Fine mapping of the hyperglycemic and obesity QTL by congenic strains suggests multiple loci on rat chromosome 14

Linkage analysis previously identified ahyperglycemic quantitative trait locus (QTL), Nidd 2/of, on rat Chromosome 14 in crosses utilizing OLETF (Otsuka Long Evans Tokushima Fatty) rat, a model for type 2 diabetes. A separate QTL study mapped an obesity QTL, Obs5, to the same chromosomal region. A congenic strain placing ca. 38cMOLETF-derivedsegments containing both Nidd2/of and Obs5 on the F344 background was shown to possess mild diabetic and obese phenotypes, suggesting the presence of mutations affecting the glucose metabolism and fat accumulation. In order to localize the loci more precisely, we generated a series of deletionsubcongenic strains in which OLETF-segments were shortened from either ends. We found that there are at least two hyperglycemic QTLs within the Nidd2/of locus. We predict that they are localized towards both ends of the Nidd2/of region. In contrast, Obs5QTL was further narrowed down to a single region of ca. 10 cM fragment

Single Diabetic QTL Derived from OLETF Rat Is a Sufficient Agent for Severe Diabetic Phenotype in Combination with Leptin-Signaling Deficiency

Obesity has been considered one of the leading causative agents for diseases such as type 2 diabetes, stroke, and heart attack. Due to their complex etiology, establishing auseful animal model is increasingly crucial for better molecular understanding of how obesity influences on disease development. OLETF rat is a spontaneous model of type 2 diabetes. We mapped 14 hyperglycemia QTLs in the genome of the OLETF rat and subsequently generated a panel of congenic strains each possessing OB-R mutation in F344 genetic background. Here we show that one of the loci, Nidd2/of, is highly responsive to obesity. When leptin receptor mutation is introgressed into the Nidd2/of congenic strain, the rat showed hyperglycemia equivalent to that of the parental OLETF rat. This suggests that the Nidd2/of locus has a strong genetic interaction with leptin signaling pathway. Furthermore, when another hyperglycemia QTL Nidd1/of is additionally combined, the strain developed overt diabetes. A single QTL dissected out in spontaneous model normally exerts only mild effect on the quantitative trait, which makes it difficult to clone the gene. Our new model may help not only to identify the causative gene but also to investigate how obesity interacts with a QTL to regulate diabetic traits

Genetic Dissection of Complex Genetic Factor Involved in NIDDM of OLETF Rat

The Otsuka Long-Evans Tokushima Fatty (OLETF) rat is an animal model for obese-type, noninsulin-dependent diabetes mellitus (NIDDM) in humans. NIDDM in this rat model was shown to be regulated by multiple genes. We have identified 14 quantitative trait loci (QTLs) responsible for NIDDM (Nidd1-14/of) on chromosomes 1, 5, 7, 8, 9, 11, 12, 14, 16, and 17 by a whole genome search in 160 F2 progenies obtained by mating the OLETF and the F344 rats. Among these loci, two QTLs, Nidd1 and 2/of, were declared significant loci at a genome-wide level. Nidd3, 8, 9, and 13/of exhibited heterosis: heterozygotes showing significantly higher glucose levels than OLETF or F344 homozygotes. We also found evidence for interaction (epistasis) between Nidd1/of and Nidd2/of, between Nidd1/of and Nidd10/of, between Nidd2/of and Nidd8/of, and between Nidd2/of and Nidd14/of. Furthermore, Nidd6 and 11/of showed linkage with body weight, and Nidd1, 2, 8, 9, 10, and 12/of had an interaction with body weight. These indicated that NIDDM in the OLETF would have a higher degree of genetic complexity. We suggest several interesting candidate genes located in rat genomic regions for Nidd1-14/of or the syntenic regions in human genome

Hospital pharmacist intervention improves the quality indicator of warfarin control : A retrospective cohort study

Background/Aims Our previous study showed that time in therapeutic range (TTR) control of warfarin therapy was negatively affected in non-valvular atrial fibrillation (NVAF) patients with heart failure. This study assesses the effect of intervention byhospital pharmacists on TTR control in Japanese NVAF patients with heart failure. Method This retrospective cohort study included NVAF patients with heart failure admitted and discharged from the cardiovascular internal medicine ward between March 2011 and July 2013. Participants were classified into two groups according to the instructions by hospital pharmacists and physicians (Intervention group) and by physicians only (Usual care group). The primary outcome was TTR. Secondary outcomes were major bleeding and minor bleeding. Results In total, 57 participants (35males, 22 females ; mean age : 69.7 years) were classified into the Intervention (n = 25) and Usual care (n = 32) groups. TTR within-therapeutic range was significantly higher and within sub-therapeutic range was significantly lower in the Intervention than the Usual care group. Major bleeding and minor bleeding were not significantly different between the two groups. Conclusion The intervention of hospital pharmacists with anticoagulation therapy can lead to proper use of warfarin, which can be useful when physicians prescribe warfarin

Distribution of allele frequencies at TTN g.231054C > T, RPL27A g.3109537C > T and AKIRIN2 c.*188G > A between Japanese Black and four other cattle breeds with differing historical selection for marbling

<p>Abstract</p> <p>Background</p> <p>Marbling defined by the amount and distribution of intramuscular fat, so-called <it>Shimofuri</it>, is an economically important trait of beef cattle in Japan. Our previous study detected 3 single nucleotide polymorphisms (SNPs), <it>g.231054C > T</it>, <it>g.3109537C > T </it>and <it>c.*188G > A</it>, respectively, in the 5' flanking region of the <it>titin </it>(<it>TTN</it>), the 5' flanking region of the <it>ribosomal protein L27a </it>(<it>RPL27A</it>) and the 3' untranslated region of the <it>akirin 2 </it>genes (<it>AKIRIN2</it>), which have been considered as positional functional candidates for the genes responsible for marbling, and showed association of these SNPs with marbling in Japanese Black beef cattle. In the present study, we investigated the allele frequency distribution of the 3 SNPs among the 5 cattle breeds, Japanese Black, Japanese Brown, Japanese Shorthorn, Holstein and Brown Swiss breeds.</p> <p>Findings</p> <p>We genotyped the <it>TTN g.231054C > T</it>, <it>RPL27A g.3109537C > T </it>and <it>AKIRIN2 c.*188G > A </it>SNPs by polymerase chain reaction-restriction fragment length polymorphism method, using 101 sires and 1,705 paternal half sib progeny steers from 8 sires for Japanese Black, 86 sires and 27 paternal half sib progeny steers from 3 sires for Japanese Brown, 79 sires and 264 paternal half sib progeny steers from 14 sires for Japanese Shorthorn, 119 unrelated cows for Holstein, and 118 unrelated cows for Brown Swiss breeds. As compared to the frequencies of the <it>g.231054C > T T</it>, <it>g.3109537C > T T </it>and <it>c.*188G > A A </it>alleles, associated with high marbling, in Japanese Black breed that has been subjected to a strong selection for high marbling, those in the breeds, Japanese Shorthorn, Holstein and Brown Swiss breeds, that have not been selected for high marbling were null or lower. The Japanese Brown breed selected slightly for high marbling showed lower frequency than Japanese Black breed in the <it>g.3109537C > T T </it>allele, whereas no differences were detected between the 2 breeds in the frequencies of the <it>g.231054C > T T </it>and <it>c.*188G > A A </it>alleles.</p> <p>Conclusions</p> <p>Based on this finding, we hypothesized that the pressure of the strong selection for high marbling in Japanese Black breed has increased the frequencies of the <it>T</it>, <it>T </it>and <it>A </it>alleles at the <it>TTN g.231054C > T</it>, <it>RPL27A g.3109537C > T </it>and <it>AKIRIN2 c.*188G > A </it>SNPs, respectively. This study, together with the previous association studies, suggested that the 3 SNPs may be useful for effective marker-assisted selection to increase the levels of marbling.</p