The Prevalence of the HNF-1α G319S Mutation in Canadian Aboriginal Youth With Type 2 Diabetes
- Elizabeth A.C. Sellers, MD,
- Barbara Triggs-Raine, PHD,
- Cheryl Rockman-Greenberg, MD and
- Heather J. Dean, MD
- 1Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Manitoba, Canada
- 2Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada
Abstract
OBJECTIVE—To investigate the prevalence of the unique HNF-1α G319S mutation in a population of aboriginal youth with type 2 diabetes and to describe the relationship between clinical and historical characteristics and the presence or absence of the HNF-1α G319S mutation.
RESEARCH DESIGN AND METHODS—Participating youth were genotyped for the G319S mutation of the HNF-1α gene. Clinical, laboratory, and historical data were collected via chart review (blinded to genotype results). Comparison data were derived from another study involving young nondiabetic pregnant aboriginal women.
RESULTS—A total of 51 youth seen sequentially in a type 2 diabetes clinic participated in this study. Of these, 21 (41.2%) had at least one copy of the mutant allele. The allele frequency in the study population was 0.29 (95% CI 0.20–0.38), which was significantly different from the allele frequency of 0.13 in the comparison population (χ2 = 6.78, P = 0.009). The frequency of the homozygous mutation (S319/S319) was 0.18. Mean BMI was significantly lower (P = 0.002), mean HbA1c was significantly higher (P = 0.02), and acanthosis nigricans was significantly less frequent (P = 0.004) in those with the mutation compared with the wild type. Mean insulin levels were lower and insulin sensitivity (assessed by homeostasis model assessment [HOMA]) was greater in the homozygote group compared with the wild-type group (P = 0.002 and P = 0.0007, respectively). A dose-dependent gradient was observed for these characteristics.
CONCLUSIONS—These data support the association between the HNF-1α G319S mutation and early-onset type 2 diabetes in this population. Those with the mutation lacked clinical characteristics of insulin resistance (e.g., obesity and acanthosis nigricans) and had lower insulin levels, suggesting that an insulin-secretory and/or -production defect plays an important role in the development of diabetes in this group. Further investigation of the pathophysiology of the S319 homo- and heterozygote is needed because it may impact treatment and/or prevention of this disease.
- HNF, hepatic nuclear factor
- HOMA, homeostasis model assessment
- MODY, maturity-onset diabetes of the young
Footnotes
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Address correspondence and reprint requests to Elizabeth A.C. Sellers, MD, Department of Pediatrics and Child Health, University of Manitoba, Rm. FE-307 685, William Ave., Winnipeg, Manitoba, Canada R3E 0Z2. E-mail: esellers{at}exchange.hsc.mb.ca.
Received for publication 18 March 2002 and accepted in revised form 15 September 2002.
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