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Physiol. Genomics 30: 95-101, 2007. First published March 13, 2007; doi:10.1152/physiolgenomics.00211.2006
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Received 29 September 2006; accepted in final form 7 March 2007.
Physiological Genomics 30:95-101 (2007)
1094-8341/07 $8.00 © 2007 American Physiological Society

Comprehensive QTL analysis of serum cholesterol levels before and after a high-cholesterol diet in SHRSP

Tomoji Mashimo 1,4, Hiroshi Ogawa 2, Zong-Hu Cui 3, Yuji Harada 3, Kohei Kawakami 5, Junichi Masuda 4, Yukio Yamori 6 and Toru Nabika 3

1 Institute of Laboratory Animals, Graduate School of Medicine, Kyoto University, Kyoto, Japan
2 Department of Hygiene, Kinki University School of Medicine, Osakasayama, Japan
3 Department of Functional Pathology, Shimane University School of Medicine, Shimane University, Izumo, Japan
4 Department of Laboratory Medicine, Shimane University School of Medicine, Shimane University, Izumo, Japan
5 Department of Experimental Animals, Center for Integrated Research in Science, Shimane University, Izumo, Japan
6 International Center for Research on Primary Prevention of Cardiovascular Diseases, Kyoto, Japan


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The stroke-prone spontaneously hypertensive rat (SHRSP) showed an exaggerated response to a high-fat, high-cholesterol (HFC) diet, and the resulting reactive hypercholesterolemia was suggested to exacerbate the atherogenic process in this rat. We thus performed a quantitative trait locus (QTL) analysis on the serum cholesterol level of SHRSP before and after the HFC diet, with the final goal being the identification of the genetic mechanisms of its reactive hypercholesterolemia. Three hundred fifty-eight F2 rats between SHRSP and Wistar-Kyoto rat were employed in the study. The serum cholesterol and apoprotein E were measured before and after 2 wk of feeding with the HFC diet. Multiple QTLs for the basal cholesterol level were identified on chromosomes 1 and 5, whereas those for the postdietary cholesterol level were on chromosomes 7, 15, and 16. The cholesterol QTLs before and after HFC diet did not overlap with one another, implying that the involved metabolic processes were considerably different between the two conditions. Supporting this, VLDL and LDL cholesterol were the major components of the postdietary serum cholesterol, whereas the basal cholesterol level consisted mainly of HDL cholesterol. A substantial difference of the QTLs between males and females was observed, especially after the HFC diet. The QTL on chromosome 15 had an inverse effect on the cholesterol level, suggesting that the congenic substitution of the SHRSP fragment with that of Wistar-Kyoto rats could induce a greater cholesterol level in SHRSP. This observation is significant in establishing a new model for atherosclerosis with hypertension in rats.

genetics; hypercholesterolemia; quantitative trait locus; apoprotein E; stroke-prone spontaneously hypertensive rat


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
HYPERLIPIDEMIA DUE TO THE CONSUMPTION of a high-fat diet is a serious health problem in developed countries (20). As the response to high cholesterol intake appears not to be genetically identical among individuals, identification of the pertinent genetic factors may be important to realize effective prevention of hyperlipidemia (2, 3).

The stroke-prone spontaneously hypertensive rat (SHRSP) is a unique model of postdietary hypercholesterolemia; the serum cholesterol level becomes greater than that in the Wistar-Kyoto rat (WKY) after feeding on a high-fat, high-cholesterol (HFC) diet, although the level in SHRSP with a normal diet is significantly lower than that in WKY (17). Hence, genetic analysis of the mechanisms of hypercholesterolemia in SHRSP may provide a clue to the genetic basis of reactive hypercholesterolemia in humans.

Furthermore, in SHRSP, the induced hypercholesterolemia exacerbated the progression of fatty streaks in the arteries, implying that SHRSP fed with the HFC diet was a good model for the atherosclerotic disorders with hypertension (22, 23).

In a previous study, we identified three quantitative trait loci (QTLs) contributing to the difference of the basal cholesterol levels between SHRSP and WKY (10). However, there has been no genetic analysis of the postdietary level of the serum cholesterol despite the fact that it may contribute more to atherogenesis in SHRSP (23). To assess the genetic mechanism of this unique response in SHRSP, we performed a QTL analysis in the present study.

The serum lipid profile in SHRSP after the HFC diet was similar to that observed in the apoprotein E (apoE)-knockout mouse, i.e., a large increase in the very low- (VLDL-C) and the low-density lipoprotein cholesterol (LDL-C) with a simultaneous decrease in the high-density lipoprotein cholesterol (HDL-C) (9, 13, 17). This apparent similarity led us to include the serum apoE level in the QTL analysis.

In this study, the genome-wide QTL analysis was performed on subfractions of the serum cholesterol as well as the apoE level. Consequently, multiple QTLs for these traits were identified. The alteration of QTLs by the dietary conditions as well as by the sex is discussed.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Animal procedures.
SHRSP/Izm and WKY/Izm were provided by the Disease Model Cooperative Research Association (Kyoto, Japan). F1 rats were obtained through reciprocal mating either between male SHRSP and female WKY [F1(pxw)] or between male WKY and female SHRSP [F1(wxp)]. F2 rats were then made by the four possible matings of the F1 rats; i.e., male F1(pxw) x female F1(pxw), male F1(pxw) x female F1(wxp), male F1(wxp) x female F1(wxp), and male F1(wxp) x female F1(pxw). Since there was no significant difference in the lipid profiles among the four F2 cohorts or between the two F1 cohorts above, we combined all of the F2 rats (174 males and 184 females) in a QTL analysis (data not shown).

Rats were fed with a standard "Japanese" diet (19.7% crude protein, 4.8% crude fat, 3.4% crude fiber, 3.7 mg/g of sodium; SP diet, Funabashi Farm, Funabashi, Japan) until 13 wk of age (24). They were then fed with an HFC diet containing 5% lard, 0.5% cholic acid, and 2% cholesterol for 2 wk. Serum samples were withdrawn from the jugular vein before and after the HFC diet under anesthesia with pentobarbital (50 mg/kg body wt). Sampling was performed between 1 and 3 PM after 5 h of food deprivation. The animal procedures were approved by the local committee for the animal research of Shimane University School of Medicine.

Lipid measurements.
Sera were separated by centrifugation at 3,000 rpm and kept at 4°C up to 4 days before the measurement of the serum cholesterol levels. The total cholesterol (TC), triglyceride (TG), HDL-C, and LDL-C were measured using commercial kits (Pure Auto S CHO-N for TC and Cholestest LDL for LDL-C, Daiichi Pure Chemicals, Tokyo, Japan, and Determina L TG for TG and Determina L HDL-C for HDL-C, Kyowa Medex, Shizuoka, Japan).

VLDL-C was measured in the fraction (density < 1.006 g/ml) obtained after the density-gradient ultracentrifugation (17). The serum apoE level was measured by the "rocket electroimmunoassay" as previously described (12, 17).

QTL analysis.
Heritability was calculated based on the data of the parental, F1, and F2 generations as previously described (10). Briefly, the broad-sense heritability was estimated as heritability2 = (variance in F2 – environmental variance)/variance in F2. The environmental variance was calculated by pooling the variances of the F1 and two parental populations.

DNA was extracted from the liver. One hundred sixty-eight simple sequence repeat markers were used in the genotyping of the 358 F2 rats. The constructed linkage map covered 1,460 cM of the rat genome that was comparable with other linkage maps [1,570 cM for SHRSP x BN and 1,630 cM for FHH x ACI according to the Rat Genome Database (http://rgd.mcw.edu)]. The averaged distance between two adjacent markers was 8.7 cM. The QTL analysis was performed with MapManager QTX version b20 (14). Before the analysis, individual phenotypic values were standardized using the formula: standardized phenotypic value = (phenotypic value – mean of the cohort)/SD of the cohort. The genome-wide significance levels proposed by Lander and Kruglyak were used in the analysis (11). ANOVA and analysis of covariance were applied when the effect of genotypes at each marker locus and the interaction between two QTLs were examined. In addition, a genome-wide screening for interacting loci was performed using the "interaction" function implemented in MapManager QTX. Phenotype data were represented as means and SE.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Table 1 shows the lipid profile of the parental strains before and after the HFC diet. Being consistent with the previous observations, TC under the basal condition was lower in SHRSP than in WKY (17). In contrast, after 2 wk of HFC diet, SHRSP showed a significantly greater TC level than in WKY. Interestingly, the female showed a much greater postdietary increase in TC level in both of the two strains. The increase in TC after the HFC diet was mainly due to the increase in LDL-C and VLDL-C. In contrast, HDL-C did not show such a large increase as LDL-C/VLDL-C did. The apoE level rather decreased as shown in the previous report (17). TG under the basal condition was greater in SHRSP. The TG level paradoxically decreased after the HFC diet, which was previously observed in different strains of rats and mice (1, 7).


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  		Table 1. The lipid profiles of WKY and SHRSP before and after the HFC diet

 
Heritability was calculated to be 0.4–0.6 for TC, LDL-C, VLDL-C, and apoE under both the basal and postdietary conditions. The heritability of HDL-C was 0.2–0.4, and that of TG varied from 0 to 0.4 among different conditions, suggesting a large environmental influence on the TG level.

Figure 1 shows a summary of the genome-wide QTL analysis on the cholesterol as well as on the TG level. Under the basal condition, QTLs for TC were identified on chromosomes (Chr) 1 and 5 at a significant level [logarithm of the odds ratio (LOD) ≥ 4.3]. As indicated with shaded boxes, the QTL peak on Chr 1 corresponded with a peak for HDL-C, whereas the peak on Chr 5 was associated with that of LDL-C and HDL-C. As the basal LDL-C level was very low (see Table 1), the basal TC seemed largely influenced by the QTLs for the HDL-C level. This was further supported by r2 between TC and HDL-C being larger than that between TC and LDL-C (r2 = 0.64 and 0.30, respectively). After HFC diet, on the other hand, strong correlation between TC and LDL-C/VLDL-C (r2 = 0.96 and 0.99, respectively) were observed, which corresponded well with observations in the QTL analysis. Interestingly, no QTL was identical before and after the HFC diet, suggesting that the sets of genes regulating the TC level were different under the two conditions. QTLs for TG were identified on Chr 4 and 6 before the HFC diet and on Chr 1 after the HFC diet.


Figure 1
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  		Fig. 1. Genome-wide quantitative trait locus (QTL) analysis on the serum total cholesterol (TC), very low-density lipoprotein cholesterol (VLDL-C), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG) before and after the high-fat high-cholesterol (HFC) diet. Shaded boxes indicate significant [logarithm of the odds ratio (LOD) ≥ 4.3] peaks for TC and corresponding peaks for VLDL-C, LDL-C, or HDL-C that show LOD scores greater than the suggestive level (LOD ≥ 2.8). The significant and suggestive levels of LOD score are indicated with dotted lines.

 
In addition to the different QTLs found before and after the HFC diet, the sexual dimorphism was apparent on the QTLs for the cholesterol levels. Figure 2A indicates the QTLs for TC obtained separately in the male and female F2 cohorts. The peak on Chr 5 for the basal TC level was male-specific, which was consistent with our previous result (10). The QTLs for the TC level after the HFC diet showed more striking sexual dimorphism; QTLs on Chr 7 and 15 were identified only in the female, whereas the QTLs on Chr 3 and 16 were shown only in the male. Figure 2B indicates the TC levels of the three genotypes at a genetic marker locus under each QTL peak. It should be noted that the QTL on Chr 15 (D15Mgh7) showed an inverse effect on the postdietary level of TC; i.e., the TC level of the WKY homozygote was greater than that of the SHRSP homozygote. In contrast to the QTLs above, the QTL on Chr 1 was identified in both sexes as a peak at a suggestive level, implying no sexual dimorphism on this locus.


Figure 2
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  		Fig. 2. Genome-wide QTL analysis on the serum TC performed on the male and female cohort separately. Top: genome-wide LOD scores are plotted for TC before and after HFC diet. Peaks shown with shaded boxes are selected for the analysis at bottom using ANOVA. Bottom: genotype effects on the TC level are examined at a marker locus under the peak selected at top. The column and the vertical line represent the means and SE. Open, shaded, and closed columns indicate the Wistar-Kyoto (WKY) homozygote, the heterozygote, and the stroke-prone spontaneously hypertensive (SHRSP) homozygote, respectively.

 
To elucidate the interaction between the QTLs, the collective effects of the two significant postdietary QTLs in each sex (Edn3 and D16Wox10 in the male, D7Rat94 and D15Mgh7 in the female) were evaluated in the F2 cohort. By analysis of covariance, synergistic effects between these QTLs were not significant (data not shown). As shown in Fig. 3, each QTL had an additive effect on TC when the F2 rats were selected according to their genotype of the markers indicated in the figure (each genotype group consisted of 5–14 rats). Due to the inverse effect of the QTL on Chr 15, the F2 female rats that were double homozygotes for the WKY allele at D15Mgh7 and for the SHRSP allele at D7Rat94 showed a significantly greater TC level than in the rats homozygous for SHRSP allele at both marker loci (P = 0.04 by Dunnett's post hoc test).


Figure 3
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  		Fig. 3. Additive effects of the two QTLs on the postdietary TC level. Additive effects of the two most potent QTLs for the postdietary TC level are shown for the two sexes separately. We selected 5–14 F2 rats with each corresponding genotype to calculate the genotype effects. Values for the parental strains are shown at left. Each column and vertical line indicates mean and SE. The P values indicated are by ANOVA.

 
We further made a genome-wide search for interacting loci using the interaction function implemented in MapManager QTX. As reported in a previous communication (21), more than 70 pairs of loci were identified to have significant interactions when the default criteria of the program (P < 10–5 for total effect and P < 0.01 for interaction) were applied. This might be due to the low stringency of the criteria for a multiple comparison. We therefore arbitrarily listed, in Table 2, interacting pairs with the interaction term at P < 0.001 (likelihood ratio statistic ≥ 18.5). The result indicated that 1) most pairs were identified in the female cohort, 2) all pairs except one (D3Rat110 and D5Mgh11) were unique for individual traits, and 3) there was no pair commonly effective in both the male and the female. These interactions should be confirmed in double congenic strains in a future study.


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  		Table 2. Interaction between loci

 
The whole genome scan on the apoE level revealed a strong QTL for the postdietary apoE on Chr 8 (Fig. 4). This QTL was found in both sexes as suggestive peaks, and no apparent sex dimorphism was therefore observed. Although the apoE level of SHRSP was lower in the parental strains (see Table 1), the SHRSP homozygotes at D8Rat16 in this QTL showed a greater apoE level (Fig. 4).


Figure 4
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  		Fig. 4. A QTL for the serum apoE level on Chr 8. Top: the QTL identified on chromosome (Chr) 8. Solid line, thick dotted, and thin dotted lines indicate LOD scores for the total, the male, and the female F2 cohorts, respectively. Bottom: the genotype effects of D8Rat16 on the apoE level in the F2. Open, shaded, and closed columns indicate the WKY homozygote, the heterozygote, and the SHRSP homozygote, respectively. Each column and vertical line indicate mean and SE.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In the present study, we conducted a search for QTLs for the serum cholesterol as well as for the apoE level in a large F2 cohort (n = 358) under both the basal and the postdietary conditions. As far as we know, this is one of the most comprehensive studies dealing with the cholesterol-related QTLs in rats.

SHRSP showed a unique cholesterol metabolism in terms of the responsiveness to the HFC diet. The basal level of TC was significantly lower in SHRSP than in WKY. The major component of the TC under this condition in rats was HDL-C, and accordingly HDL-C and the apoE levels were both lower in SHRSP (see Table 1). In contrast, after the HFC diet, the major component of the serum cholesterol switched to VLDL/LDL-C, and the TC level as well as the VLDL/LDL-C became greater in SHRSP.

Corresponding changes of the QTLs were observed; QTLs on Chr 1 and 5 disappeared, and those on Chr 7, 15, and 16 emerged after the HFC diet. The former QTLs corresponded with those for HDL-C, whereas the latter overlapped with those for VLDL/LDL-C, suggesting that the metabolic processes involved were different between the two conditions. This observation suggested the benefit of analyzing subfractions of the serum cholesterol.

The present observation is important in the deduction of candidate genes for the QTLs as well. For example, the apoE gene on Chr 1, the LDL receptor-related protein 8 (a suggestive apoE receptor) gene on Chr 5, the lipoprotein lipase gene on Chr 16, and the sterol O-acyltransferase 2 gene on Chr 7 are all reasonable positional candidates from a functional point of view. In addition, some candidates may be selected from syntenic regions of mice and humans, as proposed in the previous studies (8, 21). However, hundreds to thousands of genes are located in large QTL regions, and furthermore the responsible genes may not always be known genes. Therefore, the reduction of the QTL region as well as the identification of good intermediate phenotypes are essential to identify promising candidate genes (16).

Interestingly, female rats showed much greater TC, VLDL-C, and LDL-C levels after HFC diet both in WKY and in SHRSP. This suggested that the cholesterol metabolism was different between the two sexes in these rats. Consistent with this, QTLs for TC showed clear sexual dimorphism; LOD peaks on Chr 3, 5, 7, 15, and 16 were highly significant in one sex, but they did not even reach a suggestive level in the other sex (see Fig. 2). This striking discrepancy implied that the observed dimorphism was not spurious. However, in a recent study on Drosophila, Curtsinger pointed out that, when recombinant inbred strains were employed, a reliable statement for the sexual dimorphism needed more than 200 individuals for each recombinant inbred strain or more than 10,000 individuals in total (5). It is not clear whether this estimation can be applied directly to the F2 intercross analysis; nevertheless, the F2 cohorts used in rodent studies are, in general, much smaller when compared with the studies on Drosophila (5). We should thus be cautious to conclude that our observations support the sexual dimorphism of the QTLs. In this context, it should be noted that our previous QTL analysis on the basal TC level gave a male-specific QTL on Chr 5 in the same region found in the present study (Fig. 5 and Ref. 10). Therefore, the QTL on Chr 5 and its sexual dimorphism seemed reliable since it was reproducible in the two independent studies. Two additional QTLs for the basal TC detected in the previous study were, however, not reproducible in the present study. Instead, QTLs for the postdietary level of TC were identified in the overlapping region (Fig. 5).


Figure 5
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  		Fig. 5. Reproducibility of the QTL analysis. The QTLs for the TC level on Chr 5, 7, and 15 are compared between the two studies performed on SHRSP x WKY intercrosses. The dotted line indicates the QTLs for the basal TC identified in the previous study (13), whereas the black and gray solid lines indicate the LOD scores for the basal and postdietary TC level, respectively, obtained through the present study.

 
One factor potentially responsible for this discrepancy is the age difference of rats used in the two experiments. In the present study, QTLs for the basal cholesterol level were studied at 13 wk of age, whereas those for the postdietary level were evaluated at 15 wk. In the previous study, however, QTL analysis for the basal cholesterol was performed at 16 wk of age (10), which gave QTLs that overlap with those for the postdietary cholesterol at 15 wk of age in the present study (Fig. 5). Thus the QTLs on Chr 7 and 15 that were observed postdietary may only be a consequence of age differences between studies and not truly be a result of diet.

Another interesting observation was that the QTL on Chr 15 showed an inverse effect on the cholesterol level. This result implies that the shuffling of the Chr 15 QTL of SHRSP with WKY may induce a greater postdietary TC level in an SHRSP-based congenic strain, which may provide a better model for atherosclerosis with hypertension (23).

The lipid profile in SHRSP was similar to that in the apoE-knockout mouse (9, 13, 17). Since the apoE level after the HFC diet was lower in SHRSP than in WKY (see Table 1 and Ref. 17), we hypothesized that the relative deprivation of the apoE protein under the HFC diet might causally relate to the characteristic lipid profile in SHRSP. Despite the fact that the genetic analysis identified a potent QTL for the postdietary apoE level on Chr 8, it unexpectedly showed no overlap with the QTLs for lipoprotein cholesterol levels. A characteristic profile of the serum cholesterol in SHRSP thus seemed independent of the apoE metabolism, and the physiological significance of the apoE QTL is yet to be established.

Recently, QTL analyses on serum cholesterol levels have been performed on different strains of rats, which identified multiple QTLs (summarized in Table 3). Overlapping of the QTLs was rather exceptional, however, even if our present results were included in the list. The regions on Chr 5 either for the basal or the postdietary TC as well as those on Chr 16 for the postdietary TC showed some overlap with the QTLs identified in the present study (see Table 3). As these QTLs are different in terms of the rat strains used, as well as in terms of the dietary conditions and the sex specificity, careful evaluation of these QTLs is necessary. It should be remembered that ordinal QTL analysis can detect only the genetic regions contributing to the phenotype difference between the two particular strains used in the study.


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  		Table 3. Summary for TC QTLs in rats

 
The criterion proposed by Lander and Kruglyak (13) was more conservative when compared with a threshold obtained through permutation tests, which gave LOD = 3.4–3.7 as a genome-wide significant level (P < 0.05) for each trait examined in the present study (1,000 permutations with 10-cM intervals). However, considering the multiplicity of analyses dealing with 12 traits (TC, VLDL-C, LDL-C, HDL-C, TG, and apoE under regular and HFC diet), it may be safer to employ the conservative criterion in this study. This was supported when thresholds obtained through the permutation tests were corrected with the number of "effectively independent analyses" estimated by the method of Camp and Farnham using linear regression (4). The number of effectively independent analyses was estimated to be six in this study, and the corrected threshold was ~4.5 in LOD score, which was quite close to the criterion of Lander and Kruglyak. It should be noted that several recent QTL studies used this criterion as well (15, 19).

In summary, we identified several significant QTLs for the serum lipid levels in SHRSP through a comprehensive analysis. Construction of congenic strains is underway to confirm the QTLs.


   FOOTNOTES
 
Article published online before print. See web site for date of publication (http://physiolgenomics.physiology.org).

Address for reprint requests and other correspondence: T. Nabika, Dept. of Functional Pathology, Shimane Univ. School of Medicine, Izumo 693-8501, Japan (e-mail: nabika{at}med.shimane-u.ac.jp).


   REFERENCES
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 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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M. Asahina, W. Haruyama, Y. Ichida, M. Sakamoto, M. Sato, and K. Imaizumi
Identification of SMEK2 as a candidate gene for regulation of responsiveness to dietary cholesterol in rats
J. Lipid Res., January 1, 2009; 50(1): 41 - 46.
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M. J. Corenblum, V. E. Wise, K. Georgi, B. D. Hammock, P. A. Doris, and M. Fornage
Altered Soluble Epoxide Hydrolase Gene Expression and Function and Vascular Disease Risk in the Stroke-Prone Spontaneously Hypertensive Rat
Hypertension, February 1, 2008; 51(2): 567 - 573.
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