Rs4812829

rs4812829, rs4812829 showed a strong link to an increased susceptibility to type II diabetes in the South Asia population by itself and in Japanese population with five other risk alleles in two different studies. These results indicate that the genes and/or other factors associated with this SNP are important in the development of type 2 diabetes. rs4812829 is located at 20q13 in the intronic region of HNF4A (Hepatocyte nuclear factor 4 alpha), which encodes a transcription factor that binds DNA as a homodimer. HNF4A controls the expression of several genes, including HNF1A (hepatocyte nuclear factor 1 alpha), another transcription factor that regulates hepatic gene expression. Mutations in HNF4A have been previously shown to be cause mature-onset type I diabetes.,, thus functionally linking this region to diabetes.

Background
As the most common form of diabetes, type 2 diabetes affects almost 300 million people around the world. Asians, Africans, as well as the older population, tend to be more susceptible to the disease. Various causes, such as the inability of pancreatic β-cells to produce sufficient amount of insulin or the gradual development of insulin resistance so that regular insulin levels become insufficient, can lead to type 2 diabetes. While type 2 diabetes is associated with many environmental factors such as diet, a variety of genetic factors, which may affect β-cell function, also contribute to the individual’s susceptibility to the disease. Various single gene mutations have been reported to contribute to type 2 diabetes, but the majority of T2D cases result from the combined effect of many SNPs that each by itself have a relatively small effect on the risk of T2D. So far, more than 60 of such SNPs have been identified, and rs4812829 is one of them. All known genetic variation explains one tenth of diabetes heritability.

Relevant Studies
So far, there are two major studies conducted on the association between rs4812829 and type 2 diabetes. One was published in 2011 titled “Genome-wide association study in individuals of South Asian ancestry identifies six new type 2 diabetes susceptibility loci”, and the other is “A Single Nucleotide polymorphism within DUSP9 is Associated with Susceptibility to Type 2 Diabetes in a Japanese Population” , published in 2012. While the methods and samples in the two studies differ, they both suggest that A allele is positively associated with an increase in T2D risk. The method and results of the two studies are briefly summarized below:


 * 1) The Konner et al. study uses 5,561 South Asian cases and 14,458 South Asian controls in the primary analysis phase for 568,976 autosomal SNPs and identified one known genome-wide significant allele (P<5 x 10-18) and a further 59 genes with P<=5 x 10-4, of which 50 have been studied previously. Replication was done using 13,170 South Asian cases and 25,398 South Asian controls, and rs4812829 showed a P value of 2.6 x 10-10 in the combined analysis of the primary and replication study, with an odds ratio of 1.09. Because rs4812829 is in the  intronic region of HNF4A, the authors further explored the region, and identified four genotyped SNPs in the region that are associated with T2D at P<=5 x 10-4. Tough in a conditional analysis, these four SNPs produced a reduced effect sizes, indicating that they might not be independent.  In the same study, the authors reported another 5 SNPs that are associated with increased risk of T2D in South Asian population: rs3923113 near GRB14, rs16861329 in ST6GAL1, rs1802295 in VPS26A, rs7178572 in HMG20A, rs2028299 near AP3S2, and rs4812829 in HNF4A.
 * 2) In another study, Fukuda and colleagues genotyped Japanese 8,318 T2D cases and 3,001 controls and examined the effect of seven newly discovered SNPs, including rs4812829 and the other five identified in the above studies. The authors confirmed the previously observed increased risk with the A allele for rs4812829, but found that the six SNPs above do not reach genome-wide significance for this Japanese population. They then constructed a genetic risk score based on these 6 SNPs and found that they were significantly associated with Japanese T2D occurrence with p = 8.69 x 10-14, OR = 1.06.

These studies suggest a likely association of rs4812829 and type 2 diabetes, but the effect may be population-dependent. Individuals of South and East Asian ancestry are at elevated risk of T2D compared to European populations, and deciphering a genetic connection of the disease could help further research, diagnostics and therapies.