RESUMEN
Chronic kidney disease is a common disease with increasing prevalence in the western population. One common reason for chronic kidney failure is diabetic nephropathy. Diabetic nephropathy and hyperglycemia are characteristics of the mouse inbred strain KK/HlJ, which is predominantly used as a model for metabolic syndrome due to its inherited glucose intolerance and insulin resistance. We used KK/HlJ, an albuminuria-sensitive strain, and C57BL/6J, an albuminuria-resistant strain, to perform a quantitative trait locus (QTL) cross to identify the genetic basis for chronic kidney failure. Albumin-creatinine ratio (ACR) was measured in 130 F2 male offspring. One significant QTL was identified on chromosome (Chr) X and four suggestive QTL were found on Chrs 6, 7, 12, and 13. Narrowing of the QTL region was focused on the X-linked QTL and performed by incorporating genotype and expression analyses for genes located in the region. From the 485 genes identified in the X-linked QTL region, a few candidate genes were identified using a combination of bioinformatic evidence based on genomic comparison of the parental strains and known function in urine homeostasis. Finally, this study demonstrates the significance of the X chromosome in the genetic determination of albuminuria.
Asunto(s)
Albuminuria/genética , Regulación de la Expresión Génica , Genes Ligados a X , Riñón/fisiología , Sitios de Carácter Cuantitativo , Albúminas/análisis , Albuminuria/metabolismo , Animales , Creatinina/análisis , Femenino , Fallo Renal Crónico/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , Polimorfismo de Nucleótido Simple , Cromosoma XRESUMEN
UNLABELLED: BMD is highly heritable; however, little is known about the genes. To identify loci controlling BMD, we conducted a QTL analysis in a (B6 x 129) F2 population of mice. We report on additional QTLs and also narrow one QTL by combining the data from multiple crosses and through haplotype analysis. INTRODUCTION: Previous studies have identified quantitative trait loci (QTL) that determine BMD in mice; however, identification of genes underlying QTLs is impeded by the large size of QTL regions. MATERIALS AND METHODS: To identify loci controlling BMD, we performed a QTL analysis of 291 (B6 x 129) F2 females. Total body and vertebral areal BMD (aBMD) were determined by peripheral DXA when mice were 20 weeks old and had consumed a high-fat diet for 14 weeks. RESULTS AND CONCLUSIONS: Two QTLs were common for both total body and vertebral aBMD: Bmd20 on chromosome (Chr) 6 (total aBMD; peak cM 26, logarithm of odds [LOD] 3.8, and vertebral aBMD; cM 32, LOD 3.6) and Bmd22 on Chr 1 (total aBMD; cM 104, LOD 2.5, and vertebral aBMD; cM 98, LOD 2.6). A QTL on Chr 10 (Bmd21, cM 68, LOD 3.0) affected total body aBMD and a QTL on Chr 7 (Bmd9, cM 44, LOD 2.7) affected vertebral aBMD. A pairwise genome-wide search did not reveal significant gene-gene interactions. Collectively, the QTLs accounted for 21.6% of total aBMD and 17.3% of vertebral aBMD of the F(2) population variances. Bmd9 was previously identified in a cross between C57BL/6J and C3H/HeJ mice, and we narrowed this QTL from 34 to 22 cM by combining the data from these crosses. By examining the Bmd9 region for conservation of ancestral alleles among the low allele strains (129S1/SvImJ and C3H/HeJ) that differed from the high allele strain (C57BL/6J), we further narrowed the region to approximately 9.9 cM, where the low allele strains share a common haplotype. Identifying the genes for these QTLs will enhance our understanding of skeletal biology.
Asunto(s)
Densidad Ósea/genética , Cruzamientos Genéticos , Sitios de Carácter Cuantitativo/genética , Animales , Haplotipos , Ratones , Ratones EndogámicosRESUMEN
OBJECTIVE: The C57BL/6 (B6) and 129 mouse inbred strains differ markedly in plasma HDL-cholesterol concentrations and atherosclerosis susceptibility after a high-fat diet consumption. To identify loci controlling these traits, we performed quantitative trait loci (QTL) analysis. METHODS AND RESULTS: We fed a high-fat diet to 294 (B6x129S1/SvImJ)F2 females for 14 weeks, measured plasma HDL concentrations and size of aortic fatty-streak lesions, genotyped F2 females, and performed QTL analysis. HDL concentrations were affected by six loci: Hdlq14 and Hdlq15 on chromosome 1 (peaks cM 80 and cM 104, logarithm of odds [LOD] 5.3 and 9.7, respectively); Hdlq16 on chromosome 8 (cM 44, LOD 2.6); Hdlq17 on chromosome 9 (cM 24, LOD 2.9); Hdlq18 on chromosome 12 (cM 20, LOD 5.9); and Hdlq19 on chromosome 2 (cM 90), which interacted with Hdlq15. Atherosclerosis susceptibility was affected by five loci: Ath17 on chromosome 10 (cM 34, LOD 6.6); Ath18 on chromosome 12 (cM 16, LOD 3.7); Ath19 (chromosome 11, cM 60), which interacted with Ath18; and Ath20 (chromosome 10, cM 10), which interacted with Ath21 (chromosome 12, cM 50). CONCLUSIONS: We identified six loci for HDL and five loci for atherosclerosis susceptibility in a (B6x129S1/SvImJ)F2 intercross.
Asunto(s)
Arteriosclerosis/genética , HDL-Colesterol/sangre , Ratones Endogámicos/genética , Sitios de Carácter Cuantitativo , Animales , Arteriosclerosis/sangre , Arteriosclerosis/patología , Dieta Aterogénica , Grasas de la Dieta/toxicidad , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Escala de Lod , Ratones , Ratones Endogámicos C57BLRESUMEN
Cholesterol gallstone formation is a response to interactions between multiple genes and environmental stimuli. To determine the subset of cholesterol gallstone susceptibility (Lith) genes possessed by strains CAST/Ei (susceptible) and 129S1/SvImJ (resistant), we conducted quantitative trait locus (QTL) analyses of an intercross between these strains. Parental strains and F(1) mice of both genders were evaluated for gallstone formation after consumption of a lithogenic diet for 8 wk. Gallstone susceptibility of strain CAST was predominantly due to cholesterol hypersecretion. Male intercross offspring were genotyped and phenotyped for cholesterol gallstone formation after consumption of the lithogenic diet for 10 wk. Linkage analysis was performed using PSEUDOMARKER software. One significant, new QTL was detected and named Lith13 [chromosome (Chr) 5, 30 cM]. Statistical analyses and QTL fine mapping suggest this QTL may comprise two closely linked loci. We confirmed the presence of Lith6 (Chr 6). Suggestive QTL were detected on Chrs 1, 2, 5, 14, and 16. The QTL on Chrs 2 and 16 confirmed previously identified, suggestive QTL. Therefore, they were named Lith12 (101 cM) and Lith14 (42 cM), respectively. We identified candidate genes based on known function and location and performed mRNA expression analyses using both parental strains and intercross progeny for preliminary evaluation of their contributions to gallstone formation. Cebpb (Lith12), Pparg (Lith6), and Slc21a1 (Lith6) displayed expression differences. Our work continues to demonstrate the genetic complexity and to elucidate the pathophysiology of cholesterol gallstone formation. It should facilitate the development of new approaches for treating this common human disorder.
Asunto(s)
Colelitiasis/química , Colelitiasis/genética , Colesterol/genética , Colesterol/metabolismo , Sitios de Carácter Cuantitativo/fisiología , Alelos , Animales , Bilis/química , Colelitiasis/epidemiología , Colelitiasis/metabolismo , Mapeo Cromosómico , Cruzamientos Genéticos , Femenino , Vesícula Biliar/patología , Vesícula Biliar/fisiología , Perfilación de la Expresión Génica , Ligamiento Genético/genética , Lípidos/análisis , Masculino , Ratones , Ratones Endogámicos DBA , Ratones Endogámicos , Datos de Secuencia Molecular , Prevalencia , ARN Mensajero/metabolismo , Receptores Citoplasmáticos y Nucleares/genética , Receptores Citoplasmáticos y Nucleares/fisiología , Factores de Transcripción/genética , Factores de Transcripción/fisiologíaRESUMEN
To determine the genetic contribution to variation among lipoprotein cholesterol levels, we performed quantitative trait locus (QTL) analyses on an intercross between mouse strains RIIIS/J and 129S1/SvImJ. Male mice of the parental strains and the reciprocal F1 and F2 populations were fed a high-cholesterol, cholic acid-containing diet for 8-12 wk. At the end of the feeding period, plasma total, high-density lipoprotein (HDL), and non-HDL cholesterol were determined. For HDL cholesterol, we identified three significant QTLs on chromosomes (Chrs) 1 (D1Mit507, 88 cM, 72-105 cM, 4.8 LOD), 9 (D11Mit149, 14 cM, 10-25 cM, 9.4 LOD), and 12 (D12Mit60, 20 cM, 0-50 cM, 5.0 LOD). These QTLs were considered identical to QTLs previously named Hdlq5, Hdlq17, and Hdlq18, respectively, in crosses sharing strain 129. For total cholesterol, we identified two significant QTLs on Chrs 1 and 9, which were named Chol10 (D1Mit507, 88 cM, 10-105 cM, 3.9 LOD) and Chol11 (D11Mit149, 14 cM, 0-30 cM, 4.4 LOD), respectively. In addition, for total cholesterol, we identified two suggestive QTLs on Chrs 12 (distal) and 17, which remain unnamed. For non-HDL cholesterol, we identified and named one new QTL on Chr 17, Nhdlq3 (D17Mit221, 58 cM, 45-60 cM, 3.4 LOD). Nhdlq3 colocalized with orthologous human QTLs for lipoprotein phenotypes, and with Abcg5 and Abcg8. Overall, we detected eight QTLs for lipoprotein cholesterol concentrations on Chrs 1, 9, 12, and 17 (each two per chromosome), including a new QTL for non-HDL cholesterol, Nhdlq3, on Chr 17.
Asunto(s)
Colesterol/sangre , Lipoproteínas/sangre , Sitios de Carácter Cuantitativo , Animales , Cruzamientos Genéticos , Expresión Génica , Masculino , Ratones , Ratones EndogámicosRESUMEN
To identify genetic determinants of lipoprotein levels, we are performing quantitative trait locus (QTL) analysis on a series of mouse intercrosses in a "daisy chain" experimental design, to increase the power of detecting QTL and to identify common variants that should segregate in multiple intercrosses. In this study, we intercrossed strains CAST/Ei and 129S1/SvImJ, determined HDL, total, and non-HDL cholesterol levels, and performed QTL mapping using Pseudomarker software. For HDL cholesterol, we identified two significant QTL on chromosome (Chr) 1 (Hdlq5, 82 cM, 60-100 cM) and Chr 4 (Hdlq10, 20 cM, 10-30 cM). For total cholesterol, we identified three significant QTL on Chr 1 (Chol7, 74 cM, 65-80 cM), Chr 4 (Chol8, 12 cM, 0-30 cM), and Chr 17 (Chol9, 54 cM, 20-60 cM). For non-HDL cholesterol, we identified significant QTL on Chr 8 (Nhdlq1, 34 cM, 20-60 cM) and Chr X (Nhdlq2, 6 cM, 0-18 cM). Hdlq10 was the only QTL detected in two intercrosses involving strain CAST/Ei. Hdlq5, Hdlq10, Nhdlq1, and two suggestive QTL at D7Mit246 and D15Mit115 coincided with orthologous human lipoprotein QTL. Our analysis furthers the knowledge of the genetic control of lipoprotein levels and points to the importance of Hdlq10, which was detected repeatedly in multiple studies.
Asunto(s)
HDL-Colesterol/sangre , Mapeo Cromosómico/métodos , Cruzamientos Genéticos , Sitios de Carácter Cuantitativo/genética , Transportador 1 de Casete de Unión a ATP , Transportadoras de Casetes de Unión a ATP/genética , Alelos , Animales , Cromosomas/genética , Femenino , Regulación de la Expresión Génica/genética , Ligamiento Genético/genética , Lipoproteína Lipasa/genética , Hígado/química , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Ratones Endogámicos , ARN Mensajero/genética , Cromosoma X/genéticaRESUMEN
Quantitative trait locus (QTL) mapping was employed to investigate the genetic determinants of cholesterol gallstone formation in a large intercross between mouse strains SM/J (resistant) and NZB/B1NJ (susceptible). Animals consumed a gallstone-promoting diet for 18 weeks. QTL analyses were performed using gallstone weight and gallstone absence/presence as phenotypes; various models were explored for genome scans. We detected seven single QTLs: three new, significant QTLs were named Lith17 [chromosome (Chr) 5, peak=60 cM, LOD=5.4], Lith18 (Chr 5, 76 cM, LOD=4.3), and Lith19 (Chr 8, 0 cM, LOD=5.3); two confirmed QTLs identified previously and were named Lith20 (Chr 9, 44 cM, LOD=2.7) and Lith21 (Chr 10, 24 cM, LOD=2.9); one new, suggestive QTL (Chr 17) remains unnamed. Upon searching for epistatic interactions that contributed to gallstone susceptibility, the final suggestive QTL on Chr 7 was determined to interact significantly with Lith18 and, therefore, was named Lith22 (65 cM). A second interaction was identified between Lith19 and a locus on Chr 11; this QTL was named Lith23 (13 cM). mRNA expression analyses and amino acid haplotype analyses likely eliminated Slc10a2 as a candidate gene for Lith19. The QTLs identified herein largely contributed to gallstone formation rather than gallstone severity. Cloning the genes underlying these murine QTLs should facilitate prediction and cloning of the orthologous human genes.
Asunto(s)
Colelitiasis/química , Colelitiasis/genética , Colesterol/metabolismo , Sitios de Carácter Cuantitativo/fisiología , Animales , Cruzamientos Genéticos , Femenino , Masculino , Ratones , Ratones Endogámicos NZB/genética , Ratones Endogámicos/genética , Datos de Secuencia Molecular , Transportadores de Anión Orgánico Sodio-Dependiente/fisiología , Fenotipo , Simportadores/fisiologíaRESUMEN
To investigate genetic contributions to individual variations of lipoprotein cholesterol concentrations, we performed quantitative trait locus/loci (QTL) analyses of an intercross of CAST/Ei and DBA/2J inbred mouse strains after feeding a high-cholesterol cholic acid diet for 10 weeks. In total, we identified four QTL for HDL cholesterol. Three of these were novel and were named Hdlq10 [20 centimorgans (cM), chromosome 4], Hdlq11 (48 cM, chromosome 6), and Hdlq12 (68 cM, chromosome 6). The fourth QTL, Hdl1 (48 cM, chromosome 2), confirmed a locus discovered previously using a breeding cross that employed different inbred mouse strains. In addition, we identified one novel QTL for total and non-HDL cholesterol (8 cM, chromosome 9) that we named Chol6. Hdlq10, colocalized with a mutagenesis-induced point mutation (Lch), also affecting HDL. We provide molecular evidence for Abca1 as the gene underlying Hdlq10 and Ldlr as the gene underlying Chol6 that, coupled with evidence generated by other researchers using knockout and transgenic models, causes us to postulate that polymorphisms of these genes, different from the mutations leading to Tangier's disease and familial hypercholesterolemia, respectively, are likely primary genetic determinants of quantitative variation of lipoprotein levels in mice and, by orthology, in the human population.
Asunto(s)
HDL-Colesterol/sangre , Ratones Endogámicos DBA/genética , Ratones Endogámicos/genética , Sitios de Carácter Cuantitativo/genética , Animales , Colesterol en la Dieta/administración & dosificación , HDL-Colesterol/efectos de los fármacos , Ácido Cólico/administración & dosificación , Mapeo Cromosómico , Cruzamientos Genéticos , Relación Dosis-Respuesta a Droga , Femenino , Genotipo , Humanos , Masculino , Ratones , Datos de Secuencia Molecular , Fenotipo , Polimorfismo Genético , ARN Mensajero/genética , ARN Mensajero/metabolismo , Análisis de Secuencia de ADN , Factores de TiempoRESUMEN
The plasma lipid concentrations and obesity of C57BL/6J (B6) and 129S1/SvImJ (129) inbred mouse strains fed a high-fat diet containing 15% dairy fat, 1% cholesterol, and 0.5% cholic acid differ markedly. To identify the loci controlling these traits, we conducted a quantitative trait loci (QTL) analysis of 294 (B6 x 129) F(2) females fed a high-fat diet for 14 weeks. Non-HDL cholesterol concentrations were affected by five significant loci: Nhdlq1 [chromosome 8, peak centimorgan (cM) 38, logarithm of odds [LOD] 4.4); Nhdlq4 (chromosome 10, cM 70, LOD 4.0); Nhdlq5 (chromosome 6, cM 0) interacting with Nhdlq4; Nhdlq6 (chromosome 7, cM 10) interacting with Nhdlq1; and Nhdlq7 (chromosome 15, cM 0) interacting with Nhdlq4. Triglyceride (TG) concentrations were affected by three significant loci: Tgq1 (chromosome 18, cM 42, LOD 3.2) and Tgq2 (chromosome 9, cM 66) interacting with Tgq3 (chromosome 4, cM 58). Obesity measured by percentage of body fat mass and body mass index was affected by two significant loci: Obq16 (chromosome 8, cM 48, LOD 10.0) interacting with Obq18 (chromosome 9, cM 65). Knowing the genes for these QTL will enhance our understanding of obesity and lipid metabolism.
Asunto(s)
Lípidos/sangre , Obesidad/genética , Sitios de Carácter Cuantitativo/genética , Animales , Composición Corporal , Índice de Masa Corporal , HDL-Colesterol/sangre , Femenino , Genotipo , Lípidos/genética , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos , Obesidad/sangre , Triglicéridos/sangreRESUMEN
A complex genetic basis determines the individual predisposition to develop cholesterol gallstones in response to environmental factors. We employed quantitative trait locus/loci (QTL) analyses of an intercross between inbred strains CAST/Ei (susceptible) and DBA/2J (resistant) to determine the subset of gallstone susceptibility (Lith) genes these strains possess. Parental and first filial generation mice of both genders and male intercross offspring were evaluated for gallstone formation after feeding a lithogenic diet. Linkage analysis was performed using a form of multiple interval mapping. One significant QTL colocalized with Lith1 [chromosome (chr) 2, 50 cM], a locus identified previously. Significantly, new QTL were detected and named Lith10 (chr 6, 4 cM), Lith6 (chr 6, 54 cM), and Lith11 (chr 8, 58 cM). Statistical and genetic analyses suggest that Lith6 comprises two QTL in close proximity. Our molecular and genetic data support the candidacy of peroxisome proliferator-activated receptor gamma (Pparg) and Slc21a1, encoding Pparg, and the basolateral bile acid transporter SLC21A1 (Slc21a1/Oatp1), respectively, as genes underlying Lith6.