Studies of the genetic variability of the coding region of the hepatocyte nuclear factor-4α in Caucasians with maturity onset NIDDM |
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Authors: | A M Møller S A Urhammer L T Dalgaard R Reneland L Berglund T Hansen J O Clausen H Lithell O Pedersen |
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Institution: | (1) Steno Diabetes Center and Hagedorn Research Institute, Denmark, DK;(2) Department of Geriatrics, Uppsala University, Uppsala, Sweden, SE;(3) Center of Preventive Medicine, Glostrup University Hospital, Copenhagen, Denmark, DK |
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Abstract: | Summary Mutations in the hepatocyte nuclear factor-4α (HNF-4α) gene cause the type 1 form of maturity onset diabetes of the young
(MODY1). To address the question of whether genetic variability of HNF-4α is associated with late onset non-insulin-dependent
diabetes mellitus (NIDDM) we have sequenced the coding region and intron/exon boundaries of the gene in 36 randomly recruited
Danish NIDDM patients. Two nucleotide substitutions that changed the sequence of HNF-4α were identified: Thr/Ile130, which
has been reported previously and a novel Val/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 susceptibility. Among 509 NIDDM patients the allelic frequency of the Thr/Ile130 variant was 4.7 % (95 % confidence
interval: 3.4–6.0 %) compared to 1.9 % (0.7–3.1 %) among 239 control subjects (p = 0.008). However, 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 with 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 prevalence
of the codon 130 variant (4.7 % 3.2–6.2 %]) was similar to what was found in Swedish Caucasians. Thus, the allelic frequency
of the Thr/Ile130 variant among the control subjects in the Danish case-control study deviates from the prevalence in the
two other studies which is why we consider the significant association between the codon 130 variant and NIDDM an incidental
finding. In glucose tolerant subjects the codon 130 variant in its heterozygous form had no major effect on glucose-induced
insulin and C-peptide release although a tendency to a lower insulin secretion during an oral glucose tolerance test was seen
in middle-aged subjects. In conclusion, variability in the coding region of the HNF-4α 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 segregation studies are needed to determine whether this HNF-4α variant is a NIDDM causing mutation.
Diabetologia (1997) 40: 980–983]
Received: 17 April 1997 and in revised form: 28 May 1997 |
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