Sex-Specific and Sex-Independent Quantitative Trait Loci for Facets of the Metabolic Syndrome in WOKW Rats

Klöting, Ingrid; Kovács, Péter; Brandt, Jens van den

doi:10.1006/bbrc.2001.4932

Cited by 46 publications

(35 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Interactions with sex have been reported previously from studies of Finnish 54 and Norwegian 55 twins, from a segregation analysis of the Québec Family Study, 56 and from studies of inbred rat strains that have found sex-specific QTLs for obesity. 57 Sexual dimorphism has also been observed in such characteristics as leptin concentration and ob gene expression; 58 expression of hormone-sensitive lipase and lipoprotein lipase in subcutaneous abdominal fat in response to weight loss; 59 fat deposition in PPAR-a knockout mice; 60 the effect of variants in the leptin receptor, 61 and in the leptin gene itself. 62 While it is important to determine whether sex-specific QTLs for adiposity replicate in other studies, our results suggest that sex may have important environmental influences and that our ability to identify relevant genes may be improved by incorporating such effects into our linkage models.…”

Section: Discussionmentioning

confidence: 99%

Sex-specific findings from a genome-wide linkage analysis of human fatness in non-Hispanic whites and African Americans: The HyperGEN Study

et al. 2005

View full text Add to dashboard Cite

OBJECTIVE: To conduct a full genome search for genes potentially influencing two related phenotypes: body mass index (BMI, kg/m 2 ) and percent body fat (PBF) from bioelectric impedance in men and women. DESIGN: A total of 3383 participants, 1348 men and 2035 women; recruitment was initiated with hypertensive sibpairs and expanded to first-degree relatives in a multicenter study of hypertension genetics. MEASUREMENTS: Genotypes for 387 highly polymorphic markers spaced to provide a 10 cM map (CHLC-8) were generated by the NHLBI Mammalian Genotyping Service (Marshfield, WI, USA). Quantitative trait loci for obesity phenotypes, BMI and PBF, were examined with a variance components method using SOLAR, adjusting for hypertensive status, ethnicity, center, age, age 2 , sex, and age 2 Â sex. As we detected a significant genotype-by-sex interaction in initial models and because of the importance of sex effects in the expression of these phenotypes, models thereafter were stratified by sex. No genotype-byethnicity interactions were found. RESULTS: A QTL influencing PBF in women was detected on chromosome12q (12q24.3-12q24.32, maximum empirical LOD score ¼ 3.8); a QTL influencing this phenotype in men was found on chromosome 15q (15q25.3, maximum empirical LOD score ¼ 3.0). These QTLs were detected in African-American and white women (12q) and men (15q). QTLs influencing both BMI and PBF were found over a broad region on chromosome 3 in men. QTLs on chromosomes 3 and 12 were found in the combined sample of men and women, but with weaker significance. CONCLUSION: The locations with highest LOD scores have been previously reported for obesity phenotypes, indicating that at least two genomic regions influence obesity-related traits. Furthermore, our results indicate the importance of considering context-dependent effects in the search for obesity QTLs.

show abstract

Section: Discussionmentioning

confidence: 99%

Sex-specific findings from a genome-wide linkage analysis of human fatness in non-Hispanic whites and African Americans: The HyperGEN Study

et al. 2005

View full text Add to dashboard Cite

show abstract

“…Contributing genetic factors have been documented in both human subjects 2-4 and animal models. [5][6][7][8][9] However, only recent investigations into the sexspecific genetic architecture of complex traits led to the hypothesis that even the determinants of common conditions like hypertension, such as humoral regulation of volume, 10 and reaction to outcome events, such as myocardial infarction, 11 may have both unisex and sex-specific genetic determinants. 4 If that is the case, adjustment for sex during the analysis and interpretation of data may actually hide a significant portion of genome-driven physiology unique for men or women.…”

mentioning

confidence: 99%

Systematic, Genome-Wide, Sex-Specific Linkage of Cardiovascular Traits in French Canadians

et al. 2008

View full text Add to dashboard Cite

Abstract-The sexual dimorphism of cardiovascular traits, as well as susceptibility to a variety of related diseases, has long been recognized, yet their sex-specific genomic determinants are largely unknown. We systematically assessed the sex-specific heritability and linkage of 539 hemodynamic, metabolic, anthropometric, and humoral traits in 120 French-Canadian families from the Saguenay-Lac-St-Jean region of Quebec, Canada. We performed multipoint linkage analysis using microsatellite markers followed by peak-wide linkage scan based on Affymetrix Human Mapping 50K Array Xba240 single nucleotide polymorphism genotypes in 3 settings, including the entire sample and then separately in men and women. Nearly one half of the traits were age and sex independent, one quarter were both age and sex dependent, and one eighth were exclusively age or sex dependent. Sex-specific phenotypes are most frequent in heart rate and blood pressure categories, whereas sex-and age-independent determinants are predominant among humoral and biochemical parameters. Twenty sex-specific loci passing multiple testing criteria were corroborated by 2-point single nucleotide polymorphism linkage. Several resting systolic blood pressure measurements showed significant genotypeby-sex interaction, eg, male-specific locus at chromosome 12 (male-female logarithm of odds difference: 4.16; interaction Pϭ0.0002), which was undetectable in the entire population, even after adjustment for sex. Detailed interrogation of this locus revealed a 220-kb block overlapping parts of TAO-kinase 3 and SUDS3 genes. In summary, a large number of complex cardiovascular traits display significant sexual dimorphism, for which we have demonstrated genomic determinants at the haplotype level. Many of these would have been missed in a traditional, sex-adjusted setting. T he sexual dimorphism of many physiological traits, as well as susceptibility to a wide variety of diseases, including hypertension, has long been recognized. 1 Both social and environmental factors, as well as biological influences, contribute to this dimorphism, yet their relative relevance is not well appreciated. Contributing genetic factors have been documented in both human subjects 2-4 and animal models. [5][6][7][8][9] However, only recent investigations into the sexspecific genetic architecture of complex traits led to the hypothesis that even the determinants of common conditions like hypertension, such as humoral regulation of volume, 10 and reaction to outcome events, such as myocardial infarction, 11 may have both unisex and sex-specific genetic determinants. 4 If that is the case, adjustment for sex during the analysis and interpretation of data may actually hide a significant portion of genome-driven physiology unique for men or women. Recent investigation found that less than one quarter of 628 recently published clinical cardiovascular studies reported sex-specific results. 12 There is a potentially sizeable impact of the genetically driven, sex-specific pathophysiology on clinical manag...

show abstract

“…Body weight was recorded at an age of 3 and 6 wk, and thereafter at 2-wk intervals. The intraperitoneal glucose tolerance test was performed seven times (at 12,16,20,24,28, and 32 wk) by injecting the nonfasting rats with a glucose solution, dosage 2 g/kg body wt. Blood glucose levels were measured after tail vein incision at 0 (baseline), 10, 30, and 60 min after injection.…”

Section: Methodsmentioning

confidence: 99%

Phenotypic and genetic analyses of subcongenic BB.SHR rat lines shorten the region on chromosome 4 bearing gene(s) for underlying facets of metabolic syndrome

Klöting

Wilke

Klöting

2004

Physiological Genomics

Self Cite

View full text Add to dashboard Cite

Klöting, Nora, Barbara Wilke, and Ingrid Klöting. Phenotypic and genetic analyses of subcongenic BB.SHR rat lines shorten the region on chromosome 4 bearing gene(s) for underlying facets of metabolic syndrome. Physiol Genomics 18: [325][326][327][328][329][330] 2004. First published June 1, 2004; 10.1152/physiolgenomics.00047.2004.-Congenic BB.SHR (D4Got41-Npy-Tacr1; BB.4S) rats develop an incomplete metabolic syndrome with obesity, hyperleptinemia, and dyslipidemia compared with their progenitor strain, the diabetes-prone BB/OK rat. To narrow down the underlying gene(s), two subcongenic BB.SHR rat lines, briefly termed BB.4Sa and BB.4Sb, were generated. Male BB.4S (n ϭ 20), BB.4Sa (n ϭ 24), and BB.4Sb (n ϭ 26) were longitudinally characterized for facets of the metabolic syndrome and analyzed for expression of genes located in the region of interest in liver and blood. Body weight gain was comparable, serum triglycerides and leptin were significantly increased, and total cholesterol and HDL-cholesterol ratio were decreased in BB.4S compared with both subcongenics. Serum insulin was significantly higher in BB.4S and BB.4Sa than in BB.4Sb. The adiposity index showed a graduated decrease from BB.6S to BB.4Sb. Obvious differences in relative expression were found in 6 of 10 genes in liver and in 2 of 9 genes in blood. Only one gene, the eukaryotic translation initiation factor 2␣ kinase 3 (Eif2ak3 also called Perk or Pek), was significantly less expressed in liver and in blood of both subcongenic BB.4Sa and BB.4Sb compared with their "parental" BB.4S rats. Based on the phenotype and genotype in BB.4S and its subcongenic derivatives, the most important region on chromosome 4 can be said to lie between D4Got72 and Tacr1. Eif2ak3 is mapped in this region. Considering the function of Eif2ak3, it may be a candidate gene for the development of glucose intolerance found in both subcongenics but not in BB.4S. Allelic variants between BB/OK and SHR could influence Eif2ak3 function, possibly leading not only to glucose intolerance but also to the disturbances in hepatic and renal function found in human Wolcott-Rallison syndrome. rat model; obesity; dyslipidemia; congenic mapping LINKAGE STUDIES IN RATS have revealed a number of quantitative trait loci (QTLs) for facets of the metabolic syndrome (6, 7, 10, 12, 15-18, 20, 21). However, these localizations are only preliminary steps for the identification of the underlying gene(s), and further investigations are required to confirm the existence of QTLs; to this end, the construction of congenic strains is essential. Strains that are genetically identical except for a single chromosome segment are said to be congenic. Congenic strains are usually derived by backcross breeding and genomic selection techniques, by which a specific chromosome segment is transferred from the strain A onto the genetic background of a recipient strain B and designated B.A. If such a congenic B.A strain differs from the progenitor strain B, one can conclude that there is a locus within the transferr...

show abstract

Sex-Specific and Sex-Independent Quantitative Trait Loci for Facets of the Metabolic Syndrome in WOKW Rats

Cited by 46 publications

References 14 publications

Sex-specific findings from a genome-wide linkage analysis of human fatness in non-Hispanic whites and African Americans: The HyperGEN Study

Sex-specific findings from a genome-wide linkage analysis of human fatness in non-Hispanic whites and African Americans: The HyperGEN Study

Systematic, Genome-Wide, Sex-Specific Linkage of Cardiovascular Traits in French Canadians

Phenotypic and genetic analyses of subcongenic BB.SHR rat lines shorten the region on chromosome 4 bearing gene(s) for underlying facets of metabolic syndrome

Contact Info

Product

Resources

About