An increasing number of epidemiological studies are utilising genetic technology to provide a more detailed insight into the underlying causes of complex diseases. Recently, two such studies have identified a number of single nucleotide polymorphisms (SNPs) that may predict susceptibility to type II, or non-insulin dependant, diabetes (NIDDM). These findings have been the subject of several press releases (The Washington Times, Reuters, and NHGRI). The two studies, conducted on Finnish (Silander, K., et al. Genetic variation near the hepatocyte nuclear factor-4a gene predicts susceptibility to type 2 diabetes. Diabetes 53:1141-1149) and Ashkenazi Jewish (Love-Gregory, L.D., et al. A common polymorphism in the upstream promoter region of the hepatocyte nuclear factor-4a gene on chromosome 20q is associated with type 2 diabetes and appears to contribute to the evidence for linkage in an Ashkenazi Jewish population. Diabetes:53;1134-1140) populations identified four SNPs located in the P2 regulatory region of the hepatocyte nuclear factor 4 alpha (HNF4A) gene which may be associated with an increased risk of developing NIDDM. HNF4A is a member of the transcription factor family of genes and acts as a switch to regulate the expression of many other genes. For example, HNF4A regulates the expression of genes involved in glucose metabolism and insulin secretion and directly activates insulin gene expression. The Finland-United States Investigation of NIDDM Genetics (FUSION) study applied a DNA pool-based, case-control design and identified ten SNPs to be associated with disease status in a Finnish population, with the strongest association suggesting that one particular SNP (rs2144908) may increase the risk of NIDDM by around 30%. Genotyping of additional SNPs, identified in the Ashkenazi Jewish population by Love-Gregory and colleagues, showed evidence for an association between four HNF4A SNPs and NIDDM in both Finnish and Ashkenazi Jewish populations. When taken together these results provide some initial evidence for a variant(s) near to the P2 promoter of HNF4A that may increase the susceptibility to NIDDM, however, they require verification in larger studies conducted in different populations.
Comment: These two studies, conducted in genetically distinct populations, provide initial evidence for a variant(s) located near or within HNF4A that may increase susceptibility to NIDDM. Among its many functions, HNF4A performs a regulatory role for a number of beta cell and liver cell genes and plays a role in regulating the secretion of insulin. Given the complex nature of diseases such as NIDDM, determining the precise association between gene variants and disease is problematic. It is to the author’s credit, therefore, that they sound a note of caution when attempting to draw firm conclusions on the basis of these results, including the caveat; “Additional variant identification and genotyping, study of other populations, and, finally, functional studies will be needed to identify the true type 2 diabetes susceptibility variant(s) at 20q13”.