STUDIES OF THE GENETIC-VARIABILITY OF THE CODING REGION OF THE HEPATOCYTE NUCLEAR FACTOR-4-ALPHA IN CAUCASIANS WITH MATURITY-ONSET NIDDM

Mutations in the hepatocyte nuclear factor-4 alpha (HNF-4 alpha) gene cause the type 1 form of maturity onset diabetes of the young (MODY1). To address the question of whether genetic variability of HNF-4 alpha is associated with late onset non-insulin-dependent diabetes mellitus (NIDDM) we have sequenced the coding region and intron/exon boundarie s of the gene in 36 randomly recruited Danish NIDDM patients. Two nucl eotide substitutions that changed the sequence of HNF-4 alpha were ide ntified: Thr/Ile130, which has been reported previously and a novel Va l/Met255. The Val/Met 255 mutation was found in 4 of 477 Danish NIDDM patients and in none of 217 glucose tolerant control subjects; thus it cannot be excluded that this mutation may have an impact on NIDDM sus ceptibility. Among 509 NIDDM patients the allelic frequency of the Thr /Ile130 variant was 4.7 % (95 % confidence interval: 3.4-6.0 %) compar ed to 1.9 % (0.7-3.1 %) among 239 control subjects (p = 0.008). Howeve r, in a population sample of 942 Swedish men with an average age of 70 years the allelic frequency of the variant was similar in 246 men wit h either impaired glucose tolerance (5.6% [2.6-8.6%]) or NIDDM (5.4 % [2.7-8.1 %]) as compared to 666 glucose tolerant men (5.1% [3.9-6.3 %] ). Also in a population sample of 369 young healthy Danes the prevalen ce of the codon 130 variant (4.7 % [3.2-6.2 %]) was similar to what wa s found in Swedish Caucasians. Thus, the allelic frequency of the Thr/ Ile130 variant among the control subjects in the Danish case-control s tudy deviates from the prevalence in the two other studies which is wh y we consider the significant association between the codon 130 varian t and NIDDM an incidental finding. In glucose tolerant subjects the co don 130 variant in its heterozygous form had no major effect on glucos e-induced insulin and C-peptide release although a tendency to a lower insulin secretion during an oral glucose tolerance test was seen in m iddle-aged subjects. In conclusion, variability in the coding region o f the HNF-4 alpha gene is not a common cause of NIDDM among whites of Danish ancestry. However, a Val/Met255 mutation was found exclusively in NIDDM patients (0.8% of cases) and functional as well as family seg regation studies are needed to determine whether this HNF-4 alpha vari ant is a NIDDM causing mutation.