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Nora Franceschini

Publications and source records attributed to Nora Franceschini.

At least 19 recordsLinked to original sources
PubMed2026

2025 Donald Seldin Lecture: Leveraging Diverse Population Genomics and Multiomics Integration for Gene Discovery of Cardiovascular and Kidney Diseases.

This review discusses the implications of frameworks leveraging genetic admixture and multiomics data for advancing gene discovery in cardiovascular and kidney disease research. By broadening gene discovery efforts to additional populations that have a disproportionately high risk of disease and leveraging genetic diversity in admixed populations, studies can identify population-enriched risk variants that traditionally have been missed in genome-wide association studies. The use of multiomics approaches, including the transcriptome, proteome, and metabolome, advances a mechanistic understanding of disease beyond associations. As single-cell omics technologies continue to improve, their integration into gene discovery may help uncover cell-type-specific regulatory pathways and more precise biological contexts. The full potential of these approaches depends on sustained investment in diverse, well-characterized omics data sets, methodological innovation in multiancestry statistical approaches, and interdisciplinary collaboration bridging genomics, epidemiology, and clinical medicine. These efforts will need to be translated into clinically actionable insights, including ancestry-informed risk stratification and targeted therapeutics, to improve outcomes for cardiovascular and kidney diseases.

Humans↗
PubMed2025

Genetic architecture and analysis practices of circulating metabolites in the NHLBI Trans-Omics for Precision Medicine Program.

Circulating metabolite levels partly reflect the state of human health and diseases and can be impacted by genetic determinants. Hundreds of loci associated with circulating metabolites have been identified; however, most findings focus on predominantly European ancestry or single-study analyses. Leveraging the rich metabolomics resources generated by the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) Program, we harmonized and accessibly cataloged 1,729 circulating metabolites among 25,058 ancestrally diverse samples. From our comparison of multiple methods, we provided a set of reasonable strategies for outlier and imputation handling to process metabolite data and show that inverse normalization by study and half-minimum imputation provide mostly similar results for pooled or meta-analysis. Following the practical analysis framework, we further performed a genome-wide association analysis on 1,135 selected metabolites using whole-genome sequencing data from 16,359 individuals passing the quality-control filters and discovered 1,775 independent loci associated with 667 metabolites. Among 160 unreported locus-metabolite pairs, we identified associations with loci locating within previously implicated metabolite-associated genes, as well as associations with loci locating in genes such as GAB3 and VSIG4 (located on the X chromosome) that may play a role in metabolic regulation. In the sex-stratified analysis, we revealed 85 independent locus-metabolite pairs with evidence of sexual dimorphism, which were located in well-known metabolic genes such as FADS2, D2HGDH, SUGP1, and UGT2B17, strongly supporting the importance of exploring sex difference in the human metabolome. Taken together, our study depicted the genetic contribution to circulating metabolite levels, providing additional insight into the understanding of human health.

Humans↗
PubMed2025

Unveiling the Genetic Landscape of Coronary Artery Disease Through Common and Rare Structural Variants.

BACKGROUND: Genome-wide association studies have identified several hundred susceptibility single nucleotide variants for coronary artery disease (CAD). Despite single nucleotide variant-based genome-wide association studies improving our understanding of the genetics of CAD, the contribution of structural variants (SVs) to the risk of CAD remains largely unclear. METHOD AND RESULTS: We leveraged SVs detected from high-coverage whole genome sequencing data in a diverse group of participants from the National Heart Lung and Blood Institute's Trans-Omics for Precision Medicine program. Single variant tests were performed on 58 706 SVs in a study sample of 11 556 CAD cases and 42 907 controls. Additionally, aggregate tests using sliding windows were performed to examine rare SVs. One genome-wide significant association was identified for a common biallelic intergenic duplication on chromosome 6q21 (P=1.54E-09, odds ratio=1.34). The sliding window-based aggregate tests found 1 region on chromosome 17q25.3, overlapping USP36, to be significantly associated with coronary artery disease (P=1.03E-10). USP36 is highly expressed in arterial and adipose tissues while broadly affecting several cardiometabolic traits. CONCLUSIONS: Our results suggest that SVs, both common and rare, may influence the risk of coronary artery disease.

Humans↗
PubMed2024

The expected polygenic risk score (ePRS) framework: an equitable metric for quantifying polygenetic risk via modeling of ancestral makeup.

Polygenic risk scores (PRSs) depend on genetic ancestry due to differences in allele frequencies between ancestral populations. This leads to implementation challenges in diverse populations. We propose a framework to calibrate PRS based on ancestral makeup. We define a metric called "expected PRS" (ePRS), the expected value of a PRS based on one's global or local admixture patterns. We further define the "residual PRS" (rPRS), measuring the deviation of the PRS from the ePRS. Simulation studies confirm that it suffices to adjust for ePRS to obtain nearly unbiased estimates of the PRS-outcome association without further adjusting for PCs. Using the TOPMed dataset, the estimated effect size of the rPRS adjusting for the ePRS is similar to the estimated effect of the PRS adjusting for genetic PCs. Similarly, we applied the ePRS framework to six cardiovascular-related traits in the All of Us dataset, and the results are consistent with those from the TOPMed analysis. The ePRS framework can protect from population stratification in association analysis and provide an equitable strategy to quantify genetic risk across diverse populations.

Journal Article↗
PubMed2024

Rare variant contribution to the heritability of coronary artery disease.

Whole genome sequences (WGS) enable discovery of rare variants which may contribute to missing heritability of coronary artery disease (CAD). To measure their contribution, we apply the GREML-LDMS-I approach to WGS of 4949 cases and 17,494 controls of European ancestry from the NHLBI TOPMed program. We estimate CAD heritability at 34.3% assuming a prevalence of 8.2%. Ultra-rare (minor allele frequency ≤ 0.1%) variants with low linkage disequilibrium (LD) score contribute ~50% of the heritability. We also investigate CAD heritability enrichment using a diverse set of functional annotations: i) constraint; ii) predicted protein-altering impact; iii) cis-regulatory elements from a cell-specific chromatin atlas of the human coronary; and iv) annotation principal components representing a wide range of functional processes. We observe marked enrichment of CAD heritability for most functional annotations. These results reveal the predominant role of ultra-rare variants in low LD on the heritability of CAD. Moreover, they highlight several functional processes including cell type-specific regulatory mechanisms as key drivers of CAD genetic risk.

Humans↗
PubMed2024

A methylation risk score for chronic kidney disease: a HyperGEN study.

Chronic kidney disease (CKD) impacts about 1 in 7 adults in the United States, but African Americans (AAs) carry a disproportionately higher burden of disease. Epigenetic modifications, such as DNA methylation at cytosine-phosphate-guanine (CpG) sites, have been linked to kidney function and may have clinical utility in predicting the risk of CKD. Given the dynamic relationship between the epigenome, environment, and disease, AAs may be especially sensitive to environment-driven methylation alterations. Moreover, risk models incorporating CpG methylation have been shown to predict disease across multiple racial groups. In this study, we developed a methylation risk score (MRS) for CKD in cohorts of AAs. We selected nine CpG sites that were previously reported to be associated with estimated glomerular filtration rate (eGFR) in epigenome-wide association studies to construct a MRS in the Hypertension Genetic Epidemiology Network (HyperGEN). In logistic mixed models, the MRS was significantly associated with prevalent CKD and was robust to multiple sensitivity analyses, including CKD risk factors. There was modest replication in validation cohorts. In summary, we demonstrated that an eGFR-based CpG score is an independent predictor of prevalent CKD, suggesting that MRS should be further investigated for clinical utility in evaluating CKD risk and progression.

Humans↗
PubMed2007

Genotype-by-sex interaction on fasting insulin concentration: the HyperGEN study.

Recent studies have demonstrated the importance of sex effects on the underlying genetic architecture of insulin-related traits. To explore sex-specific genetic effects on fasting insulin, we tested for genotype-by-sex interaction and conducted linkage analysis of fasting insulin in Hypertension Genetic Epidemiology Network families. Hypertensive siblings and their first-degree relatives were recruited from five field centers. We performed a genome scan for quantitative trait loci influencing fasting insulin among 1,505 European Americans and 1,616 African Americans without diabetes. Sex-stratified linear regression models, adjusted for race, center, and age, were explored. The Mammalian Genotyping Service typed 391 microsatellite markers, spaced roughly 9 cM. Variance component linkage analysis was performed in SOLAR using ethnic-specific marker allele frequencies and multipoint IBDs calculated in MERLIN. We detected a quantitative trait locus influencing fasting insulin in female subjects (logarithm of odds [LOD] = 3.4) on chromosome 2 at 95 cM (between GATA69E12 and GATA71G04) but not in male subjects (LOD = 0.0, P for interaction = 0.007). This sex-specific signal at 2p13.2 was detected in both European-American (LOD = 2.1) and African-American (LOD = 1.2) female subjects. Our findings overlap with several other linkage reports of insulin-related traits and demonstrate the importance of considering complex context-dependent interactions in the search for insulin-related genes.

Alcohol Drinking↗
PubMed2006

A quantitative trait loci-specific gene-by-sex interaction on systolic blood pressure among American Indians: the Strong Heart Family Study.

Age-adjusted systolic blood pressure is higher in males than females. Genetic factors may account for this sex-specific variation. To localize sex-specific quantitative trait loci (QTL) influencing blood pressure, we conducted a genome scan of systolic blood pressure, in males and females, separately and combined, and tested for aggregate and QTL-specific genotype-by-sex interaction in American Indian participants of the Strong Heart Family Study. Blood pressure was measured 3 times and the average of the last 2 measures was used for analyses. Systolic blood pressure was adjusted for age and antihypertensive treatment within study center. We performed variance component linkage analysis in the full sample and stratified by sex among 1168 females and 726 males. Marker allele frequencies were derived using maximum likelihood estimates based on all individuals, and multipoint identity-by-descent sharing was estimated using Loki. We detected suggestive evidence of a QTL influencing systolic blood pressure on chromosome 17 at 129 cM between markers D17S784 and D17S928 (logarithm of odds [LOD] = 2.4). This signal substantially improved when accounting for QTL-specific genotype-by-sex interaction (P = 0.04), because we observed an LOD score of 3.3 for systolic blood pressure in women on chromosome 17 at 136 cM. The magnitude of the linkage signal on chromosome 17q25.3 was slightly attenuated when participants taking antihypertensive medications were excluded, although suggestive evidence for linkage was still identified (LOD = 2.8 in women). Accounting for interaction with sex improved our ability to detect QTLs and demonstrated the importance of considering genotype-by-sex interaction in our search for blood pressure genes.

Adult↗
PubMed2006

Prevention and treatment strategies for glucocorticoid-induced osteoporotic fractures.

Glucocorticoids are the most common cause of drug-related osteoporosis. We reviewed current evidence on risk factors for glucocorticoid-induced osteoporosis (GIOP) and prevention and treatment of GIOP-related fractures. Guidelines for GIOP management published since 2000 were also reviewed. Significant bone loss and increased fracture risk is seen with daily prednisone doses as low as 5 mg. Alternate-day glucocorticoid therapy can lead to similar bone loss. No conclusive evidence exists for a safe minimum dose or duration of glucocorticoid exposure. Physicians should consider risk factors for involutional osteoporosis such as older age, postmenopausal status, and baseline bone density measurements as they assess patients for prevention or treatment of GIOP. Bisphosphonates were reported to reduce GIOP-related vertebral fractures, but inconclusive data exist for hip fractures associated with glucocorticoid use. Hormone replacement therapy and parathyroid hormone analogs are effective in preserving bone density in GIOP. The risk of osteoporosis and fractures should be routinely assessed in patients receiving glucocorticoid therapy. Effective prevention and treatment options are available and can result in meaningful reduction of GIOP-related morbidity and mortality. Current guidelines for GIOP management recommend bisphosphonates, especially alendronate and risedronate, as first-line agents for GIOP, and these guidelines propose the preventive use of bisphosphonates early in the course of glucocorticoid therapy in high-risk patient subgroups.

Bone Density↗
PubMed2006

NPHS2 gene, nephrotic syndrome and focal segmental glomerulosclerosis: a HuGE review.

Nephrotic syndrome, characterized by edema, proteinuria, hyperlipidemia and low serum albumin, is a manifestation of kidney disease involving the glomeruli. Nephrotic syndrome may be caused by primary kidney disease such as focal segmental glomerulosclerosis. Mutations in the podocin gene, NPHS2, have been shown in familial and sporadic forms of steroid-resistant nephrotic syndrome, including focal segmental glomerulosclerosis. Podocin is an integral membrane protein located at the slit diaphragm of the glomerular permeability barrier. Complete information is lacking for the population frequency of some NPHS2 variants for all racial and ethnic groups. The most frequently reported variant, R229Q, is more common among European-derived populations than African-derived populations. We calculated crude odds ratios and 95% confidence intervals of childhood nephrotic syndrome and focal segmental glomerulosclerosis associated with R229Q heterozygosity using data from five studies. The R229Q variant is not associated with focal segmental glomerulosclerosis in the US population of African descent. In contrast, the R229Q variant is associated with a trend toward increased focal segmental glomerulosclerosis risk in European-derived populations, with an estimated increased risk of 20-40%. Our insight into the association between NPHS2 variants and nephrotic disease is hampered by the limitations of the existing studies, including small numbers of affected individuals and suboptimal control groups. Nevertheless, the available data suggest that large epidemiological case-control studies to examine the association between NPHS2 variants and nephrotic syndrome are warranted.

Amino Acid Substitution↗
PubMed2006

Immunosuppression, hepatitis C infection, and acute renal failure in HIV-infected patients.

BACKGROUND: Low CD4 cell counts predict HIV-related morbidity and mortality and may be associated with acute renal failure (ARF). OBJECTIVE: To estimate the effect of CD4 cell count on the incidence rate (IR) of ARF in ambulatory HIV-infected patients with access to highly active antiretroviral therapy. METHODS: Observational clinical cohort of HIV-infected patients recruited from a university-based infectious diseases clinic, between 2000 and 2002, and followed up until December 31, 2002. Poisson log-linear regression models were used to calculate ARF IRs, IR differences, and IR ratios. RESULTS: The mean age of the 705 study participants was 40 years, two thirds were male, and 61% were African American. Incidence rates of ARF were higher at lower CD4 cell counts and among patients who were coinfected with hepatitis C. Patients with hepatitis C coinfection who also had low CD4 cell counts had the highest adjusted IR of ARF. CONCLUSION: Immunosuppression and hepatitis C virus coinfection are associated with increased IRs of ARF in ambulatory HIV-1-infected patients.

Acute Kidney Injury↗
PubMed2005

Maternal urine albumin excretion and pregnancy outcome.

BACKGROUND: Vascular dysfunction has been hypothesized as a causal pathway for preeclampsia, impaired fetal growth, and early parturition. The relationship between increased urine albumin excretion (albuminuria), a marker of endothelial dysfunction, and preterm birth has not been fully evaluated. METHODS: We conducted a nested case-control study of 404 pregnancies from 1998 to 2000 within the Pregnancy, Infection and Nutrition cohort. Cases consisting of live births delivered before 37 weeks of gestation (preterm birth, n = 111) were compared with term births from the same cohort (n = 293). Albumin-creatinine ratio (in milligrams per gram) was measured in urine collected around 27 weeks of gestation. We compared risks for preterm birth in mothers with albuminuria with albumin levels of 3 to 20 mg/g and greater than 20 mg/g relative to those with albumin levels less than 3 mg/g by using logistic regression. RESULTS: Median albuminuria was albumin level of 2.7 and 4.3 mg/g for term and preterm births, respectively. Albuminuria was strongly associated with preterm birth in a dose-response fashion, with adjusted odds ratios of 1.9 (95% confidence interval, 1.1 to 3.1) and 4.7 (95% confidence interval, 1.7 to 12.6) for albuminuria with albumin of 3 to 20 mg/g and greater than 20 mg/g, respectively. The association was present for both spontaneous and medically induced preterm births, but the effect was decreased and the dose-response relationship was eliminated by excluding high-risk groups and those with pregnancy complications. CONCLUSION: Low levels of albuminuria are associated with preterm birth. The mechanism underlying this association warrants additional exploration.

Adult↗
PubMed2005

Incidence and etiology of acute renal failure among ambulatory HIV-infected patients.

BACKGROUND: Acute renal failure (ARF) is a cause of renal dysfunction in human immunodeficiency virus (HIV)-infected patients. Its incidence and causes have not been studied since the introduction of highly active antiretroviral therapy (HAART) in HIV ambulatory patients. METHODS: This is a prospective cohort study of 754 HIV patients, 18 years or older, seen at a university-based infectious disease clinic between 2000 and 2002. ARF was identified using proportional increases in serum creatinine from baseline and by chart review. Clinical conditions were assessed at the time of the ARF event. ARF incidence rates (IR) were calculated by dividing the number of events by person time at risk. To compare patients with and without ARF, t test or chi-square test were used. RESULTS: Patient's mean age was 40 years; 68% were male and 61% were black. One hundred-eleven ARF events occurred in 71 subjects (IR 5.9 per 100 person-years; 95% CI 4.9, 7.1). ARF was more common in men, in those with CD4 cell count <200 cells/mm(3), and HIV RNA levels >10,000 copies/mL. These patients more often had acquired immunodeficiency syndrome (AIDS), hepatitis C infection (HCV), and have received HAART. ARF was mainly community-acquired, due to prerenal causes or acute tubular necrosis, and associated with opportunistic infections and drugs. Liver disease was a cause of ARF in HCV-infected patients. CONCLUSION: ARF is common in ambulatory HIV patients. Immunosuppression, infection, and HCV are important conditions associated with ARF in the post-HAART era.

AIDS-Associated Nephropathy↗
PubMed2004

Calcimimetics and the treatment of primary and secondary hyperparathyroidism.

OBJECTIVE: To review the mechanism of action, development, and clinical application of the calcimimetic compounds being investigated for the treatment of primary and secondary hyperparathyroidism (HPT). DATA SOURCES: A MEDLINE search (1990-April 2004) was performed to identify all published articles related to calcimimetics. Published abstracts over the previous 5 years from various scientific meetings (American Society of Nephrology, American Society for Clinical Pharmacology and Therapeutics, American Society of Bone and Mineral Research) were also searched for reports regarding investigational calcimimetic agents. Data on cinacalcet HCl were provided by Amgen, Inc. STUDY SELECTION AND DATA EXTRACTION: Studies were selected based on number of patients included, relevance to the approved indications, and inclusion of pharmacokinetic and drug interaction information. DATA SYNTHESIS: The investigational calcimimetic compounds directly modulate the calcium-sensing receptor and can produce at least a 30% reduction in parathyroid hormone (PTH) secretion in secondary HPT. Cinacalcet appears to have more predictable pharmacokinetics and a lower risk of symptomatic hypocalcemia than the older agent, R-568. The safety profile and effective reduction in PTH and simultaneous reductions in calcium and phosphorus (and the calcium-phosphorus product) induced by cinacalcet make this agent advantageous over previously used therapies, such as vitamin D and phosphate-binding agents. More studies are required to determine additional uses of cinacalcet. CONCLUSIONS: Cinacalcet has a unique mechanism for reducing PTH concentration and appears to be a safe and effective oral therapy for both primary and secondary HPT.

Aniline Compounds↗
PubMed2004

N-acetylcysteine for the prevention of radiocontrast induced nephropathy: a meta-analysis of prospective controlled trials.

N-acetylcysteine has been recommended for patients with renal insufficiency who are to receive radiocontrast media. However, trials of oral N-acetylcysteine for the prevention of radiocontrast-induced nephropathy have yielded inconsistent results. A systematic review of patient and study characteristics was undertaken to discover possible explanations of the inconsistencies. The databases MEDLINE, EMBASE, and CENTRAL (1966 to March 2003) were searched in all languages, and conference proceedings from several professional societies from the years 1999 to 2003 were also searched. Only prospective controlled trials of oral N-acetylcysteine were included. Risk difference estimates and 95% confidence intervals were calculated. The estimates were examined for evidence of publication bias and heterogeneity. Stratified and meta-regression analyses were used to compare estimates by study and patient characteristics. Identified were 16 studies, 15 published and 1 unpublished. There was no evidence of publication bias, but there was substantial evidence of heterogeneity, thus precluding reliance on a meaningful summary effect estimate. Meta-regression identified several patient and study characteristics, with some evidence of association with study-specific estimates. None of these characteristics, however, formed subsets of studies with results that were homogeneous enough to aggregate. Research on N-acetylcysteine and the incidence of radiocontrast nephropathy is too inconsistent at present to warrant a conclusion on efficacy or a recommendation for its routine use. Identified patient and study characteristics may be responsible for some, but not all, of this inconsistency. A large, randomized, placebo-controlled trial, a pooled analysis of patient-level data, or both may resolve this issue.

Acetylcysteine↗
PubMed2003

Inhibition of prolyl-4-hydroxylase ameliorates chronic rejection of mouse kidney allografts.

Interstitial fibrosis, glomerulosclerosis and arteriosclerosis are the major components of chronic allograft nephropathy (CAN), the leading cause of late graft failure after transplantation. To investigate the mechanism of collagen deposition in CAN, we studied the effects of prolyl-hydroxylase inhibitor (PHI), an enzyme essential for collagen formation, using a mouse model of kidney transplantation. Kidneys from H-2b mice were transplanted into MHC-incompatible H-2d recipients (allografts) and at 3 weeks post-transplant, received either PHI or vehicle treatment daily for 3 weeks. At 6 weeks post-transplant, GFR was significantly improved in the allografts receiving PHI (3.3 +/- 0.5 mL/min/kg) compared with those receiving vehicle (1.8 +/- 0.5 mL/min/kg, p < 0.05), while renal function was relatively unimpaired in the nonrejecting isografts (6.45 +/- 0.53 mL/min/kg). Allografts had histologic changes of CAN but the severity was significantly reduced with PHI treatment compared with vehicle, with reductions in interstitial inflammation and fibrosis. Furthermore, TGFâ and connective tissue growth factor mRNA expression was enhanced in both allograft groups compared with the isografts. In conclusion, PHI-treated allografts had improved renal function and reduced the severity of renal injury as a result of CAN. Inhibition of matrix synthesis may be a useful adjunct in ameliorating the development of CAN in humans.

Animals↗
PubMed2003

Primum non nocere: Should adults with idiopathic FSGS receive steroids?

Corticosteroids have been widely recommended for the treatment of patients with idiopathic focal segmental glomerulosclerosis (FSGS), despite the lack of evidence-based data to support the use of steroids in this disease. The published studies have a number of limitations. They primarily have been retrospective, have included few patients, and have not been uniform with respect to the steroid treatment protocol. Furthermore, side effects associated with corticosteroid use have not been well documented. The Glomerular Disease Collaborative Network's experience with steroids in idiopathic FSGS has shown a low rate of remission even when steroids were used in the recommended doses and for prolonged periods. Recommendations regarding a specific subset of patients who may benefit from steroid treatment are discussed. The controversies regarding steroids in idiopathic FSGS will only be resolved with data from controlled clinical trials.

Clinical Trials as Topic↗