Genetic Dissection of “OLETF,” a Rat Model for Non-Insulin-Dependent Diabetes Mellitus: Quantitative Trait Locus Analysis of (OLETF × BN) × OLETF

Watanabe, Takeshi; Okuno, Shiro; Oga, Keiko; Mizoguchi-Miyakita, Ayako; Tsuji, Atsushi B.; Yamasaki, Yoshio; Hishigaki, Haretsugu; Kanemoto, Naohide; Takagi, Toshihisa; Takahashi, Ei; Irie, Yasuo; Nakamura, Yusuke; Tanigami, Akira

doi:10.1006/geno.1999.5789

Cited by 50 publications

(90 citation statements)

References 39 publications

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“…York, Lei, and West (25) previously reported on the syntenic QTL region in mice to this QTL for WAT weight. Watanabe et al (26) also reported QTLs related to fat level and body weight on rat chromosome 1 (Dmo1) in a genetic analysis of OLETF rats. The D1Rat90 marker that showed the peak LOD score at the Dmo1 locus was mapped near the telomere (148 cM).…”

Section: Discussionmentioning

confidence: 99%

Genetic analysis of diet-induced hypercholesterolemia in exogenously hypercholesterolemic rats

Amaki

Sato

Imaizumi

2005

Journal of Lipid Research

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The exogenously hypercholesterolemic (ExHC) rat is an established strain that exhibits a polygenic syndrome of hypercholesterolemia after feeding on a cholesterol-containing diet, and the extent of this differs between male and female rats in the strain. The present study was performed to determine the genetic background of diet-induced hypercholesterolemia in ExHC rats. We used quantitative trait locus (QTL) analyses of the F2 progeny derived from ExHC and Brown-Norway rats. Rats were fed a diet containing 1% cholesterol, and a genome-wide scan was then performed. Significant QTLs for serum total cholesterol levels were revealed on chromosomes 5 and 14 in the vicinity of markers D5Rat95 and D14Rat43, having maximum logarithm of the odds scores of 6.0 and 5.8, respectively. A suggestive QTL for the trait was also detected on chromosome 3 at D3Rat140. In particular, the QTL on chromosome 5 was specific for female rats. These loci were novel QTLs for postdietary serum total cholesterol levels. In addition, cross-mating analysis in F1 generations suggested that the responsiveness to dietary cholesterol in ExHC rats is partly attributable to X-linked inheritance. Identifying such genetic factors may be useful in predicting the risks associated with diet-induced hypercholesterolemia in humans. (2) is provoked by dietary cholesterol, but the extent varies even in the same species because it has a polygenic basis (3, 4). One study showed that the sex of the subject affects responses of serum total cholesterol to dietary cholesterol in human (5), although another study did not supported the sex difference (6). Individual genetic variability makes it difficult to estimate the influence of dietary cholesterol on serum total cholesterol levels. Thus, animal strains that exhibit consistent hypercholesterolemia after feeding on a cholesterol-containing diet are important models for dissecting the components involved in hypercholesterolemia and for identifying underlying gene variants.Exogenously hypercholesterolemic (ExHC) rats isolated from Sprague-Dawley (SD) strains by Imai and Matsumura (7) easily elicit hypercholesterolemia after feeding on a cholesterol-containing diet without exhibiting hyperthyroidism. Multiple genes are involved in stable hypercholesterolemia in this strain, but the detailed mechanisms responsible for this have not been clarified (8). Our previous results showed that ExHC rats less effectively take up 125 I-labeled ␤ -VLDL via the liver and excrete bile acid into the feces to a lesser extent than do SD rats, although the absorption rates of dietary cholesterol do not differ between the strains (9). These results indicate that ExHC rats specifically alter cholesterol metabolism in an undefined manner in response to dietary cholesterol.To analyze the genetic background of hypercholesterolemia in ExHC rats, we performed genome scanning of F2 progeny derived from ExHC and the genetically distant Brown-Norway (BN) rat inbred strains after feeding on a cholesterol-containing diet. We detected tw...

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Section: Discussionmentioning

confidence: 99%

Genetic analysis of diet-induced hypercholesterolemia in exogenously hypercholesterolemic rats

Amaki

Sato

Imaizumi

2005

Journal of Lipid Research

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“…Genomewide linkage analyses in humans (Duggirala et al 1999;Reynisdottir et al 2003), mice (Stoehr et al 2000;Kim et al 2001), and the OLETF rat model (Watanabe et al 1999) have also located QTL for diabetes in chromosome regions homologous to Niddm1i, human chromosome 10q24.3-q26.11, and mouse chromosome 19. Recently, two genes residing within Niddm1i have been associated with diabetes in humans (Tcf7l2; Grant et al 2006), and fasting insulin levels in an obesity-induced mouse model for diabetes (Sorcs1; Clee et al 2006).…”

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confidence: 99%

High-Resolution Quantitative Trait Locus Analysis Reveals Multiple Diabetes Susceptibility Loci Mapped to Intervals <800 kb in the Species-ConservedNiddm1iof the GK Rat

et al. 2006

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Niddm1i, a 16-Mb locus within the major diabetes QTL in the diabetic GK rat, causes impaired glucose tolerance in the congenic NIDDM1I strain. Niddm1i is homologous to both human and mouse regions linked with type 2 diabetes susceptibility. We employed multiple QTL analyses of congenic F 2 progeny selected for one recombination event within Niddm1i combined with characterization of subcongenic strains. Fine mapping located one hyperglycemia locus within 700 kb (Niddm1i4, P ¼ 5 3 10 À6 ). Two adjacent loci were also detected, and the GK allele at Niddm1i2 (500 kb) showed a glucose-raising effect, whereas it had a glucose-lowering effect at Niddm1i3 (400 kb). Most proximally, Niddm1i1 (800 kb) affecting body weight was identified. Experimental data from subcongenics supported the four loci. Sorcs1, one of the two known diabetes susceptibility genes in the region, resides within Niddm1i3, while Tcf7l2 maps outside all four loci. Multiple-marker QTL analysis incorporating the effect of cosegregating QTL as cofactors together with genetically selected progeny can remarkably enhance resolution of QTL. The data demonstrate that the species-conserved Niddm1i is a composite of at least four QTL affecting type 2 diabetes susceptibility and that two adjacent QTL (Niddm1i2 GK and Niddm1i3 GK) act in opposite directions.

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“…This region contains several QTLs for body weight including Bw24, 31, and 36 (1, 39) and for body fat amount such as Niddm46 (44) in other strains.…”

Section: Discussionmentioning

confidence: 99%

Identification of a major locus for islet inflammation and fibrosis in the spontaneously diabetic Torii rat

Fuse

Yokoi

Shinohara³

et al. 2008

Physiological Genomics

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of inflammation and fibrosis in the pancreatic islets in diabetes is largely unknown. Spontaneously diabetic Torii (SDT) rats exhibit inflammation and fibrosis in and around the islets during the development of the disease. We investigated genetic factors for diabetes, islet inflammation, and fibrosis in the SDT rat. We produced F1 and F2 rats by intercross between SDT and F344 rats, examined the onset of diabetes, glucose tolerance, and histology of the pancreas, and performed genetic analysis of these traits. We then established a congenic strain carrying the SDT allele at the strongest diabetogenic locus on the F344 genetic background and characterized glucose tolerance and histology of the pancreas. F1 rats showed glucose intolerance and inflammatory changes mainly in the islets. Genetic analysis of diabetes identified a major locus on chromosome 3, designated Dmsdt1, at which a dominantly acting SDT allele was involved. Quantitative trait locus (QTL) analysis of glucose tolerance revealed, in addition to Dmsdt1 [logarithm of odds (LOD) 5.3 near D3Mit12], three other loci, designated Dmsdt2 (LOD 4.2 at D8Rat46), Dmsdt3 (LOD 3.8 near D13Arb5), and Dmsdt4 (LOD 5.8 at D14Arb18). Analysis of a congenic strain for Dmsdt1 indicates that the dominantly acting SDT allele induces islet inflammation and fibrosis. Thus we have found a major locus on chromosome 3 for islet inflammation and fibrosis in the SDT rat. Identification of the genes responsible should provide insight into the pathogenesis of diabetes. congenic analysis; diabetes; genetic factor; glucose tolerance; quantitative trait locus DIABETES MELLITUS IS a multifactorial disease involving interaction of genetic and environmental factors. Spontaneous animal models of diabetes are widely used in research and have provided valuable information on the nature of the disease. Inflammation and fibrosis in pancreatic islets have been described in human type 2 diabetes (4) and in spontaneous animal models of type 2 diabetes, including the Goto-Kakizaki (GK) rat (12), the Zucker diabetic fatty rat (33), and the Otsuka Long-Evans Tokushima fatty (OLETF) rat (16). A role of inflammation and fibrosis in the pathogenesis of type 2 diabetes has been suggested (17), but the mechanism and genetic factors remain to be elucidated. Genetic, pathophysiological, and histological analyses using animal models should provide useful information for understanding the molecular mechanism of the inflammatory process in the development of the disease.The spontaneously diabetic Torii (SDT) rat was established from an outbred colony of Sprague-Dawley rats in 1997 as a nonobese diabetic animal model (37,38). Male SDT rats develop diabetes at 15 wk of age or later and show 100% incidence of diabetes by 40 wk of age. Pathological changes including microvascular congestion and hemorrhage in pancreatic islets appear from ϳ8 wk of age and are followed by inflammation and fibrosis in and around the islets. These pathological changes in the pancreas of SDT rats differ from those of typical autoi...

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Genetic Dissection of “OLETF,” a Rat Model for Non-Insulin-Dependent Diabetes Mellitus: Quantitative Trait Locus Analysis of (OLETF × BN) × OLETF

Cited by 50 publications

References 39 publications

Genetic analysis of diet-induced hypercholesterolemia in exogenously hypercholesterolemic rats

Genetic analysis of diet-induced hypercholesterolemia in exogenously hypercholesterolemic rats

High-Resolution Quantitative Trait Locus Analysis Reveals Multiple Diabetes Susceptibility Loci Mapped to Intervals <800 kb in the Species-ConservedNiddm1iof the GK Rat

Identification of a major locus for islet inflammation and fibrosis in the spontaneously diabetic Torii rat

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Genetic Dissection of “OLETF,” a Rat Model for Non-Insulin-Dependent Diabetes Mellitus: Quantitative Trait Locus Analysis of (OLETF × BN) × OLETF

Cited by 50 publications

References 39 publications

Genetic analysis of diet-induced hypercholesterolemia in exogenously hypercholesterolemic rats

Genetic analysis of diet-induced hypercholesterolemia in exogenously hypercholesterolemic rats

High-Resolution Quantitative Trait Locus Analysis Reveals Multiple Diabetes Susceptibility Loci Mapped to Intervals &lt;800 kb in the Species-ConservedNiddm1iof the GK Rat

Identification of a major locus for islet inflammation and fibrosis in the spontaneously diabetic Torii rat

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High-Resolution Quantitative Trait Locus Analysis Reveals Multiple Diabetes Susceptibility Loci Mapped to Intervals <800 kb in the Species-ConservedNiddm1iof the GK Rat