A Whole Genome Association Search for Type 2 Diabetes Genes in African Americans

This sub-study phs000140 CIDR T2D Bowden contains genotype data and selected phenotype of subjects available from the phs000140 study. Summary level phenotypes for the NIDDK T2D Seq GWAS AA Cohort study participants can be viewed at the top-level study page phs001167 T2D Seq GWAS AA Cohort. Individual level phenotype data and molecular data for all T2D Seq GWAS AA Cohort top-level study and sub-study are available by requesting Authorized Access to the NIDDK T2D Seq GWAS AA Cohort phs001167 study.

Over 2.8 million African Americans have type 2 diabetes mellitus (T2DM). This represents approximately 13% of the African American population and a significant proportion of the 21 million Americans living with diabetes. On average, an African American individual is twice as likely to have T2DM as a European American peer. Our research group has been actively involved in the study of African American diabetes genetics for over 15 years. We hypothesize that genes contributing to the development of T2DM in African Americans exist and can be located using modern molecular genetic methods. With the exception of TCF7L2(Transcription factor 7-like 2) evidence to date suggests variants that contribute T2DM risk in European-derived populations are not significant contributors to African American T2DM risk. We have performed a SNP-based Whole Genome Association (WGA) analysis on the Affymetrix 6.0 in a case control population of over 1000 African American T2DM cases and over 1000 non-diabetic controls. The DNAs have been collected from participants using uniform criteria from North Carolina and neighboring states. Genotype data will be subjected to extensive genetic analysis with the goal of defining a priority list of SNPs for genotyping in independent populations for confirmation and further detailed analysis.

• Study Design:
  • Case-Control
• Study Type:
  • Case-Control
• Total number of consented subjects: 2004
• Subject Sample Telemetry Report (SSTR)

Cases: For this study we propose to focus on the unrelated cases and controls in our collection. Consenting self-identified African Americans, age 35 or older, born in North Carolina, South Carolina, Georgia, Virginia, or Tennessee, were eligible for participation. Recruiting was performed at clinical facilities, health fairs, church participation, and through public advertising using a uniform ascertainment. T2DM was diagnosed in patients who received oral hypoglycemic agents or dietary therapy without insulin for at least one year after initial diagnosis and in whom initial diagnosis of diabetes mellitus occurred after age 35. Patients with a history of diabetic ketoacidosis or who developed diabetes mellitus prior to age 25 and received continuous insulin therapy since diagnosis, were presumed to have type 1 diabetes and were ineligible. For the 1000 cases proposed for the WGA analysis, we wish to use DNAs from cases with T2DM and DM-ESRD (Diabetes Mellitus - End Stage Renal Disease), which make up a majority of our collection. The great advantage of this approach is that these cases are clearly long term diabetes affected individuals and with the WGA of T2DM we will also get a WGA of DM-ESRD. Importantly, as outlined below, we have the capability to differentiate between genes which contribute solely to T2DM and solely DM-ESRD through our other collections and collaborations. There is no extant literature that suggests that there are any population-based differences between subjects with T2DM (without ESRD) and subjects with T2DM and DM-ESRD. If there are unperceived differences we would note that subjects with DM-ESRD has one of the most devastating complications of diabetes and are thus of high importance to study.

Controls: Control samples have been recruited from health fairs, church participation, and public advertising. The great majority of the control subjects have fasting plasma glucose (FPG) measures and renal function analysis and are designated (diabetes) controls if they have FPG ≤ 100 mg/dL consistent with current American Diabetes Association (ADA) definition and no evidence of microalbuminuria. It is noteworthy that the mean BMI of cases and controls are similar and that the mean age of examination for the controls is 8.7 years later than the mean age of diagnosis for the cases.

Exclusions: Inability to provide informed consent.

The development of this study reflects a 15 year commitment to the study of the genetics of type 2 diabetes and complications of diabetes in the African American population. Multiple studies in the African American population have contributed to creating a sample collection appropriate for the initial GWAS and subsequent follow-up replication studies.

• Primary Phenotype: Diabetes Mellitus, Type 2
• Diabetic Nephropathies

• Principal Investigator
  • Donald Bowden, PhD. Center for Human Genomics, Center for Diabetes Research, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
• Institute
  • Wake Forest University School of Medicine, Winston-Salem, NC, USA.
• Funding Source
  • R01 DK53591. National Institutes of Health, Bethesda, MD, USA.
  • R01 DK066358. National Institutes of Health, Bethesda, MD, USA.
• Genotyping Center
  • Johns Hopkins University Center for Inherited Disease Research (CIDR), Baltimore, MD, USA.
• Funding Source for Genotyping
  • HHSN268200782096C. NIH contract "High throughput genotyping for studying the genetic contributions to human disease". National Institutes of Health, Bethesda, MD, USA.