |
| 	men | <40 mg/dL | < 0.9 mM | <40 mg/dL |
| 	women | <50 mg/dL | < 1.0 mM | <50 mg/dL |
| IV.  	Blood Pressure | ≥130/≥85 | ≥160/90 | ≥130/≥85 |
| V.  	Fasting Glucose |  ≥100 mg/dL | IGT/IFG | ≥100 mg/dL |
| VI Microalbuminuria |  | ≥ 20 g/min |  |

## Prevalence of Diagnosed Type 2 Diabetes is Elevated in Black and Hispanic Males & Females

**Prevalence of Diagnosed Type 2 Diabetes is Elevated in Black and Hispanic Males & Females**

## Prevalence of the Metabolic Syndrome is not Increased in African Americans:  NHANESIII

- Ford et al,* JAMA.* 2002;287:356-359.

- AA

- AA

- W

- W

## Hypothesis

- There are racial differences in the pathophysiology of the Metabolic Syndrome
- The Increased risk of diabetes in African Americans has a genetic basis.

## Slide 11

## Gullah Speaking African Americans

## Coastal Africa showing historical areas of rice culture

- Littlefield, D.C. 1995. Rice and the making of South Carolina. Columbia, SC: SC Department of Archives and History.

**Notes:**
	Rice had been in cultivation in Africa, and particularly in Sierra Leone, for centuries before the trans-Atlantic slave trade began.  Thus, Sierra Leone became a significant slave exportation site, especially for slaves bound for South Carolina rice plantations. Though today’s overall African American population is an admixed population of, primarily, African and Caucasian populations, numerous cultural, linguistic, culinary, and historical studies have demonstrated closer associations between the current Gullah and Sierra Leone populations than between between other African Americans and African populations.

## Links between Gullahs and ‘Rice Coast’ of West Africa

- Colonists need rice growing expertise
- Historical record
- Language: Gullah – Krio
- Cultural similarities
- Genetic studies

## Advantages for Genetic Studies in the Gullahs

- Minimal genetic admixture
- Geographical isolation and cultural identity
- Large stable multi-generational families
- 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)

## Admixture Estimates in African American Populations: Autosomal Markers

| Population | Admixture Estimate 
(%±SE) |
| --- | --- |
| Gullah Sea Islanders |  3.5 ± 0.8 |
| Charleston |   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, 2001
- Parra et al, Am J Hum Genet, 63:1839, 1998

## Neighbor-joining trees of genetic distance of Y-haplotypes

- DSW

- DA

**Notes:**
	As expected, Caucasians are consistently more genetically distant from all other populations for each genetic distance model studied. No other consistent interpretation across all samples follows from these trees, but the Gullah and Sierra Leone samples are generally close across each genetic distance model. The represented distance between Sierra Leone and each of Jamaican, Charleston African American, and west coast African American samples varies across the models. 

## Slide 18

## Project Sugar Objectives

_***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

- Funding:  W M Keck Foundation, NIH DK47461, ADA (GENNID Study),
-                 NIH/NCRR MUSC Dental COBRE, MUSC Dept of Medicine

## Slide 20

## COMMUNITY Research Coupled with Community Service, Education, and Participation

## Charleston

**Charleston**

## Insulin Resistance Trait Cluster in Gullah-speaking African Americans

|  | Caucasians |  | African Americans |  |
| --- | --- | --- | --- | --- |
|  | r | p | r | p |
| Waist | -.53 | <.001 | -.47 | <.02 |
| SBP | -.25 | <.05 | +.05 | NS |
| TG | -.43 | <.001 | +.04 | NS |
| HDL | +.25 | <.03 | -.14 | NS |
| small LDL | -.41 | <.001 | +.11 | NS |
| lg HDL | +.39 | <.001 | -.20 | NS |

## Lipid Panel Values are Benign in Gullah Speaking African Americans with uncontrolled Type 2 Diabetes and Obesity

|  | Men | Women | P |
| --- | --- | --- | --- |
| Age, y | 54.0 ± 13.1 | 55.4 ± 12.1 | NS |
| Duration of diabetes, y | 8.9 ± 8.1 | 9.6 ± 8.4 | NS |
| HbA1c, % hemoglobin | 9.0 ± 2.1 | 9.2 ± 2.1 | NS |
| BMI, kg/m2 | 31.9 ± 6.7 | 35.0 ± 7.9 | 0.0044 |
| Waist/Hip ratio | 0.94 ± 0.07 | 0.89 ± 0.08 | 0.0001 |
| Systolic BP, mm Hg | 134.2 ± 23.2 | 136.8 ± 21.1 | NS |
| Diastolic BP, mm Hg | 83.8 ± 13.0 | 81.5 ± 11.1 | NS |
| Total Cholesterol, mg/dL | 196 ± 41 | 201 ± 45 | NS |
| LDL-C, mg/dL | 128 ± 39 | 127 ± 41 | NS |
| HDL-C, mg/dL | 41 ± 13 | 50 ± 14 | 0.0000 |
| TG, mg/dL | 151 ± 98 | 124 ± 69 | 0.0440 |
| Smoker, % | 19 | 13 | NS |
| Hypertension, % | 61 | 71 | NS |

**Lipid Panel Values are Benign in Gullah Speaking African Americans with uncontrolled Type 2 Diabetes and Obesity**

## Multiple Criteria for Metabolic Syndrome

| RISK FACTOR | ATPIII | WHO | IDF |
| --- | --- | --- | --- |
|  | 3 out of 5 | IGT/IFG + 2 | Waist + 2 |
| I.	Waist  |  |  |  |
| 	men	 |  >102 cm (40 in) | W/H > .90
BMI > 30 |  94 cm (Europid) |
| 	women               | >88 cm (35 in) | W/H > .85
BMI > 30 |  80 cm (Europid) |
| II.	Triglycerides | ≥150 mg/dL | ≥ 1.7 mM | ≥150 mg/dL |
| III.	HDL Cholesterol |  | and/or |  |
| 	men | <40 mg/dL | < 0.9 mM | <40 mg/dL |
| 	women | <50 mg/dL | < 1.0 mM | <50 mg/dL |
| IV.  	Blood Pressure | ≥130/≥85 | ≥160/90 | ≥130/≥85 |
| V.  	Fasting Glucose |  ≥100 mg/dL | IGT/IFG | ≥100 mg/dL |
| VI Microalbuminuria |  | ≥ 20 g/min |  |

## Hypothesis

- Are there genes unique to African ancestry that affect cardiometabolic risk?
-   Candidate Genes
-   Whole Genome Scan

## Mitochondrion

- H+

**Outer membrane**

**Inner membrane**

- FA-

- H+

- FA-H

- FA-

**UCP**

- FA-H

- H+

- H+

- ADP     ATP

- ATP
- Synthase

- FA-CoA

- FA
- Oxidation

- CPT2

**CPT1**

## UCP3 Polymorphisms and Mutations in African Americans

**UCP3 Polymorphisms and Mutations in African Americans**

## Slide 29

## Allele Frequency for Exon 6 Splice Donor Polymorphism

|  | g/g | g/a | a/a |
| --- | --- | --- | --- |
| 
Gullah | 80% | 20% | 0% |
|  | (230) | (57) | (0%) |
|  |      G: 90%    A: 10%
 |  |  |
| 
Mende | 82% | 16% | 1% |
|  | (158) | (31) | (3) |
|  |     G: 90%     A: 10% |  |  |

## UCP3 exon 6 splice variant affects macronutrient fuel partitioning

- RQ

- Lipid oxidation

## UCP3 Exon 6 Splice-Donor Variant is Associated with Severe Obesity

**BMI **_**<**_** 26**

**BMI **_**>**_** 38**

## Project SugarWhole genome scan for Diabetes/Obesity Genes in Gullah-Speaking African Americans

- Key phenotypes: Type 2 Diabetes, BMI, NMR lipoprotein subclass profile
- DNA submitted to CIDR 1028
- Represent 426  families (2-7 members)
- Affected sib-pair study design with T2DM 834, Unaffected 194
- CIDR recently completes Panel IV Illumina SNP scan = ~6,000 SNPs
- Statistical Genetics: Michele Sale (UVa) and Carl Langefeld (WFU)

## Chromosome 3 Linkages for Diabetes              With and Without Regard to Age of Onset                        

**All Diabetes**

**Early Onset**

**1.79**

**3.06**

## Chromosome 7 Linkages for Diabetes              With and Without Regard to Age of Onset                        

**DM1.72**

**DM 1.24**

**DM 3.41**

**WHR 3.27**

**Chromosome 7 Linkages for Diabetes**              *With and Without Regard to Age of Onset*

**All Diabetes**

**Early Onset**

## Chromosome 14 Linkages for Diabetes              With and Without Regard to Age of Onset                        

**DM 2.1**

**DM 3.82**
**WHR 3.89**

**Chromosome 14 Linkages for Diabetes**              *With and Without Regard to Age of Onset*

**All Diabetes**

**Early Onset**

## Individuals with Disease

**Environmental**
**Factor 1**

**Gene 1**

**Gene 2**

**Individuals with Disease**

- Susceptibility Genes Interact with the Environment

## Diabetes Gene – Gene Interactions

- Chr 8 & Chr 9

- Chr 8: Waist LOD = 3.0

## Diabetes Gene – Gene Interactions

- Chr 17 & Chr 15

## Slide 40

## Community-Based Research

- Ida Spruill
- Ann Smuniewski
- Gloria Smith
- Deborah Daniels
- Andrea Collins
- Pam Wilson

- Genetics & Molecular Studies
- 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 (WFU)
- Lingyi Lu (WFU)

- Citizen’s Advisory Committee

## Slide 42

## Metabolic Evolution of Type 2 Diabetes

*Pre-Diabetes*

*Overt Diabetes*

- Late Phase Insulin
- Secretion

- 1st Phase Insulin Secretion

- Insulin Sensitivity

- Fasting Glucose

## Hypothesis

- The Increased risk of diabetes in African Americans has a genetic basis.
- There are racial differences in the pathophysiology of the Metabolic Syndrome?

## Slide 45

## Linkages for Waist Circumference in Gullah Speaking Americans

**4.19 (opt)**

**Chr 2**

**Chr 8**

**3.0 (large)**

**3.3 (opt, small)**

**Chr 20**

**3.13 (large)**

**Chr 22**

## The correlation between HMW Adiponectin and components of the metabolic syndrome varies by ethnicity 

**European American**

**African-American**