© 2000 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
The Private Hepatocyte Nuclear Factor-1
G319S Variant Is Associated With Plasma Lipoprotein Variation in Canadian Oji-Cree
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Abstract |
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Abstract—We previously showed an extremely strong association between type 2 diabetes and a private polymorphism, namely G319S, in the hepatocyte nuclear transcription factor (HNF)-1
. Because HNF-1 is involved in the
transcription of several apolipoprotein genes, we tested for an
association between the private HNF1A G319S variant and
plasma lipoproteins in a sample of 55 unrelated Oji-Cree subjects with
type 2 diabetes and 175 unrelated Oji-Cree subjects without type 2
diabetes. In Oji-Cree subjects with type 2 diabetes, we found that the
HNF1A G319S genotype was significantly
associated with lower plasma concentrations of total
cholesterol, low density lipoprotein
cholesterol, and apolipoprotein (apo) B. In Oji-Cree
subjects without type 2 diabetes, we found that the
HNF1A G319S genotype was significantly
associated with higher plasma concentrations of high density
lipoprotein cholesterol and apo AI. There were no
associations with plasma triglycerides or lipoprotein(a).
Regression analysis indicated that the HNF1A
genotype accounted for 
10% of the variation in the apo
B–related traits in the diabetic subjects and for 5% of the
variation in the apo AI–related traits in the nondiabetic subjects.
Furthermore, the regression model indicated that the
HNF1A S319 allele affected these traits in a
dominant manner in subjects with and without type 2 diabetes. These
findings provide the first evidence that a rare variant in a nuclear
transcription factor is associated with variation in plasma
lipoprotein traits.
Key Words: transcription factors • diabetes • polygenic traits • atherosclerosis
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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We previously showed that the Oji-Cree of northern Canada have a private variant in the hepatocyte nuclear transcription factor-1
(HNF1A) gene, namely G319S, which
was very strongly associated with early-onset type 2 diabetes
mellitus.1 2 Subjects with 1 or 2 copies of
HNF1A S319 had onset of diabetes 1 or 2 decades earlier,
respectively, than did noncarriers.1 2 Our findings
strongly suggested that HNF1A S319 was a dysfunctional
variant that created susceptibility to type 2 diabetes, which then
required the presence of a high-fat diet and sedentary lifestyle to be
expressed clinically.1 2 Other mutations in
HNF1A cause a specific, rare form of maturity-onset diabetes
of the young, called MODY3.3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 MODY3 is clinically
distinct from typical type 2 diabetes and probably results from
defective pancreatic insulin secretion.3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 However, the
underlying mechanistic relationship with the dysfunctional
HNF1A gene product is not fully understood for either
MODY3 or type 2 diabetes in the Oji-Cree.1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
The HNF1A gene has been mapped to chromosome 12q24 and is
expressed predominantly in the liver, kidney, and
pancreas.20 21 22 The HNF1A gene
product, HNF-1, is a transcriptional activator of
several hepatic genes, including albumin, 1-antitrypsin, and
- and ß-fibrinogen.21 22 In addition, HNF-1
was shown to enhance transcription of apolipoprotein (apo)
B23 24 25 and apo(a)26 and to downregulate
transcription of apo CIII and apo AI.27 Because it
regulates the transcription of several apolipoprotein genes, it is
possible that naturally occurring mutations in HNF-1 could affect
plasma lipoprotein metabolism. However, there is
surprisingly little information regarding the plasma lipoprotein
phenotypes in subjects with HNF1A mutations, such as
patients with MODY3.28 Because we had determined
plasma lipoprotein phenotypes in the Oji-Cree, we could test
for an association between the HNF1A G319S genotype
and the variation in plasma lipoproteins and apolipoproteins.
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Methods |
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Study Subjects
The isolated community of Sandy Lake, Ontario, is located
2000 km northwest of Toronto, in the subarctic boreal forest
of central Canada. The ancestors of the contemporary residents of this
region lived a nomadic, hunting-gathering subsistence typical of other
native peoples of the northeastern subarctic. Since the development of
the reservation and residential school systems, the lifestyle changed
from very physically active to very sedentary. The primary source of
food changed from wildlife with roots and berries to processed foods
high in animal fats. Seven hundred twenty-eight members of this community aged 10 years and older participated in a community-wide screening project to determined the prevalence of type 2 diabetes and associated risk factors.29 30 31 32 Subjects answered a questionnaire for medical history. Physical examination included determination of body mass index (BMI) defined as weight/height2 (kg/m2). No subject took lipid-lowering medications. A small proportion (3.8%) of subjects were taking antihypertensive medications, which were almost all angiotensin-converting enzyme inhibitors. Blood samples were obtained with informed consent after a 10-hour fasting period. Diabetes was diagnosed according to pre-1997 criteria.33 Exclusion criteria for the current study included a diagnosis of impaired glucose tolerance34 and/or an inadequate blood sample for all determinations. The project was approved by the University of Toronto Ethics Review Committee.
Biochemical and Genetic Analyses
Blood samples for lipoprotein analyses were
centrifuged at 2000 rpm for 30 minutes and the plasma was
stored at -70°C. Fasting plasma concentrations of glucose, insulin,
lipids, lipoproteins, and apolipoproteins, along with postchallenge
glucose, were determined as described.1 29 35 36
Restriction analysis with BseDI detected the DNA
change underlying the HNF1A G319S amino acid
variation.1 2
Statistical Analysis
For this analysis, we studied a subset of Oji-Cree aged
18 years and above who were no more closely related than third-degree
relatives to one another. This was done to control for artifacts
related to the nonindependence of samples that could have arisen from
studying closely related subjects, such as members of the same nuclear
family.
The distribution of each lipoprotein variable was significantly nonnormal in this dataset. Therefore, for parametric statistical analyses, each variable was transformed and subjected to analysis of normality. Logarithmically transformed total, LDL, and HDL cholesterol; triglycerides (TGs); apo AI; apo B; and Lp(a) had distributions that were not significantly different from normal. The transformed variables were used for statistical analyses, but the nontransformed values are presented in the Tables.
The significance of deviations of observed genotype frequencies
from those predicted by the Hardy-Weinberg equation was evaluated with
2 analysis. 2
analysis was also used to assess differences in proportions of
alleles and genotypes between subjects with and without
type 2 diabetes. Estimates of relative risk of type 2 diabetes between
genotypes were determined by using Mantel-Haenszel odds
ratios.37
ANOVA in SAS version 6.1237 was used to determine whether there were statistically significant differences in quantitative traits between subjects with type 2 diabetes and those without. One ANOVA each was performed for age and BMI by using each as the dependent variable and diabetes status as the only independent variable. One ANOVA each was performed for fasting plasma concentrations of total, LDL, and HDL cholesterol; TGs; apo AI and B; Lp(a); and insulin by using the logarithmically transformed fasting plasma value for each as the dependent variable and diabetes status, age, and BMI as the independent variables.
Multivariate regression analysis in SAS version 6.1237 was used to determine the sources of variation for transformed lipoprotein traits in subjects with and without type 2 diabetes. A forward stepwise regression procedure was used to assist in the model building, with the P value for inclusion set at <0.15. The dependent variables in each regression analysis included transformed fasting plasma concentrations of total, LDL and HDL cholesterol; TGs; apo AI and B; and Lp(a). The independent variables in the model for each analysis included HNF1A genotype, with assumption of a dominant effect on each phenotype. This was done by setting the HNF1A genotype variable at 0 for G319/G319 subjects and at 1 for S319/G319 and S319/S319 subjects. Age, sex, BMI, fasting plasma insulin concentration, and medication use were also used as independent variables.
When a significant genetic contribution to the variation in a biochemical trait was detected for the HNF1A genotype, the general linear models procedure for least-squares means was used to determine the level of significance of differences in pairwise comparisons between genotype classes.37 Least-squares means (also called population marginal means) are the values for class means after adjustment for all covariates included in the model.37 Bonferroni adjustments were made to account for multiple comparisons. For all analyses, the nominal level of statistical significance was taken to be P<0.05.
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Results |
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Clinical and Biochemical Features of Study Subjects
The baseline clinical and biochemical attributes of the 55 subjects with type 2 diabetes and the 175 subjects without type 2 diabetes are shown in Table 1
. Among the
subjects with type 2 diabetes, 44% (24/55) took oral hypoglycemic
agents and 7% (4/55) took insulin injections. Subjects with type 2
diabetes had a significantly greater age and BMI than did subjects
without type 2 diabetes (both P<0.0001). Among the
biochemical traits, after adjustment for age and BMI, only the fasting
plasma concentrations of TG and insulin were significantly different
between the subjects with and without type 2 diabetes
(P=0.0003 and 0.018, respectively).
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HNF1A G319S Allele and Genotype Frequencies
In this sample of unrelated Oji-Cree, the HNF1A S319
allele frequency was 0.190 (21/110) in subjects with diabetes and
0.063 (22/350) in subjects without diabetes
(2=11.8, P<0.0001). The relative
risk of type 2 diabetes was 2.6 (95% confidence interval 1.5 to 4.5)
for carriers of at least 1 copy of the HNF1A S319
allele. Among subjects with type 2 diabetes, 37 had the
HNF1A G319/G319 genotype, 15 had the S319/G319
genotype, and 3 had the S319/S319 genotype. Among
subjects without type 2 diabetes, 153 had the HNF1A
G319/G319 genotype, 22 had the S319/G319 genotype, and
none had the S319/S319 genotype. Because there were so few
HNF1A S319/S319 homozygotes, S319 was treated as a dominant
allele for the purposes of subsequent hypothesis testing. Thus,
among the subjects with type 2 diabetes, the 3 S319/S319 homozygotes
were grouped with the 15 S319/G319 heterozygotes. The HNF1A
G319S genotype frequencies in the diabetic and nondiabetic
groups did not deviate from Hardy-Weinberg expectations.
Regression Analysis for Sources of Variation in Plasma
Lipoproteins
The results of the stepwise multivariate
regression analysis in the 55 unrelated Oji-Cree with type 2
diabetes are shown in Table 2. All
biochemical traits, except for Lp(a), had at least 1 significantly
associated independent variable. The HNF1A G319S
genotype was a significant source of variation for log total
cholesterol, log LDL cholesterol, and log apo B
(P=0.020, 0.007, and 0.029, respectively). In addition, age
was significantly associated with log TG, sex was significantly
associated with both log HDL cholesterol and log apo AI,
and medication use was significantly associated with log HDL
cholesterol. Plasma insulin concentration was not
significantly associated with any biochemical variable. The
proportion of the total variation that was due to HNF1A
genotype, as estimated by the partial regression coefficients,
was 10%, 14%, and 9% for log total cholesterol, log
LDL cholesterol, and log apo B, respectively.
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To determine whether the HNF1A genotype was associated with the variation in LDL composition in the 55 unrelated Oji-Cree with type 2 diabetes, we performed an additional post hoc stepwise multivariate regression analysis. We used the ratio of LDL cholesterol to plasma apo B as the dependent variable. The independent variables in the model for this last analysis included HNF1A genotype, with assumption of a dominant effect on each phenotype as described above. Age, sex, BMI, fasting plasma insulin concentration, and medication use were also used as independent variables. This analysis indicated that the HNF1A G319S genotype was not significantly associated with the LDL cholesterol to apo B ratio (P=0.14). Thus, the HNF1A G319S genotype appeared to be associated with the quantity but not the composition of plasma apo B–containing particles.
The results of the stepwise multivariate regression
analysis in the 175 unrelated Oji-Cree without type 2 diabetes
are shown in Table 3. All biochemical
traits except Lp(a) had at least 1 significantly associated independent
variable. The HNF1A G319S genotype was a
significant source of variation for log HDL cholesterol and
tended to be associated with variation in log apo AI
(P=0.042 and 0.07, respectively). In addition, BMI was
significantly associated with all variables, age was significantly
associated with all variables but log TG, and sex was significantly
associated with all variables but log apo AI but tended to be
associated with log apo AI (P=0.06). Medication use was
significantly associated with log TG. Plasma insulin concentration was
not significantly associated with any biochemical variable. The
proportion of the total variation due to HNF1A
genotype, as estimated by the partial regression coefficients,
was 2% each for log HDL and log apo AI.
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Biochemical Variables According to HNF1A
Genotypes
The clinical and biochemical attributes of the Oji-Cree with
type 2 diabetes according to their HNF1A genotypes
are shown in Table 4. There was no
significant difference in age or BMI between the 2 groups. There were
significant differences in total and LDL cholesterol and
apo B (all P<0.05). For each variable, the mean
concentration was lower in the HNF1A S319 carriers by
10%. There were no significant differences in the remainder of the
lipoprotein variables. Also, the mean values for plasma
concentrations of fasting and postprandial glucose and fasting insulin
were compared between the 2 genotypic classes of diabetic subjects, and
no significant differences were found for this study sample (Table 4).
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The clinical and biochemical attributes of the Oji-Cree without type 2
diabetes according to their HNF1A genotypes are
shown in Table 5. There was no
significant difference in either age or BMI between the 2 groups. There
were significant differences in HDL cholesterol and apo AI
(both P<0.05). For both variables, the mean
concentration was higher in the HNF1A S319 carriers by
5%. There were no significant differences in the remainder of the
lipoprotein variables. Also, the mean values for plasma
concentrations of fasting and postprandial glucose and fasting insulin
were compared between the 2 genotypic classes of diabetic subjects.
There was a significantly lower fasting plasma insulin concentration in
HNF1A S319/G319 heterozygotes compared with G319/G319
homozygotes (88±30 versus 116±74 U/L, P=0.03) but no other
significant differences for this study sample (data not shown).
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Discussion |
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In a sample of unrelated Oji-Cree subjects with and without type 2 diabetes, we found significant associations between the private HNF1A G319S polymorphism and variations in plasma lipoprotein concentrations. Specifically, we found (1) lower plasma concentrations of apo B–related traits, namely, total and LDL cholesterol and apo B, in carriers of HNF1A S319 with type 2 diabetes and (2) higher plasma concentrations of apo AI–related traits, namely, HDL cholesterol and apo AI, in HNF1A S319/G319 heterozygotes without type 2 diabetes. There were no associations with plasma TGs or Lp(a). The HNF1A genotype accounted for
10% of the total variation in the
apo B–related traits in the subjects with type 2 diabetes. The
HNF1A genotype accounted for 5% of the total
variation in the apo AI–related traits in the subjects without type 2
diabetes. Furthermore, the regression model indicated that the
HNF1A S319 allele had a dominant effect on these traits
in Oji-Cree subjects with and without type 2 diabetes. These findings
provide the first evidence that a rare variant in a nuclear
transcription factor is associated with variations in plasma
lipoprotein traits. The findings in this unrelated Oji-Cree sample confirmed our earlier observation of an extremely strong association of the HNF1A S319 variant with type 2 diabetes.1 2 However, among subjects with type 2 diabetes in the current study, there was no significant phenotypic difference between the HNF1A G319S genotype classes in age, BMI, or traits related to glycemia. This suggests that the association of HNF1A S319 with plasma apo B–related traits in subjects with type 2 diabetes was not related to other phenotypic differences between the HNF1A genotype classes.
In contrast, among subjects without type 2 diabetes, there was a significant difference in plasma insulin concentration between the HNF1A G319S genotype classes. In particular, the HNF1A S319/G319 heterozygotes had significantly lower plasma insulin values than did G319/G319 homozygotes. This suggests that the association of HNF1A S319 with plasma apo AI–related traits in subjects without type 2 diabetes might have been related to the between-genotype plasma insulin difference. However, regression analysis indicated that plasma insulin was not a significant determinant of either plasma apo AI or HDL cholesterol in the subjects without type 2 diabetes. This suggests that the relationship between the genotype and the apo AI–related traits in the subjects without type 2 diabetes was not mediated through differences in plasma insulin concentration but possibly through another more direct mechanism.
There are several lines of evidence to indicate that the
HNF1A S319 allele encodes a dysfunctional protein
product. First and foremost is the genetic evidence.
HNF1A S319 is as unique to the Oji-Cree as the sickle cell
anemia allele of hemoglobin is to African
people.1 2 Within the Oji-Cree, we have shown a
strong, specific relationship of HNF1A S319 with type 2
diabetes.1 2 Subjects with the S319 variant have an
increased relative risk of having type 2 diabetes, with odds ratios of
2 and 4 for subjects with 1 and 2 copies of the allele,
respectively.1 2 The probability values for these
associations were <10-5.1 2
Furthermore, there was a strong gene-dosage effect related to the age
of onset of type 2 diabetes and other quantitative
phenotypes.1 2 In addition, the wild-type G319
residue is within the critical proline-rich domain II of the
transactivation domain of HNF-1.20 21 This residue has
been conserved throughout evolution,20 21 suggesting that
it has an important functional role. We also found no other variant
affecting the coding sequence, intron-exon boundaries, or the 5'- and
3'-untranslated regions of HNF1A.1 2
These facts taken together support the idea that the HNF1A
S319 allele product is dysfunctional.
We are in the process of carrying out in vitro functional
experiments to assess whether the HNF1A S319 product
loses its ability to regulate gene expression through binding to the
cognate HNF-1 recognition sequence. If we could demonstrate that
HNF1A S319 has a reduced ability to activate target
genes, this could provide a direct mechanistic explanation of the
lipoprotein phenotypes. However, it might also be difficult to
relate the results of in vitro experiments involving S319, or indeed
any other mutation in HNF1A, to the development of diabetes
or other in vivo phenotypes. This is because HNF-1 has both
wide tissue expression, including the liver and pancreas, and a very
wide variety of gene targets.19 20 HNF-1 also
functions as a dimer,19 20 and at least 1 HNF1A
mutation appears to act as a dominant-negative because of
this.15 Thus, there are many possible mechanisms
through which dysfunctional HNF-1 can lead to abnormal
phenotypes. This complexity might cloud any attempt to relate a
simple loss of transactivation in vitro to the development of type 2
diabetes.
With the assumption that the HNF1A S319 product is
functionally abnormal, how might it produce abnormal lipoprotein
phenotypes? The normal actions of HNF-1 include enhancing
the transcription of apo B23 24 25 and suppressing the
transcription of apo AI.27 Thus, in subjects with type 2
diabetes, the lower plasma total and LDL cholesterol and
apo B levels would also be consistent with transactivational
loss of function of the HNF1A S319 product. Furthermore,
in the subjects without type 2 diabetes, the higher plasma HDL
cholesterol and apo AI levels would be consistent
with a transactivational loss of function of the HNF1A S319
product.
Why would the associations differ in subjects with and without
type 2 diabetes? The specificity of the associations might be related
to the fundamental metabolic differences between the
subjects with and without diabetes. For example, the subjects without
type 2 diabetes were significantly younger and leaner and had
significantly lower plasma insulin concentrations compared with the
subjects with type 2 diabetes. This suggests that the loss of
suppression of apo AI gene transcription from HNF-1 S319 is
expressed on a metabolic background that is relatively
unperturbed. Furthermore, the effect appeared to be lost in the context
of the highly perturbed metabolic state of type 2 diabetes.
This further suggests that factors other than genetic variation in
HNF1A are important determinants of plasma apo AI–related
traits in the older and heavier Oji-Cree with type 2 diabetes and high
plasma insulin concentration. Thus, HNF1A variation appears
to be an important determinant of plasma apo AI–related traits in a
relatively unperturbed metabolic context.
A complementary mechanism might explain the association of
HNF1A S319 with plasma apo B–related traits in subjects
with type 2 diabetes. The subjects with type 2 diabetes were
significantly older and heavier and had significantly higher plasma
insulin concentrations compared with the subjects without type 2
diabetes. This means that the loss of enhancement of apo B gene
transcription from the S319 allele occurred on a
metabolic background that was highly perturbed.
Furthermore, the effect was not seen in the context of the
less-perturbed metabolic state of subjects without type 2
diabetes. This could mean that genetic variation in HNF1A is
an important determinant of plasma apo B–related traits on the
background of a highly perturbed metabolic context, such as
diabetes, obesity, and hyperinsulinemia, and a
propensity for hypersecretion of apo B–containing lipoproteins. It may
be of some interest that subjects with HNF1A S319 tended to
have higher plasma fasting and postchallenge glucose levels (Table 4
) but also had lower plasma apo B–related traits, suggesting
that the metabolic consequences of worsened glycemia are
not the basis for the association with lipoprotein traits. In contrast,
variation in HNF1A appears not to be an important
determinant of the quantity, but not the composition, of plasma apo
B–related traits in a relatively unperturbed metabolic
context.
HNF-1 also enhances in vitro transcription of apo(a)26
and suppresses in vitro transcription of apo CIII.27
However, we found no association of HNF1A S319 with either
plasma Lp(a) or TGs. One explanation for the absence of these
associations is that these traits have more important determinants
other than variation in HNF1A in the Oji-Cree.
It is also possible that HNF-1 affects the expression of other gene
products that are involved in lipoprotein metabolism.
If this were the case, our findings would still be consistent
with an influence of genetic variation in HNF1A on plasma
lipoproteins, albeit through a different mechanism than modulation of
the expression of apo AI and apo B. As always, we cannot rule out the
possibility that HNF1A was in linkage disequilibrium with a
functional variant of another gene on chromosome 12. However, this
possibility may prove to be less likely after completion of studies of
an in vitro functional impact of the HNF1A S319
product.
In summary, we have detected associations between plasma lipoproteins and genetic variation in a nuclear transcription factor whose targets include some apolipoprotein genes. There is substantial genetic evidence that HNF1A S319 encodes a dysfunctional variant that leads to type 2 diabetes.1 2 The data presented herein suggest that the possible dysfunction of HNF1A S319 can affect lipoprotein metabolism. Furthermore, there appear to be differential effects of the genetic variation in HNF1A on specific lipoprotein phenotypes. The associations appear to depend on the background metabolic state of the study subjects. The results are consistent with a loss of suppression of apo AI and HDL production in the nondiabetic state and with a loss of enhancement of apo B and LDL production in the diabetic state. Mechanistic studies might help to better understand these associations.
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Acknowledgments |
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This work was supported by grants from the National Institutes of Health (DK44597-01) and the Ontario Ministry of Health (No. 04307) (to B.Z. and S.B.H.), the Medical Research Council of Canada (MT13430), the Canadian Diabetes Association, the Heart and Stroke Foundation of Ontario (No. 3628), and the Blackburn Group (to R.A.H.). Dr Hegele is a Career Investigator of the Heart and Stroke Foundation of Ontario (No. 2729). Dr Harris is a Career Investigator of the Ontario Ministry of Health. Mr Hanley is supported by Health Canada through a National Health Research and Development Program Research Training Award. We would like to acknowledge the chief and council of the community of Sandy Lake, the Sandy Lake community surveyors, the Sandy Lake nurses, and the staff of the University of Toronto Sioux Lookout program.
Received March 19, 1999; accepted June 22, 1999.
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