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Original Studies |
G319S Variant Is Associated with Early-Onset Type 2 Diabetes in Canadian Oji-Cree1
Robarts Research Institute (R.A.H., H.C.) and the Center for Studies in Family Medicine (S.B.H.), University of Western Ontario, London, Canada N6A 5K8; and the Samuel Lunenfeld Research Institute and Department of Medicine, Mount Sinai Hospital, University of Toronto (A.J.G.H., B.Z.), Toronto, Ontario, Canada M5B 1X5
Address all correspondence and requests for reprints to: Dr. Robert A. Hegele, Blackburn Cardiovascular Genetics Laboratory, Robarts Research Institute, 406–100 Perth Drive, London, Ontario, Canada N6A 5K8. E-mail: robert.hegele{at}rri.on.ca
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Abstract |
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(HNF-1)
have been found in patients with maturity-onset diabetes of the young.
We identified a new variant in the HNF-1 gene, namely G319S, in
Ontario Oji-Cree with type 2 diabetes. G319S is within the proline
II-rich domain of the trans-activation site of HNF-1
and alters a glycine residue that is conserved throughout evolution.
S319 was absent from 990 alleles taken from subjects representing six
other ethnic groups, suggesting that it is private for Oji-Cree. We
found that 1) the S319 allele was significantly more prevalent in
diabetic than nondiabetic Oji-Cree (0.209 vs. 0.087;
P = 0.000001); 2) S319/S319 homozygotes and
S319/G319 heterozygotes, respectively, had odds ratios for type 2
diabetes of 4.00 (95% confidence interval, 2.65–6.03) and 1.97 (95%
confidence interval, 1.44–2.70) compared with G319/G319 homozygotes;
3) there was a significant difference in the mean age of onset of type
2 diabetes, with G319/G319, S319/G319, and S319/S319 subjects affected
in the fifth, fourth, and third decades of life, respectively. In
subjects with type 2 diabetes, we also found significantly lower body
mass index and significantly higher postchallenge plasma glucose in
S319/S319 and S319/G319 compared with G319/G319 subjects. Finally,
among nondiabetic subjects, S319/G319 heterozygotes had significantly
lower plasma insulin than G319/G319 homozygotes. The presence of the
private HNF-1 G319S variant in a large number of Oji-Cree with type
2 diabetes and its strong association with type 2 diabetes
susceptibility are unique among human populations. Also, G319S is
associated with a distinct form of type 2 diabetes, characterized by
onset at an earlier age, lower body mass, and a higher postchallenge
plasma glucose. |
Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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It is possible that understanding those factors involved in the development of type 2 diabetes in Oji-Cree might help to direct preventive and therapeutic strategies. One such factor is the recent change in the Oji-Cree lifestyle, which has been characterized by an increase in their intake of dietary fat and a decrease in their level of activity, both of which have led to obesity and expression of diabetes (1, 2, 3, 4). The especially high prevalence of type 2 diabetes in the Oji-Cree suggests that these people may also harbor some genetic predisposition. Defining the genetic component might help to understand the metabolic pathway(s) involved in type 2 diabetes susceptibility in Oji-Cree. This might, in turn, allow for predictive testing that would target subjects who would be at higher risk for developing type 2 diabetes and who might therefore benefit from specific intervention strategies.
We are using both positional cloning and candidate gene approaches to
identify genetic variants that are associated with type 2 diabetes
susceptibility in the Oji-Cree (5, 6, 7, 8, 9, 10). One candidate gene for type 2
diabetes susceptibility encodes hepatic nuclear factor-1 (HNF-1),
a transcriptional activator of many hepatic genes, including albumin,
1-antitrypsin, and - and ß-fibrinogen (11, 12). The
gene encoding HNF-1, also called TCF1, is related to the
homeo box gene family, has been mapped to chromosome 12q24, and is
expressed predominantly in liver and kidney (11, 12, 13). Mutations in
HNF-1 are found in some subjects with maturity-onset diabetes of the
young (MODY) and in rare subjects with early-onset type 2 diabetes
(14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30). People with mutations in HNF-1 have defective insulin
secretion, which may be the basis for their diabetes phenotype
(23, 24, 25, 26). In the course of sequencing the HNF-1 gene in Oji-Cree
with and without type 2 diabetes, we have identified a new amino acid
variant, namely G319S. This private variant had a very strong
statistical association with type 2 diabetes, occurring in about 40%
of diabetic Oji-Cree, and was associated with an earlier age of onset,
lower body mass, and higher postchallenge plasma glucose levels.
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Subjects and Methods |
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The community of Sandy Lake, Ontario, is located about 2000 km northwest of Toronto, in the subarctic boreal forest of central Canada. Seven hundred and twenty-eight members (72% of the total population) of this community, aged 10 yr and above, participated in the Sandy Lake Health and Diabetes Project (1). Assessments included assessment of medical history, including a history of type 2 diabetes. The project was approved by the University of Toronto ethics review committee and the Sandy Lake First Nations Band Council.
Biochemical analyses
Plasma samples were obtained with informed consent. Exclusion criteria were an inadequate blood sample available for all biochemical and/or genetic determinations. Subjects gave plasma samples after fasting overnight for 12 h. Blood was centrifuged at 2000 rpm for 30 min, and the plasma was stored at -70 C. Concentrations of fasting plasma glucose and insulin were determined as previously described (1). A standard 75-g oral glucose tolerance test (OGTT) was then administered, and a second blood sample was collected after 120 min for plasma glucose determination. Subjects were excluded from the OGTT if they had physician-diagnosed diabetes and/or were currently receiving treatment with insulin and/or oral hypoglycemic agents or if they had a fasting blood glucose level exceeding 11.1 mmol/L. Subjects who were pregnant at the time of recruitment had their OGTT deferred until 3 months postpartum. Type 2 diabetes, impaired glucose tolerance, and normal glucose tolerance (nondiabetic) were diagnosed using established criteria (1).
Genetic analyses
We used published primer sequences to amplify all of the coding
regions, intron-exon boundaries, and 5'- and 3'-untranslated regions of
the gene encoding HNF-1 (16). We used these primers to screen
genomic DNA from three unrelated subjects with type 2 diabetes, less
than 50 yr of age and with body mass index (BMI) values below 30
kg/m2, and from three unrelated nondiabetic subjects, 60 yr
of age or older and with BMI of 35 kg/m2 or higher.
Amplified products were directly sequenced in both directions with an
ABI 377 automated DNA sequencer (PE Applied Biosystems,
Inc., Mississauga, Canada). ABI Sequence Navigator software (PE Applied Biosystems) was used to align and compare amplified DNA
fragments for sequence differences. Sequence differences that fulfilled
all of the following criteria were then further investigated: 1) the
sequence change was not simply a known polymorphism in HNF-1 (15);
2) the sequence change had the potential to be functionally relevant if
it resulted in an amino acid change, occurred at an intron-exon
boundary, or affected a putatively important sequence in the 5'- or
3'-untranslated regions; and 3) the sequence change was present among
the six alleles from the three diabetic subjects, but was absent from
the six alleles from the three nondiabetic subjects.
When a sequence change that fulfilled the above criteria was found, a
rapid screening method was developed to determine allele and genotype
frequencies. For example, BseDI digestion of the amplified
HNF-1 exon 4 fragment and electrophoresis in 10% polyacrylamide
were used to determine genotypes of the G319S mutation.
BseDI digestion of the G319 allele gave two distinct
fragments of 82 and 39 bp. BseDI digestion of the S319
allele gave a single 121-bp fragment.
Determinations of allele and genotype frequencies were made in diabetic and nondiabetic adult Oji-Cree only. To avoid a possible bias from studying nonindependent study samples, allele frequencies were first determined in unrelated subjects, with only one diabetic and one nondiabetic subject selected from each kindred. This resulted in a subset of adult Oji-Cree who were no closer to each other than second degree relatives, of whom 55 had diabetes and 148 did not have diabetes. If the difference in the subgroup of unrelated subjects was found to be significant, the allele and genotype frequencies were next assessed in the entire adult Oji-Cree sample, of whom 117 had diabetes and 334 did not have diabetes. Genotypes were also determined in 495 nondiabetic Canadians from other ethnic groups, including 147 Ojibwa, 87 Inuit, 72 Africans, 78 South Asians, 51 Chinese, and 60 Caucasians.
Statistical analyses
SAS (version 6.12, SAS Institute, Cary, NC) was used for all
statistical comparisons (31). Between-group differences in allele and
genotype frequencies were compared using 
2 analysis and
two-tailed Fisher’s exact test, respectively. Estimates of relative
risk of type 2 diabetes between genotypes were determined using odds
ratios from the Mantel-Haenszel method. The LIFETEST Wilcoxon procedure
was used to determine differences between the genotypes with respect to
age of onset for type 2 diabetes.
For continuous traits, ANOVAs were performed using the general linear
models procedure separately in diabetic and nondiabetic subjects. All
continuous traits had distributions that were significantly nonnormal
according to Wilk’s test of normality, but after transformation using
the natural logarithm (log), each trait had a distribution was no
longer significantly different from normal. ANOVA was used to determine
the sources of variation for log BMI, log fasting plasma glucose, log
fasting insulin, log fasting C peptide, log fasting leptin, and log
plasma glucose 2 h after the standard glucose load. F tests were
computed from the type III sums of squares (31). This form of sums of
squares is applicable to unbalanced study designs and adjusts the level
of significance to account for other independent variables included in
the model. Independent variables for each ANOVA were sex, age, and
HNF-1 genotype. Independent variables in ANOVAs for plasma
biochemical traits also included BMI. When a new significant
genotype-phenotype association was identified, the mean values for the
trait were compared between genotypic classes using pairwise
comparisons of least squares means (31). Untransformed biochemical
variables are presented in the tables.
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Results |
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We studied 117 subjects with type 2 diabetes, of whom 70 had a
previous medical diagnosis of type 2 diabetes and 47 were newly
diagnosed based upon fasting and/or 2-h postchallenge plasma glucose
concentrations. We also studied 334 subjects who had normal glucose
tolerance according to the established diagnostic criteria (1).
Baseline attributes of the study sample are shown in Table 1
.
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sequence variants
The described sequencing strategy revealed no sequence differences
among diabetic subjects, normal controls, and a reference HNF-1
genomic sequence in the 5'- and 3'-untranslated regions. There were
five sequence variants within introns, but none of these was close to
an intron-exon boundary, and each was found in both diabetic subjects
and nondiabetic controls. There were two silent variants that did not
affect the coding sequence, and each was found in both diabetic
subjects and nondiabetic controls. There were two previously reported
amino acid polymorphisms (I/L27 and N/S487) (15), and each was found in
both diabetic subjects and nondiabetic controls. There was one novel
mutation in codon 319, namely GGT
AGT, which resulted in a
substitution of Ser for Gly at this position. The G319S variant was
found in two of the three diabetic subjects screened (one homozygote
and one heterozygote), but was absent from all six alleles screened
from the normal controls and was also absent from the reference
HNF-1 genomic sequence. Since the G319S variant met all three
a priori criteria for being a possible relevant mutation, it
was studied further.
Allele frequency of HNF-1 S319 in Sandy Lake adults with and
without diabetes
Allele frequencies are shown in Table 2. In a subset of adult Oji-Cree who were
no more closely related than second degree relatives to each other, the
HNF-1 S319 allele frequency was 0.182 (20 of 110) in those with
diabetes and 0.068 (20 of 296) in those without diabetes
(2 = 10.5; P = 0.001). Given this
significant difference, we genotyped the entire adult Oji-Cree sample.
In the overall sample, the HNF-1 S319 allele frequency of 0.209 (49
of 234) in adult Oji-Cree with diabetes was significantly higher than
the allele frequency of 0.087 (58 of 668) in adult Oji-Cree without
diabetes (2 = 23.7; P = 0.000001). In a
subset of adult Oji-Cree whose BMI was less than 30 kg/m2
and whose age was less than 55 yr, the HNF-1 S319 allele frequency
was 0.277 (26 of 94) in those with diabetes and 0.102 (45 of 440) in
those without diabetes (2 = 22.1; P =
0.000005).
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genotype frequencies in Sandy Lake adults with and without
diabetes
Genotype frequencies are shown in Table 2
. Genotype frequencies
did not deviate from those predicted by the Hardy-Weinberg equation. In
the overall adult Oji-Cree sample, the genotype frequencies of subjects
with HNF-1 G319/G319, S319/G319, and S319/S319 were 0.624 (73 of
117), 0.333 (39 of 117), and 0.043 (5 of 117) in subjects with type 2
diabetes and 0.829 (277 of 334), 0.168 (56 of 334), and 0.003 (1 of
334) in subjects without type 2 diabetes (2 = 26.3;
P = 0.000003). The odds ratio for having type 2
diabetes for a HNF-1 S319/G319 heterozygote compared with a
G319/G319 homozygote was 1.97 [95% confidence interval (CI),
1.44–2.70]. The odds ratio for having type 2 diabetes for a HNF-1
S319/S319 homozygote compared with a G319/G319 homozygote was 4.00
(95% CI, 2.64–6.03).
In a subset of adult Oji-Cree with BMI less than 30 kg/m2
and age less than 55 yr, the HNF-1 G319/G319, S319/G319, and
S319/S319 genotype frequencies were 0.511 (24 of 47), 0.423 (20 of 47),
and 0.064 (3 of 47) in subjects with type 2 diabetes and 0.800 (176 of
220), 0.196 (43 of 220), and 0.005 (1 of 220) in subjects without type
2 diabetes (2 = 22.3; P = 0.00005). In
this subgroup, the odds ratio for having type 2 diabetes for a HNF-1
S319/G319 heterozygote compared with a G319/G319 homozygote was 2.65
(95% CI, 1.57–4.46). The odds ratio for having type 2 diabetes for a
HNF-1 S319/S319 homozygote compared with a G319/G319 homozygote was
6.25 (95% CI, 3.17–12.3).
Prevalence of HNF-1 S319 in other ethnic groups
S319 was completely absent from 990 alleles of subjects from six other ethnic groups (P < 10-13). The S319 allele frequency of 0.087 (57 of 334) in nondiabetic Oji-Cree was significantly different from the complete absence of S319 among 478 alleles of the two other Canadian aboriginal groups (P < 10-11), suggesting that it is unique to Oji-Cree.
Age of onset in diabetic subjects according to HNF-1
genotype
The mean (±SD) ages of onset of diabetes in subjects
with HNF-1 G319/G319, S319/G319, and S319/S319 genotypes were
43.0 ± 11.6, 36.6 ± 12.4, and 28.0 ± 5.8 yr,
respectively (P = 0.003). Figure 1 shows a plot of the cumulative
proportion of subjects with type 2 diabetes by age of onset. The curves
were significantly different between the HNF-1 genotypes (by
Wilcoxon test, P = 0.0015). A post-hoc
pairwise comparison indicated significant differences between the
curves for the S319/G319 and G319/G319 subjects (by Wilcoxon test,
P = 0.009) and the S319/S319 and G319/G319 subjects (by
Wilcoxon test, P = 0.001).
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genotype
Clinical attributes of diabetic subjects according to HNF-1
genotype are shown in Table 3. The
age-adjusted mean (±SD) BMI values in subjects with
HNF-1 G319/G319, S319/G319, and S319/S319 genotypes were 30.6
± 4.7, 29.5 ± 4.2, and 27.7 ± 6.4 kg/m2,
respectively (P = 0.046). A post-hoc
pairwise comparison found a significant difference between the
S319/S319 and G319/G319 subjects (P = 0.017) and a
borderline significant difference between the S319/G319 and G319/G319
subjects (P = 0.058). Separate post-hoc
subgroup analyses showed that there were significant between-genotype
differences in BMI for subjects with type 2 diabetes when the BMI was
less than 30 kg/m2 (P = 0.0006; data not
shown). However, for subjects with type 2 diabetes with BMI of 30
kg/m2 or greater, BMI was not significantly different
between genotypes (P = NS; data not shown).
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genotype
Subjects with and without diabetes were evaluated separately for
differences between genotypes in plasma biochemical traits. Among
diabetic subjects (Table 3), there was a higher plasma 2 h
postchallenge glucose concentration in HNF-1 S319/G319 heterozygotes
compared with G319/G319 homozygotes (17.0 ± 4.3 vs.
14.8 ± 5.8 mmol/L; P = 0.008) and a significantly
higher plasma 2-h postchallenge glucose concentration in HNF-1
S319/S319 homozygotes compared with G319/G319 homozygotes (20.8 ±
5.1 vs. 14.8 ± 5.8 mmol/L; P = 0.010).
Among nondiabetic subjects (Table 4),
there was a significantly lower fasting plasma insulin concentration in
HNF-1 S319/G319 heterozygotes compared with G319/G319 homozygotes
(96.4 ± 70.0 vs. 113.4 ± 74.4 U/L;
P = 0.025; Table 4). The single nondiabetic S319/S319
homozygote, a 25-yr-old male with a BMI of 27.2 kg/m2, had
fasting plasma glucose and insulin levels of 5.9 mmol/L and 57 U/L,
respectively. None of the other biochemical variables differed
significantly between diabetic and nondiabetic subgroups.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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,
namely G319S, that is unique to the Oji-Cree of Northern Ontario and
was strongly associated with type 2 diabetes mellitus. Almost 40% of
diabetic Oji-Cree were either homozygous or heterozygous for G319S.
G319S was completely absent from all other ethnic groups studied,
including two other Canadian aboriginal groups, suggesting that it is
unique to the Oji-Cree of Northern Ontario. The Gly at residue 319 is
within the proline-rich domain II of the trans-activation
domain of HNF-1 and has been conserved throughout evolution (15).
Although linkage disequilibrium between G319S and another functional
variant at the HNF-1 gene is possible, the absence of other sequence
variants make this possibility less likely. We cannot rule out linkage
disequilibrium with a functional variant of another gene on chromosome
12, but this possibility may prove to be less likely after completion
of studies of an in vitro functional effect of G319S.
There was a marked gene-dosage effect of G319S with the age of onset of
diabetes, as S319/S319 homozygotes, S319/G319 heterozygotes, and
G319/G319 homozygotes had their diabetes onset, respectively, in the
third, fourth, and fifth decades of life. This is consistent with
observations that HNF-1 mutations are associated with an earlier age
of onset in both MODY3 (14, 15, 16) and rare instances of type 2 diabetes
(17). Also, MODY3 subjects appear to develop diabetes more rapidly than
subjects with MODY1 or MODY2 (21). These data taken together with our
results suggest that HNF-1-associated diabetes has a relatively
early age of onset.
The association of a later age of onset and a higher BMI in type 2
diabetic Oji-Cree with the HNF-1 G319/G319 genotype suggests that
the development of diabetes in these people is more strongly associated
with age and BMI than the diabetes in the approximately 40% of
subjects who were carriers of the S319 allele. If there is a genetic
basis for the diabetes in Oji-Cree without the S319 allele, it may be a
more typical form of type 2 diabetes. The observations also indicate
that diabetes could be genetically heterogeneous in Oji-Cree. Knowing
that there is a mutation in HNF-1 will reduce the complexity
involved in identifying a second Oji-Cree gene for diabetes, because
subsequent analyses can be performed by taking the HNF-1 genotype
into account.
The decreased stimulation of glucose utilization, oxidation, and
nonoxidative glucose disposal and the blunted suppression of endogenous
glucose output that are seen in MODY3 patients with HNF1 mutations
appear to result from insulinopenia, whereas insulin sensitivity
appears to be intact in these subjects (25). Also, mice with a targeted
disruption of the HNF-1 gene have defective insulin secretion (23).
In vitro studies have shown that HNF-1 mutations may lead
to ß-cell dysfunction by different mechanisms, including a dominant
negative effect and a simple loss of function (24). Our observations of
a significantly lower fasting plasma insulin concentration in HNF-1
S319/G319 heterozygotes compared with G319/G319 homozygotes and
especially of the very low plasma insulin in the single nondiabetic
S319/S319 homozygote are consistent with deficient insulin secretion
associated with the S319 allele. Furthermore, the 25-yr-old nondiabetic
S319/S319 homozygote was 3 yr younger than the mean age of onset of
type 2 diabetes in the five other homozygotes. It is thus possible that
this subject might become glucose intolerant with time. Another
glucose-tolerant subject with a different HNF-1 mutation, namely
P447L, had low insulin secretion in response to oral glucose, but a
marked increase in insulin secretion in response to iv glucose
and other secretagogues (26). Other studies have shown no
relationship between diabetes severity and the type of the mutation in
HNF-1 (27).
The data suggest that the private HNF-1 G319S mutation is associated
with a younger age of onset of type 2 diabetes. As microangiopathic
complications are observed with the same frequency in patients with
MODY3 diabetes as in type 1 and type 2 diabetes (32), it is likely that
the HNF-1 G319S will be a major contributor to the development of
complications of type 2 diabetes in Ontario Oji-Cree. Assuming that the
allele and genotype frequencies in Sandy Lake are representative of the
approximately 16,000 aboriginal residents of Northwestern Ontario,
there may be as many as 200 and 3000 S319/S319 homozygotes and
S319/G319 heterozygotes, respectively. Therefore, the HNF-1 S319
allele may contribute considerably to diabetes morbidity, in both
absolute and relative terms, among the native people in Northern
Canada.
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Acknowledgments |
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Footnotes |
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2 Career Investigator with the Heart and Stroke Foundation of
Ontario.
3 Career Investigator with the Ontario Ministry of Health.
4 Supported by Health Canada through a National Health Research and
Development Program Research Training Award.
Received October 28, 1998.
Revised December 4, 1998.
Accepted December 8, 1998.
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E. A.C. Sellers, B. Triggs-Raine, C. Rockman-Greenberg, and H. J. Dean The Prevalence of the HNF-1{alpha} G319S Mutation in Canadian Aboriginal Youth With Type 2 Diabetes Diabetes Care, December 1, 2002; 25(12): 2202 - 2206. [Abstract] [Full Text] [PDF]
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 B. L. Triggs-Raine, R. D. Kirkpatrick, S. L. Kelly, L. D. Norquay, P. A. Cattini, K. Yamagata, A. J. G. Hanley, B. Zinman, S. B. Harris, P. H. Barrett, et al. HNF-1alpha G319S, a transactivation-deficient mutant, is associated with altered dynamics of diabetes onset in an Oji-Cree community PNAS, April 2, 2002; 99(7): 4614 - 4619. [Abstract] [Full Text] [PDF]
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A. Mok, H. Cao, B. Zinman, A. J. G. Hanley, S. B. Harris, B. P. Kennedy, and R. A. Hegele A Single Nucleotide Polymorphism in Protein Tyrosine Phosphatase PTP-1B Is Associated with Protection from Diabetes or Impaired Glucose Tolerance in Oji-Cree J. Clin. Endocrinol. Metab., February 1, 2002; 87(2): 724 - 727. [Abstract] [Full Text] [PDF]
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 S. S. Fajans, G. I. Bell, and K. S. Polonsky Molecular Mechanisms and Clinical Pathophysiology of Maturity-Onset Diabetes of the Young N. Engl. J. Med., September 27, 2001; 345(13): 971 - 980. [Full Text] [PDF]
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R. A. Hegele, S. B. Harris, B. Zinman, A. J.G. Hanley, and H. Cao Absence of Association of Type 2 Diabetes With CAPN10 and PC-1 Polymorphisms in Oji-Cree Diabetes Care, August 1, 2001; 24(8): 1498 - 1499. [Full Text] [PDF]
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 T. K. Young, J. Reading, B. Elias, and J. D. O'Neil Type 2 diabetes mellitus in Canada's First Nations: status of an epidemic in progress Can. Med. Assoc. J., September 1, 2000; 163(5): 561 - 566. [Abstract] [Full Text] [PDF]
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R. A. Hegele, H. Cao, S. B. Harris, B. Zinman, A. J. G. Hanley, and C. M. Anderson Peroxisome Proliferator-Activated Receptor-{gamma}2 P12A and Type 2 Diabetes in Canadian Oji-Cree J. Clin. Endocrinol. Metab., May 1, 2000; 85(5): 2014 - 2019. [Abstract] [Full Text]
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 R. A. Hegele, H. Cao, S. B. Harris, A. J. G. Hanley, B. Zinman, and P. W. Connelly The Private Hepatocyte Nuclear Factor-1{alpha} G319S Variant Is Associated With Plasma Lipoprotein Variation in Canadian Oji-Cree Arterioscler Thromb Vasc Biol, January 1, 2000; 20(1): 217 - 222. [Abstract] [Full Text] [PDF]
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B. L. Triggs-Raine, R. D. Kirkpatrick, S. L. Kelly, L. D. Norquay, P. A. Cattini, K. Yamagata, A. J. G. Hanley, B. Zinman, S. B. Harris, P. H. Barrett, et al. HNF-1alpha G319S, a transactivation-deficient mutant, is associated with altered dynamics of diabetes onset in an Oji-Cree community PNAS, April 2, 2002; 99(7): 4614 - 4619. [Abstract] [Full Text] [PDF]
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