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Saunak Sen

Publications and source records attributed to Saunak Sen.

17 recordsLinked to original sources
PubMed2006

The X chromosome in quantitative trait locus mapping.

The X chromosome requires special treatment in the mapping of quantitative trait loci (QTL). However, most QTL mapping methods, and most computer programs for QTL mapping, have focused exclusively on autosomal loci. We describe a method for appropriate treatment of the X chromosome for QTL mapping in experimental crosses. We address the important issue of formulating the null hypothesis of no linkage appropriately. If the X chromosome is treated like an autosome, a sex difference in the phenotype can lead to spurious linkage on the X chromosome. Further, the number of degrees of freedom for the linkage test may be different for the X chromosome than for autosomes, and so an X chromosome-specific significance threshold is required. To address this issue, we propose a general procedure to obtain chromosome-specific significance thresholds that controls the genomewide false positive rate at the desired level. We apply our methods to data on gut length in a large intercross of mice carrying the Sox10Dom mutation, a model of Hirschsprung disease. We identified QTL contributing to variation in gut length on chromosomes 5 and 18. We found suggestive evidence of linkage to the X chromosome, which would be viewed as strong evidence of linkage if the X chromosome was treated as an autosome. Our methods have been implemented in the package R/qtl.

Animals↗
PubMed2006

An angiotensin converting enzyme haplotype predicts survival in patients with end stage renal disease.

The renin-angiotensin system is implicated in the development of a variety of human diseases. Many studies have sought to characterize the clinical implications of polymorphisms in the angiotensin converting enzyme (ACE) gene. Given the high mortality rate of individuals on chronic hemodialysis (HD), we sought to investigate whether genetic diversity in the ACE gene correlates with mortality in this population. We assembled a racially diverse cohort of prevalent individuals on chronic outpatient HD, and followed it prospectively for a mean of 2.1 years. Subjects were genotyped for seven single nucleotide polymorphisms (SNPs) in the ACE gene. Haplotype probabilities were calculated using an expectation-maximization algorithm. Cox proportional hazards regression was used to determine associations between haplotype and time to mortality from initiation of HD. There was strong linkage disequilibrium (LD) across the ACE gene, with three tagging SNPs found to account for all seven-SNP haplotypes that had a frequency of greater than 4%. After adjustment for age, race, gender, and diabetes status, a three-locus haplotype was associated with a 72% risk reduction in mortality (P = 0.004). The majority of this association was captured by the TT genotype of A-239T promoter polymorphism. The TGG (non-wild-type) haplotype, consisting of three tagging SNPs in the ACE gene, is associated with significantly decreased risk of all-cause mortality in HD patients independent of age, race, gender, and diabetic status. This "protective" haplotype may encompass loci with functional significance in the ACE gene.

Aged↗
PubMed2006

Poor performance of bootstrap confidence intervals for the location of a quantitative trait locus.

The aim of many genetic studies is to locate the genomic regions (called quantitative trait loci, QTL) that contribute to variation in a quantitative trait (such as body weight). Confidence intervals for the locations of QTL are particularly important for the design of further experiments to identify the gene or genes responsible for the effect. Likelihood support intervals are the most widely used method to obtain confidence intervals for QTL location, but the nonparametric bootstrap has also been recommended. Through extensive computer simulation, we show that bootstrap confidence intervals behave poorly and so should not be used in this context. The profile likelihood (or LOD curve) for QTL location has a tendency to peak at genetic markers, and so the distribution of the maximum-likelihood estimate (MLE) of QTL location has the unusual feature of point masses at genetic markers; this contributes to the poor behavior of the bootstrap. Likelihood support intervals and approximate Bayes credible intervals, on the other hand, are shown to behave appropriately.

Bayes Theorem↗
PubMed2006

Isolation and confirmation of a calcium excretion quantitative trait locus on chromosome 1 in genetic hypercalciuric stone-forming congenic rats.

Hypercalciuria is the most common risk factor for kidney stones and has a substantial genetic component. The genetic hypercalciuric stone-forming (GHS) rat model displays complex changes in physiology involving intestine, bone, and kidney and overexpression of the vitamin D receptor, thereby reproducing the human phenotype of idiopathic hypercalciuria. Through quantitative trait locus (QTL) mapping of rats that were bred from GHS female rats and normocalciuric Wistar Kyoto (WKY) male rats, loci that are linked to hypercalciuria and account for a 6 to eight-fold phenotypic difference between the GHS and WKY progenitors were mapped. GHS x WKY rats were backcrossed to breed for congenic rats with the chromosome 1 QTL HC1 on a normocalciuric WKY background. Ten generations of backcrosses produced N10F1 rats, which were intercrossed to produce rats that were homozygous for GHS loci in the HC1 region between markers D1Mit2 and D1Mit32. On a high-calcium diet (1.2% calcium), significantly different levels of calcium excretion were found between male congenic (1.67 +/- 0.71 mg/24 h) and male WKY control rats (0.78 +/- 0.19 mg/24 h) and between female congenic (3.11 +/- 0.90 mg/24 h) and female WKY controls (2.11 +/- 0.50 mg/24 h); the congenics preserve the calcium excretion phenotype of the GHS parent strain. Microarray expression analyses of the congenic rats, compared with WKY rats, showed that of the top 100 most changed genes, twice as many as were statistically expected mapped to chromosome 1. Of these, there is a clear bias in gene expression change for genes in the region of the HC1. Of >1100 gene groups analyzed, one third of the 50 most differentially expressed gene groups have direct or secondary action on calcium metabolism or transport. This is the first QTL for hypercalciuria to be isolated in a congenic animal.

Animals↗
PubMed2006

Mortality risk stratification in chronic kidney disease: one size for all ages?

Current National Kidney Foundation Kidney Disease Outcomes Quality Initiative staging criteria for chronic kidney disease (CKD) are intended to apply to all age groups. However, it is unclear whether different levels of estimated GFR (eGFR) have the same prognostic significance in older and younger patients. The study cohort was composed of Department of Veterans Affairs (VA) patients who were aged 18 to 100 yr and had at least one outpatient serum creatinine measurement between October 1, 2001, and September 30, 2002 (n=2583,911). Patients with ESRD were excluded. GFR was estimated using the Modification of Diet in Renal Disease equation using each patient's first outpatient creatinine measurement during the study period. The association of eGFR with survival was measured by age group. Twenty percent of cohort patients had an eGFR<60 ml/min per 1.73 m2, ranging from 3% among 18- to 44-yr-olds to as high as 49% among 85- to 100-yr-olds. Fifty-two percent (n=266,421) of cohort patients with an eGFR<60 ml/min per 1.73 m2 had "very" moderate reductions in eGFR into the 50- to 59-ml/min per 1.73 m2 range. The association of eGFR with mortality was weaker in the elderly than in younger age groups: Whereas severe reductions in eGFR were associated with an increased risk for death in all age groups, "very" moderate reductions in eGFR (50 to 59 ml/min per 1.73 m2) were associated with an increased adjusted risk for death only among patients who were younger than 65 yr. Age-related attenuation of the association of eGFR with mortality was also present among women and black patients. In the clinical setting, mortality risk stratification in elderly patients should not be based on the same eGFR cut points as for younger age groups and would benefit from finer categorization of the 30- to 59-ml/min per 1.73 m2 eGFR group.

Adolescent↗
PubMed2006

Self-rated health among women with coronary disease: depression is as important as recent cardiovascular events.

BACKGROUND: Prior studies have shown an association between depression and self-rated health among patients with coronary disease. However, the magnitude of the effect of depression on self-rated health compared with that of major clinical events is unknown. Our main objective was to clarify the association between depression and self-rated health using longitudinal data. METHODS: We performed a prospective cohort study of 2675 postmenopausal women with coronary disease. The primary predictor variable was a 4-state categorical depression variable based on the Burnam depression screen assessed at sequential visits. The outcome variable was self-rated overall health (excellent, very good, or good vs fair or poor). RESULTS: After adjustment for age, comorbidities, prior self-rated health, and interim events, women with depression at both current and prior annual visits had a >5-fold increased odds of fair/poor self-rated health (odds ratio [OR] 5.1, 95% CI 3.8-6.8). New depression was associated with a >2-fold increased odds of fair/poor self-rated health (OR 2.6, 95% CI 2.0-3.4). Having a history of depression at the preceding annual visit but not at the current visit was associated with a slight increased odds of fair/poor self-rated health (OR 1.3, 95% CI 1.0-1.7). The magnitude of the impact of persistent or new depression was comparable to that of recent angina, myocardial infarction, angioplasty, heart failure, or bypass surgery. CONCLUSIONS: Women with persistent or new depression are more likely to report fair/poor self-rated health. The magnitude of the impact of persistent or new depression is comparable to that of major cardiac events.

Aged↗
PubMed2006

Polypharmacy and prescribing quality in older people.

OBJECTIVES: To evaluate the relationship between inappropriate prescribing, medication underuse, and the total number of medications used by patients. DESIGN: Cross-sectional study. SETTING: Veterans Affairs Medical Center. PARTICIPANTS: One hundred ninety-six outpatients aged 65 and older who were taking five or more medications. MEASUREMENTS: Inappropriate prescribing was assessed using a combination of the Beers drugs-to-avoid criteria (2003 update) and subscales of the Medication Appropriateness Index that assess whether a drug is ineffective, not indicated, or unnecessary duplication of therapy. Underuse was assessed using the Assessment of Underutilization of Medications instrument. All vitamins and minerals, topical and herbal medications, and medications taken as needed were excluded from the analyses. RESULTS: Mean age was 74.6, and patients used a mean+/-standard deviation of 8.1+/-2.5 medications (range 5-17). Use of one or more inappropriate medications was documented in 128 patients (65%), including 73 (37%) taking a medication in violation of the Beers drugs-to-avoid criteria and 112 (57%) taking a medication that was ineffective, not indicated, or duplicative. Medication underuse was observed in 125 patients (64%). Together, inappropriate use and underuse were simultaneously present in 82 patients (42%), whereas 25 (13%) had neither inappropriate use nor underuse. When assessed by the total number of medications taken, the frequency of inappropriate medication use rose sharply from a mean of 0.4 inappropriate medications in patients taking five to six drugs, to 1.1 inappropriate medications in patients taking seven to nine drugs, to 1.9 inappropriate medications in patients taking 10 or more drugs (P<.001). In contrast, the frequency of underuse averaged 1.0 underused medications per patient and did not vary with the total number of medications taken (P=.26). Overall, patients using fewer than eight medications were more likely to be missing a potentially beneficial drug than to be taking a medication considered inappropriate. CONCLUSION: Inappropriate medication use and underuse were common in older people taking five or more medications, with both simultaneously present in more than 40% of patients. Inappropriate medication use is most frequent in patients taking many medications, but underuse is also common and merits attention regardless of the total number of medications taken.

Aged↗
PubMed2005

Genetic modifiers interact with Cpe(fat) to affect body weight, adiposity, and hyperglycemia.

Obesity and Type II diabetes are complex diseases in the human population. The existence of a large number of contributing loci and gene-gene as well as gene-environment interactions make it difficult to identify the disease genes underlying these complex traits. In mouse models of obesity and Type II diabetes such as the murine fat mutation, genetic crosses can be used to dissect the genetic complexity influencing the observed phenotypes. The underlying defect in the fat mutant is a Ser202Pro change in carboxypeptidase E (CPE), an enzyme responsible for the final proteolytic processing step of prohormone intermediates. On the HRS/J (HRS) inbred strain background, mice homozygous for the fat mutation exhibit early onset hyperinsulinemia followed by postpubertal moderate obesity without hyperglycemia. In contrast, on the C57BLKS/J (BKS) genetic background, fat/fat mice become severely obese, hyperinsulinemic, and hyperglycemic. Therefore, in the Cpe(fat) genetic model, the fat mutation is necessary but not sufficient for the development of obesity, Type II diabetes, and related metabolic disorders. To dissect the susceptibility loci responsible for modifying obesity- and diabetes-associated traits, we characterized, both genetically and phenotypically, fat/fat male progeny from a large intercross between BKS. HRS-fat/fat and HRS-+/+ mice. Four major loci were mapped, including a locus for body weight (body weight 1) on chromosome 14; a locus for hyperglycemia (fat-induced diabetes 1) on chromosome 19; a locus for hyperglycemia, hyperinsulinemia, and hypercholesterolemia (fat-induced diabetes 2) on chromosome 5; and a locus for adiposity and body weight (fat-induced adiposity 1) on chromosome 11. The identification of these interacting genetic determinants for obesity and Type II diabetes may allow better definition of the obesity/diabetes-related hormone signaling pathways and ultimately may provide new insights into the pathogenesis of these complex diseases.

Adiposity↗
PubMed2005

Quantitative trait locus study design from an information perspective.

We examine the efficiency of different genotyping and phenotyping strategies in inbred line crosses from an information perspective. This provides a mathematical framework for the statistical aspects of QTL experimental design, while guiding our intuition. Our central result is a simple formula that quantifies the fraction of missing information of any genotyping strategy in a backcross. It includes the special case of selectively genotyping only the phenotypic extreme individuals. The formula is a function of the square of the phenotype and the uncertainty in our knowledge of the genotypes at a locus. This result is used to answer a variety of questions. First, we examine the cost-information trade-off varying the density of markers and the proportion of extreme phenotypic individuals genotyped. Then we evaluate the information content of selective phenotyping designs and the impact of measurement error in phenotyping. A simple formula quantifies the information content of any combined phenotyping and genotyping design. We extend our results to cover multigenotype crosses, such as the F(2) intercross, and multiple QTL models. We find that when the QTL effect is small, any contrast in a multigenotype cross benefits from selective genotyping in the same manner as in a backcross. The benefit remains in the presence of a second unlinked QTL with small effect (explaining <20% of the variance), but diminishes if the second QTL has a large effect. Software for performing power calculations for backcross and F(2) intercross incorporating selective genotyping and marker spacing is available from http://www.biostat.ucsf.edu/sen.

Animals↗
PubMed2005

Interleukin-1 gene cluster polymorphisms predict risk of ESRD.

BACKGROUND: Patients with chronic kidney disease manifest an inflammatory state relative to healthy individuals. Inflammation is regulated in part by genes of the interleukin-1 (IL-1) gene cluster. We hypothesized that polymorphisms in this gene cluster may be associated with risk of end-stage renal disease (ESRD). METHODS: Polymorphisms in the IL-1 gene cluster were examined in a cohort of 239 racially diverse hemodialysis (HD) patients and 252 controls. These individuals were genotyped for 3 single nucleotide polymorphisms (SNPs) in the IL-1alpha and beta genes, and a variable-number-of-tandem-repeats polymorphism in the IL-1 receptor antagonist gene (IL-1RN). Polymorphisms were analyzed by logistic regression for their independent associations with ESRD, and the effect of allele dose of IL-1RN on risk for ESRD was examined. The interaction between race and genotype was also investigated. RESULTS: A logistic regression model demonstrated that homozygosity for allele 2 of the IL-1RN variable-number-of-tandem-repeats (VNTR) polymorphism was associated with ESRD independent of race (P < 0.0005). The IL-1alpha-889 promoter SNP was associated with ESRD independent of race and of the IL-1RN polymorphism (P= 0.04). The IL-1beta-511 promoter SNP is associated with ESRD, but this is accounted for by race (P= 0.04). CONCLUSION: Two polymorphisms within the IL-1 gene cluster are associated with ESRD independent of race. This finding is one of the strongest associations between genotype and ESRD reported, and suggests that polymorphisms in the IL-1 gene cluster affect the risk of development of ESRD.

Aged↗
PubMed2004

Impact of renal insufficiency on mortality in advanced lower extremity peripheral arterial disease.

Renal insufficiency predicts mortality among patients who are treated for myocardial infarction and congestive heart failure, but its clinical significance in advanced peripheral arterial disease has not been evaluated. A national cohort of 5787 male veterans who received an initial diagnosis of rest pain, ischemic ulceration, or gangrene between January 1, 2000, and September 30, 2002, and had at least one serum creatinine measurement within 3 mo before diagnosis were identified. Sixty-two percent (n = 3561) of cohort members had normal or mildly reduced renal function (GFR > or =60 ml/min per 1.73 m(2)), 30% (n = 1742) had moderate renal insufficiency (GFR 30 to 59 ml/min per 1.73 m(2)), and 8% (n = 484) had severe renal insufficiency or renal failure (GFR <30 ml/min per 1.73 m(2)) but were not on dialysis. The percentages of patients who presented with gangrene or ischemic ulceration rather than rest pain increased with declining renal function (70, 77, and 87%; P < 0.001), as did 1-yr mortality risk (17, 27, and 44%; P < 0.001). After adjustment for demographic and clinical characteristics, patients with a GFR of 30 to 59 ml/min per 1.73 m(2) (odds ratio, 1.32; 95% confidence interval, 1.13 to 1.53) and <30 ml/min per 1.73 m(2) (odds ratio, 2.97; 95% confidence interval, 2.39 to 3.69) had a significantly increased odds of death within 1 yr of cohort entry. Both moderate and severe renal insufficiency are associated with an increased odds of death in patients with critical limb ischemia. Death rates were particularly high among those with a GFR <30 ml/min per 1.73 m(2). This finding may be partly explained by their more frequent presentation with ischemic ulceration or gangrene rather than rest pain.

Aged↗
PubMed2004

Locating Ath8, a locus for murine atherosclerosis susceptibility and testing several of its candidate genes in mice and humans.

A previous study revealed that the difference in susceptibility to atherosclerotic lesions between inbred mouse strains SM/J and NZB/BlNJ was determined by one major locus (Ath8). In this study a (SM/J x NZB/BlNJ) F(1) x SM/J backcross localized Ath8 by quantitative trait locus mapping to chromosome 4 with a suggestive LOD score of 2.7. This quantitative trait locus (QTL) was confirmed using an (SM/J x NZB/BlNJ) intercross; Ath8 mapped to a 23cM region with a significant LOD score of 3.6. The genes for toll-like receptor 4 (T1r4), arachidonic acid epoxygenase (Cyp2j5), and angiopoietin-like protein 3 (Angptl3) map to this region. These candidate genes were analyzed for expression and sequence differences in the mouse and for associations with cardiovascular traits in human. Sequence analysis of Angptl3 shows a base pair substitution in SM, the susceptible strain, giving rise to an amino acid change in the fibrinogen homology domain of the protein. We found a significant association between ANGPTL3 and atherosclerotic lesions (P < 0.05) in human. These results suggest that Angptl3 is involved in atherosclerosis susceptibility in both mouse and human.

Animals↗
PubMed2004

QTL analysis for discovery of genes involved in drug responses.

The completed Plasmodium falciparum genome sequence poses a significant challenge: how do we bring this wealth of data to bear against the steady march of malaria parasites towards multiple-drug resistance? Studies of parasite drug resistance have until now focused on a qualitative, single-gene concept of resistance determination; however, the emergence of powerful genomics tools insists that these questions be rephrased. It is now possible to address the true genetic complexity underlying quantitative drug sensitivities. Quantitative trait loci (QTL) mapping is an effective tool for tracking multi-gene traits by partitioning genetic effects that influence these traits into specific genomic regions. A cross between two parasite clones captures allele combinations that have segregated into progeny clones that display varying sensitivity to drugs. The specific allele forms and their combinations contributed by each parent are, in effect, genetic signatures of their unique evolutionary histories. In addition to resistance genes, per se, a drug resistant parasite carries co-evolved gene combinations comprising a genetic background of drug resistance. Research into drug resistance necessarily has been directed at specific genes and mechanisms favored by a priori knowledge and assumptions about how resistance works. QTL mapping, by superimposing real biological phenotypes on genome sequence, structural polymorphisms, and gene expression data, can provide an alternative, unbiased view of the network of gene actions that build a complex phenotype. Through an integrated approach, studies can move beyond the search for markers of resistance to instead characterize the predisposition of parasites to develop new resistances and cross-resistances.

Alleles↗
PubMed2003

Mapping quantitative trait loci for vertebral trabecular bone volume fraction and microarchitecture in mice.

UNLABELLED: BMD, which reflects both cortical and cancellous bone, has been shown to be highly heritable; however, little is known about the specific genetic factors regulating trabecular bone. Genome-wide linkage analysis of vertebral trabecular bone traits in 914 adult female mice from the F2 intercross of C57BL/6J and C3H/HeJ inbred strains revealed a pattern of genetic regulation derived from 13 autosomes, with 5-13 QTLs associated with each of the traits. Ultimately, identification of genes that regulate trabecular bone traits may yield important information regarding mechanisms that regulate mechanical integrity of the skeleton. INTRODUCTION: Both cortical and cancellous bone influence the mechanical integrity of the skeleton, with the relative contribution of each varying with skeletal site. Whereas areal BMD, which reflects both cortical and cancellous bone, has been shown to be highly heritable, little is known about the genetic determinants of trabecular bone density and architecture. MATERIALS AND METHODS: To identify heritable determinants of vertebral trabecular bone traits, we evaluated the fifth lumbar vertebra from 914 adult female mice from the F2 intercross of C57BL/6J (B6) and C3H/HeJ (C3H) progenitor strains. High-resolution microCT was used to assess total volume (TV), bone volume (BV), bone volume fraction (BV/TV), trabecular thickness (Tb.Th), separation (Tb.Sp), and number (Tb.N) of the trabecular bone in the vertebral body in the progenitors (n = 8/strain) and female B6C3H-F2 progeny (n = 914). Genomic DNA from F2 progeny was screened for 118 PCR-based markers discriminating B6 and C3H alleles on all 19 autosomes. RESULTS AND CONCLUSIONS: Despite having a slightly larger trabecular bone compartment, C3H progenitors had dramatically lower vertebral trabecular BV/TV (-53%) and Tb.N (-40%) and higher Tb.Sp (71%) compared with B6 progenitors (p < 0.001 for all). Genome-wide quantitative trait analysis revealed a pattern of genetic regulation derived from 13 autosomes, with 5-13 quantitative trait loci (QTLs) associated with each of the vertebral trabecular bone traits, exhibiting adjusted LOD scores ranging from 3.1 to 14.4. The variance explained in the F2 population by each of the individual QTL after adjusting for contributions from other QTLs ranged from 0.8% to 5.9%. Taken together, the QTLs explained 22-33% of the variance of the vertebral traits in the F2 population. In conclusion, we observed a complex pattern of genetic regulation for vertebral trabecular bone volume fraction and microarchitecture using the F2 intercross of the C57BL/6J and C3H/HeJ inbred mouse strains and identified a number of QTLs, some of which are distinct from those that were previously identified for total femoral and vertebral BMD. Identification of genes that regulate trabecular bone traits may ultimately yield important information regarding the mechanisms that regulate the acquisition and maintenance of mechanical integrity of the skeleton.

Animals↗
PubMed2003

R/qtl: QTL mapping in experimental crosses.

SUMMARY: R/qtl is an extensible, interactive environment for mapping quantitative trait loci (QTLs) in experimental populations derived from inbred lines. It is implemented as an add-on package for the freely-available statistical software, R, and includes functions for estimating genetic maps, identifying genotyping errors, and performing single-QTL and two-dimensional, two-QTL genome scans by multiple methods, with the possible inclusion of covariates. AVAILABILITY: The package is freely available at http://www.biostat.jhsph.edu/~kbroman/qtl.

Algorithms↗
PubMed2003

Quantitative trait loci for hypercalciuria in a rat model of kidney stone disease.

Hypercalciuria is the most common risk factor for kidney stones and has a recognized familial component. The genetic hypercalciuric stone-forming (GHS) rat is an animal model that closely resembles human idiopathic hypercalciuria, with excessive intestinal calcium absorption, increased bone resorption, and impaired renal calcium reabsorption; overexpression of the vitamin D receptor (VDR) in target tissues; and calcium nephrolithiasis. For identifying genetic loci that contribute to hypercalciuria in the GHS rat, an F2 generation of 156 rats bred from GHS female rats and normocalciuric WKY male rats was studied. The calcium excretion was six- to eightfold higher in the GHS female than in the WKY male progenitors. Selective genotyping of those F2 rats with the highest 30% and lowest 30% rates of calcium excretion was performed, scoring 98 markers with a mean interval of 23 cM across all 20 autosomes and the X chromosome. With the use of strict criteria for significance, significant linkage was found between hypercalciuria and a region of chromosome 1 at D1Rat169 (LOD, 2.91). Suggestive linkage to regions of chromosomes 4, 7, 10, and 14 was found. The proportion of phenotypic variance contributed by the region on chromosome 1, with appropriate adjustments, was estimated to be 7%. Candidate genes encoding the VDR and the calcium-sensing receptor were localized to regions on rat chromosomes 7 and 11, respectively, but the suggestive quantitative trait locus on chromosome 7 was not in the region of the VDR gene locus. Identification of genes that contribute to hypercalciuria in this animal model should prove valuable in understanding idiopathic hypercalciuria and kidney stone disease in humans.

Animals↗