© 1997 American Heart Association, Inc.
Articles |
Genetic Variation in Factor VII Associated with Variation in Plasma Lipoprotein(a) Concentration
From the Departments of Medicine and Clinical Biochemistry, St. Michael's Hospital and University of Toronto, Ontario (R.A.H., P.W.C.), the Department of Biochemistry, Dalhousie University, Halifax, Nova Scotia (W.C.B.); the School of Nursing, University of Victoria, British Columbia (J.H.B.); and the Department of Biochemistry, University of Toronto, Ontario, Canada (P.W.C.).
Correspondence to Robert A. Hegele, MD, DNA Research Laboratory, St. Michael's Hospital, 30 Bond Street, Toronto, Ontario, M5B 1W8, Canada. E-mail: robert.hegele{at}utoronto.ca.
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Abstract |
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Abstract Cross-sectional and prospective studies have shown that individuals with high plasma lipoprotein(a) [Lp(a)] concentrations are at increased risk for coronary heart disease. Size polymorphism of the apolipoprotein(a) [apo(a)] glycoprotein accounts for
35% of the variation in
plasma Lp(a) concentrations. However, there is no convincing evidence
for associations between plasma Lp(a) and common genetic variation
outside APO(a), the gene that encodes apo(a). We tested for
association of common genetic variation of candidate genes in lipid
metabolism and also of F7 with variation of plasma Lp(a)
concentrations in Alberta Hutterites. Variation at codon 353 of
F7 has been associated with variation in the plasma factor
VII activity (FVIIc), with the 353Q allele associated with lower
FVIIc and the 353R allele associated with higher FVIIc. We found
significant associations between variation in plasma concentrations of
Lp(a) and both apo(a) isoform size and F7 codon 353
genotype (both P<.0001). The effects on plasma
Lp(a) concentration of the alleles at codon 353 were additive. The
average effects of the F7 353Q and 353R alleles were,
respectively, to decrease by 1.71 µg/mL and to increase by 0.301
µg/mL plasma Lp(a) concentration from the sample mean. This suggests
that common genomic variation in F7 is associated with
variation in plasma Lp(a) concentration.
Key Words: coagulation • lipids • polygenic traits • small effects • thrombolysis
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Introduction |
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Lipoprotein(a) [Lp(a)] is a cholesterol ester rich LDL-like particle with unique molecular, biochemical, and genetic properties.1 Cross-sectional and prospective studies have shown that individuals with high plasma Lp(a) concentrations are at increased risk for coronary heart disease (CHD),2 3 4 5 6 with some notable exceptions.7 8 9 The plasma concentration of Lp(a) has a skewed distribution that varies over a 1000-fold range in white populations, with most subjects having low plasma Lp(a).10 In whites, studies in sibships indicate that over 90% of the interindividual variation in plasma Lp(a) concentrations has been attributed to DNA variation of the APO(a) gene11 ; however, in other ethnic groups the contribution of this locus may be smaller.12 13 14
The APO(a) gene varies in size due to the variation in
number of tandem repeats of a DNA sequence encoding a peptide that
resembles kringle 4 (K4) of plasminogen.15 The
plasma concentrations of Lp(a) tend to be inversely related to the
number of K4 repeats in apolipoprotein (apo) a.11 15 16 17 18 19
The size polymorphism in the apo(a) glycoprotein
accounts for 35% of the variation in plasma Lp(a) concentration,
but this estimate has varied from 19% in African
individuals13 14 to 42% for Caucasians from
Austria.16 When variation in the length of the K4 DNA
tandem repeat region of the APO(a) gene was used as a
genetic marker, a greater proportion, 69%, of the variation in
plasma Lp(a) concentrations was attributed to this
locus.11 However, even in subjects with APO(a)
alleles of the same size, there can be a wide range of plasma Lp(a)
concentrations,1 20 21 suggesting that other sequences at
APO(a) account for the remainder of the variation
attributable to this locus, such as variants in the promoter
sequence.22 23 There is no convincing evidence for
associations between plasma Lp(a) and common genetic variation outside
APO(a). For example, variation in plasma Lp(a) concentration
was not associated with genetic variation of
APOB19 and was inconsistently
associated with variation in APOE.24 25 26
Factor VII is a vitamin K–dependent coagulation factor that is synthesized primarily in the liver and is secreted as a single-chain 48-kd glycoprotein.27 The cleavage of factor VII to its active form, factor VIIa, is mediated by activated coagulation factors such as factors XIIa, IXa, Xa, and thrombin.28 Factor VIIa binds to tissue factor and in the presence of phospholipid and Ca2+ converts factor X to factor Xa.28 Plasma factor VII activity (FVIIc) is an independent CHD risk factor,29 30 31 32 with some exceptions.33 Variation in plasma FVIIc has been associated with variation in plasma lipids, particularly triglycerides.34 35 36 37 38
A common polymorphism in codon 353 of the F7 gene on chromosome 13q24 leads to the replacement of arginine by glutamine (R353Q).39 This variation has been associated with approximately 20% of the variation of FVIIc,39 40 41 42 with the 353Q/Q homozygotes having the lowest FVIIc, 353R/Q heterozygotes having intermediate FVIIc and 353R/R homozygotes having the highest FVIIc. Furthermore, the F7 genotype and plasma triglycerides may interact to produce variation in FVIIc and factor VII antigen levels.40 41 We recently determined plasma concentrations of Lp(a) and apo(a) protein isoforms in a large sample of Alberta Hutterites. We hypothesized that common variation of candidate genes in lipid metabolism and of F7 would be associated with variation of plasma Lp(a) concentrations.
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Methods |
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Study Subjects
The Hutterite Brethren are an Anabaptist sect with approximately 30 000 members who live in Western Canada and the adjacent American states. They have an agrarian lifestyle and live on communal farms called colonies.43 44 45 46 Contemporary Hutterites are descended from fewer than 100 founders who are considered to have been unrelated to each other.43 44 45 46 The Hutterites have had a high intrinsic growth rate and their population remains closed to immigration. They are subdivided into three endogamous sects: Dariusleut, Lerherleut and Schmiedeleut. A high degree of consanguinity relative to the founders has accumulated over about 12 generations, with the average inbreeding coefficient of the current generation being 0.05. Hutterite society has a static inter- and intra-generational lifestyle. Colonies are effective surrogates for extended families; women marry between colonies, but males tend to remain within a colony. While the incidence of CHD in the Hutterites is unknown, the prevalence of risk factors seems to be similar to that seen in other populations.43 44 45 46
Subjects from 21 colonies of the Alberta Dariusleut and Lerherleut sects took part in the Canadian Heart Health Survey screening for CHD risk factors.43 44 45 46 Physical examination included determination of body mass index (BMI), defined as weight/height2 (kg/m2). Plasma samples from 846 Hutterites were obtained with informed consent. Exclusion criteria included an inadequate blood sample available for all biochemical and/or genetic determinations. The study was approved by ethical review panels of the Universities of Alberta and Toronto.
Biochemical Analyses
After a 12- to 14-hour period of fasting, plasma Lp(a)
concentrations were determined with a sandwich enzyme-linked
immunoadsorbent assay using monoclonal antibodies 3A5 and 5C4 (47) as
capture and probe antibodies, respectively. The assay was standardized
with purified Lp(a) containing isoforms 3 and 5, with isoform 3
representing approximately 60% of the apo(a) content as
assessed by Western blotting.47 The protein content was
determined using two methods: (1) the Lowry method after treatment with
deoxycholate and trichloroacetic acid precipitation and (2) the Lowry
method with 0.4% SDS in samples and standards. The results are
reported as micrograms per milliliter of Lp(a) total protein. Both
plasminogen and factor VII demonstrated no significant
reactivity in the assay or interference in the determination of Lp(a)
when they were assayed in 0.1% bovine serum albumin or in
increasing concentrations corresponding to physiologic levels of these
components in plasma to standards of Lp(a) or plasma-containing Lp(a).
Apo(a) isoforms were phenotyped after resolving total plasma
proteins by 4% PAGE in the presence of SDS and using a sensitive
chemiluminescent immunoblotting system.47
The detection limit was 5 pg for each isoform.47 The high
sensitivity allowed for the detection of isoforms in all plasma
samples, despite a wide range of isoform size. Antibody 5C4 did not
react with K4 type 2 repeats and the assay was not apparently sensitive
to apo(a) size heterogeneity.
Genetic Analyses
Sufficient DNA and phenotypic information was obtained for most
analyses from 735 Hutterites. Genotypes were performed
using established methods43 44 45 46 48 49 50 51 and are summarized in
Table 1
. Genotyping reactions were run
with known controls.
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Statistical Analysis
SAS (version 6) was used for all statistical
comparisons.52 The distribution of Lp(a) was significantly
non-normal; the distribution of log transformed Lp(a) was not
significantly different from normal. ANOVA was performed using the GLM
procedure to determine the sources of variation for log Lp(a), with F
tests computed from the type III sums of squares.52 This
form of the sums of squares applies to unbalanced study designs and
reports the effect of an independent variable after adjustment for
all other variables included in the model. Independent
variables were age, log BMI, sex, and colony of origin, with the
latter variable included to correct for variation that was related
to other shared genetic and environmental factors. Also included as
independent variables in each ANOVA were apo(a) isoform
phenotypes in addition to genotypes of F7,
AGT, APOB, AGTR1, FABP2,
HSP70-2, PON, LPL, VLDLR,
APOC3, LRP, HL, LDLR, and
APOE and an interaction term with colony for each
genotype. Significance levels for the multiple ANOVAs were
adjusted using a Bonferroni-Holm correction.53
The genetic variables that were significantly associated with plasma Lp(a) concentration were included in a regression analysis with backward elimination. ANOVA was performed using a random effects setting as in Boerwinkle et al11 to cope with the numerous apo(a) size isoform phenotypes. ANOVA was also performed to test for colony*F7 and colony*apo(a) isoform phenotype interaction terms.
In order to determine whether the influence of F7 codon 353 genotype on plasma Lp(a) was additive or dominant, two variables, Additive and Dominant, were created. Additive took the value 0, 1/2, and 1 when the F7 codon 353 genotype was R/R, R/Q, and Q/Q, respectively. Dominant took the value 1 when the F7 codon 353 genotype was Q/Q and took the value 0 otherwise. A general linear model ANOVA was then performed using the variables Additive and Dominant, and covariates age, sex, BMI, and colony. If the final model indicated a significant association between log Lp(a) and Additive but not Dominant, the genetic effect of F7 codon 353 genotype was interpreted as being additive (codominant) rather than dominant.
Regression analysis was performed and partial r2 was used to estimate the contributions to plasma Lp(a) concentration of independent variables including colony*F7 genotype and colony*apo(a) size isoform interaction terms. The average effects of the 353Q and 353R alleles of F7 on the mean sample plasma Lp(a) concentration were computed as described by Templeton.54
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Results |
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Allele and Genotype Frequencies (Table 1
)The frequencies of the alleles of the genotype systems studied are shown in Table 1
. Observed frequencies for
genotypes derived from DNA markers did not deviate from those
predicted by the Hardy-Weinberg equation for genotypes of all
candidate genes (all P>.10). Apo(a) phenotyping revealed
nine size isoforms, numbered from 0 to 8, with isoform 0 having an
apparent molecular weight less than that of apo B-100, isoform 1 having
an apparent molecular weight equivalent to that of apo B-100, and
isoform 8 having the greatest apparent molecular weight. Given the
resolution of this method, there are likely to be several alleles
in some single isoform bands. Thirty-two apo(a) size isoform
phenotypes were detected in the study sample; 406 subjects
(55.1% of the study sample) were heterozygous for two apo(a) isoforms.
Apo(a) isoform 7 was the most prevalent in this study sample, with 355
subjects (48.1% of the study sample) either homozygous or heterozygous
for this particular isoform.
Phenotype-Genotype Associations (Table 2)
The results of the multiple ANOVAs for Lp(a) showed
significant associations only with apo (a isoform phenotype
(adjusted P=.0018) and with F7 codon 353
genotype (adjusted P=.034). The results of the ANOVA
after elimination of nonsignificant independent variables are shown
in Table 2. Sex, age, and BMI were not significantly associated with
variation in log Lp(a). Colony of origin, apo (a isoform size, and
F7 codon 353 genotype were each strongly associated
(each P<.0001) with variation of log Lp(a) (Table 2).
Similar levels of significance were obtained using an ANOVA that did
not eliminate nonsignificant variables, using regression
analysis with backward elimination and using a random effects
ANOVA (data not shown). ANOVA that included colony*F7 codon
353 genotype and colony*apo(a) isoform interaction terms
revealed that both interactions were significant (P=.025 and
<.0001, respectively). The associations between log Lp(a) and both
F7 genotype and apo(a) size isoform
phenotype also remained significant when the interaction terms
were included (data not shown). This suggests that shared genetic
and/or environmental factors within colonies interact with both
F7 genotype and apo(a) size isoform
phenotype to further affect Lp(a).
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Additivity of F7 Codon 353 Genotype and Average
Effects of Alleles (Table 3)
The median Lp(a), least squares mean±standard deviation (SD) for
unadjusted Lp(a) and log Lp(a) are shown for subjects classified by
F7 genotype in Table 3. The mean±SD for the whole
sample was 19.4±28.4 µg/mL. The ANOVA to test for additivity
and/or dominance of the F7 alleles included only the
Additive variable (P<.0001) but not the Dominant
variable (NS). This indicated that the genetic effect of the
F7 genotype was strictly additive and meant that we
could calculate the average effect of the F7 codon 353
alleles. The average effects of the F7 353Q and 353R
alleles were, respectively, to decrease plasma Lp(a) concentration
by 1.71 µg/mL and to increase plasma Lp(a) concentration by
0.301 µg/mL from the sample mean. The average effects of the
F7 353Q and 353R alleles were, respectively, to decrease
log Lp(a) by 0.179 and to increase log Lp(a) by 0.012 from the sample
mean.
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Genetic Contribution to Plasma Lp(a) Concentration
The percentage contribution of independent variables to plasma
Lp(a) concentrations was estimated using partial
r2 derived from univariate ANOVA.
Using this approach, 53% of the variance in log Lp(a) could be
attributed to five variables: 17.2% from apo(a) isoform
phenotype, 4.9% from the colony of origin term, 0.3% from
F7 codon 353 genotype, 24.0% from the colony*apo(a)
isoform phenotype interaction term, and 17.2% from the
colony*F7 codon 353 genotype interaction term (all
P<.05).
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Discussion |
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We have found a significant association between F7 genomic variation in codon 353 and variation in plasma Lp(a) concentration. We have also confirmed that plasma Lp(a) concentrations in this study sample were significantly associated with apo(a) size polymorphism. The effect of the F7 alleles on plasma Lp(a) concentration in this sample was strictly additive with the 353Q allele associated with a decrease in plasma Lp(a) and the 353R allele associated with an increase in plasma Lp(a). Thus subjects predicted to have lower FVIIc based upon having the 353Q allele also had lower plasma Lp(a) concentration and subjects predicted to have higher FVIIc based upon having the 353R allele also had higher plasma Lp(a) concentration.
Using regression analysis, we estimated that the direct contribution of F7 codon 353 genotype variation to the total variance of Lp(a) was <1%. However, the contribution of F7 codon 353 genotype to plasma Lp(a) concentration in this sample is probably considerably higher, especially when the estimate of 17.2% from the colony*F7 codon 353 genotype interaction term is considered. It is possible that a much larger effect of the F7 codon 353 genotype upon plasma Lp(a) was subsumed into the colony*F7 effect; for example, the genotypic variation in F7 may itself appear as a difference in the distribution of the F7 genotype between the colonies. Considering that the sum of the average effects of the F7 codon 353 alleles (ie, 1.71+0.301=2.011 µg/mL) is about 10% of the mean Lp(a) in this sample, it is likely that the partial r2 from the regression analysis is an underestimate of the true contribution of F7 genetic variation to plasma Lp(a) concentration variation. Differences between estimates of genetic effects on quantitative traits obtained using regression analysis and average effects statistics have previously been noted.55
Our estimate of the proportion of the total variance of Lp(a) that is
directly attributable to apo(a) isoform phenotype (17%) is
lower than some estimates reported in Boerwinkle et al.16
However, the contribution of apo(a) isoform phenotype to plasma
Lp(a) concentration in this sample is probably considerably higher,
especially when the estimate of 24% from the colony*apo(a) isoform
phenotype interaction term is considered. The interaction term
suggests also that there are differences in the distributions of the
apo(a) isoform phenotypes across the colonies. One
consideration is that the "direct" effect may reflect the
contribution of the isoforms, which is related to APO(a)
size, but the interaction term with colony may reflect the contribution
of other cis-acting elements at the APO(a) locus for which
the isoform is an effective marker within a colony. The interaction
requires further study.
Other estimates of the contribution of apo(a) size isoform
phenotype to variation in plasma Lp(a) concentration have
varied from 19% in Sudanese12 to 27% in African
Americans13 to 35% in Europeans.12 In a
linear regression analysis similar to the one we used, apo(a)
isoform size explained 24% of the variance of plasma Lp(a) in
Mexican Americans.56 Those estimates of the genetic
contribution to Lp(a) exceeding 90%11 were derived from
different analytic strategies that used the APO(a) gene DNA
size polymorphism in a quantitative trait analysis in
siblings.11 Attributes of the analysis such as the
marker used, the use of sibling units, and the statistic used to
estimate variance or variation affect the contribution of a gene to a
quantitative trait.
There are several possible bases for the association between variation in F7 and variation in plasma Lp(a). The F7 codon 353 amino acid variation in the Hutterites might have been in linkage disequilibrium with other functional determinants of plasma Lp(a) concentration either within F7 itself, or within a nearby gene on chromosome 13q34, such as F10.57 There may also be a nearby gene whose as yet uncharacterized function may have an impact upon plasma Lp(a). Genetic variation of F7 may directly affect apo(a) synthesis and Lp(a) assembly, secretion, or catabolism. The change at position 353 has been suggested to affect the binding of FVIIc to lipoproteins.40 However, FVIIc is important near the initiation of coagulation,27 28 whereas Lp(a) is presumed to be important near the terminal phase, when thrombolysis is imminent.58 59 60 61 The association between F7 and Lp(a) might also be related to the association between triglycerides and FVIIc.34 35 36 37 38 However, we found no relationship between plasma triglycerides and either Lp(a) or F7 genotype (data not shown).
Most genetic factors affecting other plasma lipoproteins have no association with plasma Lp(a). Only one study has reported that genetic variation in APOE was associated with variation in plasma Lp(a),24 but others showed that variation in plasma Lp(a) concentration was not associated with genetic variation of either APOB19 or APOE.25 26 LDLR mutations were initially associated with higher plasma Lp(a),62 but this has not been consistently observed.63 64 Furthermore, the LDL receptor is not required for Lp(a) catabolism.65 Also, mutations in APOB that decrease apo B synthesis and secretion but do not affect the putative apo(a)-bonding site, do not affect plasma Lp(a) concentration.66
In summary, we have identified a locus outside APO(a) that is significantly associated with variation in plasma Lp(a). It would be important to replicate these findings to determine whether mechanistic studies are warranted. Our findings in the Hutterites suggest that complex traits have a significant genetic component that is the aggregate of many small effects.43 44 45 46 Such subtle genotype-phenotype associations may be more readily identified in such human samples, in which genetic background and environmental noise are minimized.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported by grants from the Medical Research Council of Canada (MA-13430), the National Health Research and Development Program of Canada, and the Heart and Stroke Foundation of Ontario (T2978). We thank Stanley Chan (APOB codon 3611 genotypes), Bryan Chung (AGTR1 genotypes), Kevin Higgins (APOB codon 4154 genotypes), Greg Ip (APOE and LPL genotypes), Ulana Kawun (F7 genotypes), Dennis Lam (LDLR and VLDLR genotypes), Edwin Lee (AGT and PON genotypes), Bireen Manuel (HSP70-2 genotypes), Patricia Ram (AGT and HL genotypes), Stefan Sadikian (LRP and FABP2 genotypes), and Tammy Znajda (APOC3 genotypes) for their technical assistance. Dr. Aiala Barr provided expert statistical advice. Teresa Lippingwell and Liling Tu archived the phenotypic and genotypic data. R.A.H. is a career investigator of the Heart and Stroke Foundation of Ontario.
Received August 26, 1996; accepted January 31, 1997.
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