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Diabetes 53:1134-1140, 2004
© 2004 by the American Diabetes Association, Inc.

A Common Polymorphism in the Upstream Promoter Region of the Hepatocyte Nuclear Factor-4{alpha} Gene on Chromosome 20q Is Associated With Type 2 Diabetes and Appears to Contribute to the Evidence for Linkage in an Ashkenazi Jewish Population

Latisha D. Love-Gregory1, Jonathon Wasson1, Jiyan Ma1, Carol H. Jin2, Benjamin Glaser3, Brian K. Suarez2,4, and M. Alan Permutt1

1 Division of Endocrinology, Diabetes and Metabolism, Washington University School of Medicine, St. Louis, Missouri
2 Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri
3 Endocrinology and Metabolism Service, Internal Medicine Department, The Hadassah-Hebrew University Medical Center, Jerusalem, Israel
4 Department of Genetics, Washington University School of Medicine, St. Louis, Missouri

Variants in hepatocyte nuclear factor-4{alpha} (HNF4{alpha}), a transcription factor that influences the expression of glucose metabolic genes, have been correlated with maturity-onset diabetes of the young, a monogenic form of diabetes. Previously, in a genome scan of Ashkenazi Jewish type 2 diabetic families, we observed linkage to the chromosome 20q region encompassing HNF4{alpha}. Here, haplotype-tag single nucleotide polymorphisms (htSNPs) were identified across a 78-kb region around HNF4{alpha} and evaluated in an association analysis of Ashkenazi Jewish type 2 diabetic (n = 275) and control (n = 342) subjects. We found that two of nine htSNPs were associated with type 2 diabetes: a 3' intronic SNP, rs3818247 (29.2% case subjects vs. 21.7% control subjects; P = 0.0028, odds ratio [OR] 1.49) and a 5' htSNP located ~3.9 kb upstream of P2, rs1884614 (26.9% case subjects vs. 20.3% control subjects; P = 0.0078, OR 1.45). Testing of additional SNPs 5' of rs1884614 revealed a >10-kb haplotype block that was associated with type 2 diabetes. Conditioning on the probands’ rs1884614 genotype suggested that the chromosomal region identified by the htSNP accounted for the linkage signal on chromosome 20q in families in which the proband carried at least one risk allele. Notably, the associations and the partitioned linkage profiles near P2 were independently observed in a Finnish sample, suggesting the presence of potential regulatory element(s) that may contribute to the risk for type 2 diabetes.

Address correspondence and reprint requests to M. Alan Permutt, MD, Division of Endocrinology, Diabetes and Metabolism, Washington University School of Medicine, St. Louis, MO 63110. E-mail: apermutt{at}im.wustl.edu


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