The overall objective of this study is to determine pro-inflammatory cytokine allele frequencies in West Africans and African Americans with NIDDM and to determine the linkage of these alleles to clinical phenotypes of NIDDM. Specifically we will 1) determine the frequency of allelic polymorphisms in the TNF-a gene promoter (-238, -308), IL-6 gene promoter (174) and IL-1b gene promoter (-511); and their receptor gene polymorphisms (TNFR-1, TNFR-2 593-598-620); and the association of these alleles with insulin sensitivity and BMI in a cohort of West Africans and a subgroup of African Americans with NIDDM. 2) to determine cytokine and cytokine receptor gene expression relative to their promoter polymorphisms, insulin sensitivity and BMI phenotypes; 3) to determine plasma cytokine and soluble receptor ;levels in the AADM, recruited control sets, in LPS-treated GENNID diabetic samples and control sets. Increasing evidence exists that TNF-a, IL-6 and IL-1b play a key role in obesity and insulin resistance. Obesity and insulin resistance are hallmarks of NIDDM. Because of their regulatory role in the immune system and also in the endocrine system, cytokines have become significant markers for genetic and functional studies. Most genetic studies of obesity and NIDDM are performed with samples from Caucasian populations while are few studies on African Americans and a paucity of information on Africans, considering the global nature of this disease. This study will be the largest and most comprehensive study of the genetics of cytokine polymorphisms in NIDDM in Africans and African Americans thus far. Data from these studies may provide insights into the relationships, if any, between Americans and their ancestral counterparts as it relates to the activity of these cytokine genes in NIDDM.
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