Nora Franceschini

Guidelines for the Management of Chronic Kidney Disease in HIV-Infected Patients: Recommendations of the HIV Medicine Association of the Infectious Diseases Society of America

Samir K. Gupta, Joseph A. Eustace, Jonathan A. Winston, Ivy I. Boydstun, Tejinder S. Ahuja, Rudolph A. Rodriguez, Karen T. Tashima, Michelle Roland, Nora Franceschini, Frank J. Palella, Jeffrey L. Lennox, Paul E. Klotman, Sharon A. Nachman, Stephen D. Hall, and Lynda A. Szczech Divisions of Infectious Diseases and Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis; Division of Nephrology, Johns Hopkins University, School of Medicine and Department of Epidemiology, Bloomberg School of Public Health, Baltimore, Maryland; Division of Nephrology, Department of Medicine, Mount Sinai School of Medicine, New York, and Division of Nephrology and Hypertension and Division of Infectious Diseases, Department of Pediatrics, State University of New York, Stony Brook; Division of Nephrology, Department of Medicine, University of Texas Medical Branch, Galveston; Division of Nephrology, Department of Medicine, San Francisco General Hospital and Positive Health Program at San Francisco General Hospital and the UCSF AIDS Research Institute, Department of Medicine, University of California at San Francisco; Division of Infectious Diseases, Department of Medicine, The Miriam Hospital, Brown Medical School, Providence, Rhode Island; Division of Nephrology and Hypertension, Department of Medicine, University of North Carolina at Chapel Hill, and Duke Clinical Research Institute and the Division of Nephrology, Department of Medicine, Duke University Medical Center, Durham, North Carolina; Division of Infectious Diseases, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois; and Grady Infectious Disease Program, Division of Infectious Diseases, Department of Medicine, Emory University, Atlanta, Georgia

Meta-analyses of genome-wide association studies identify multiple loci associated with pulmonary function

Spirometric measures of lung function are heritable traits that reflect respiratory health and predict morbidity and mortality. We meta-analyzed genome-wide association studies for two clinically important lung-function measures: forced expiratory volume in the first second (FEV1) and its ratio to forced vital capacity (FEV1/FVC), an indicator of airflow obstruction. This meta-analysis included 20,890 participants of European ancestry from four CHARGE Consortium studies: Atherosclerosis Risk in Communities, Cardiovascular Health Study, Framingham Heart Study and Rotterdam Study. We identified eight loci associated with FEV1/FVC (HHIP, GPR126, ADAM19, AGER-PPT2, FAM13A, PTCH1, PID1 and HTR4) and one locus associated with FEV1 (INTS12-GSTCD-NPNT) at or near genome-wide significance (P < 5 × 10−8) in the CHARGE Consortium dataset. Our findings may offer insights into pulmonary function and pathogenesis of chronic lung disease.

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.

Meta-analysis of genome-wide association data identifies two loci influencing age at menarche.

We conducted a meta-analysis of genome-wide association data to detect genes influencing age at menarche in 17,510 women. The strongest signal was at 9q31.2 (P = 1.7 × 10−9), where the nearest genes include TMEM38B, FKTN, FSD1L, TAL2 and ZNF462. The next best signal was near the LIN28B gene (rs7759938; P = 7.0 × 10−9), which also influences adult height. We provide the first evidence for common genetic variants influencing female sexual maturation.

Change in Estimated GFR Associates with Coronary Heart Disease and Mortality

Kidney function predicts cardiovascular and all-cause mortality, but little is known about the association of changes in estimated GFR (eGFR) with clinical outcomes. We investigated whether 3- and 9-yr changes in eGFR associated with risk for coronary heart disease (CHD) and all-cause mortality among 13,029 participants of the Atherosclerosis Risk in Communities (ARIC) Study. After adjustment for baseline covariates including eGFR in Cox proportional hazards models, the quartile of participants with the greatest annual decline (annual decline > or =5.65%) in eGFR were at significantly greater risk for CHD and all-cause mortality (hazard ratio 1.30 [95% confidence interval 1.11 to 1.52] and 1.22 [95% confidence interval 1.06 to 1.41], respectively) compared with the third quartile (annual decline between 0.33 and 0.47%). We observed similar results when we analyzed 9-yr changes in eGFR. Adjustment for covariates at the second eGFR used to estimate change reduced the association with CHD but not with mortality. Among participants with stage 3 chronic kidney disease, an increase in eGFR during the first 3 yr also associated with a higher risk for mortality, perhaps as a result of clinical instability. In conclusion, a steeper than average decline in eGFR associates with a higher risk for CHD and all-cause mortality. Increases in eGFR among participants with chronic kidney disease associate with similar increased risks.

A Bivariate Genome-Wide Approach to Metabolic Syndrome: STAMPEED Consortium

OBJECTIVE The metabolic syndrome (MetS) is defined as concomitant disorders of lipid and glucose metabolism, central obesity, and high blood pressure, with an increased risk of type 2 diabetes and cardiovascular disease. This study tests whether common genetic variants with pleiotropic effects account for some of the correlated architecture among five metabolic phenotypes that define MetS. RESEARCH DESIGN AND METHODS Seven studies of the STAMPEED consortium, comprising 22,161 participants of European ancestry, underwent genome-wide association analyses of metabolic traits using a panel of ∼2.5 million imputed single nucleotide polymorphisms (SNPs). Phenotypes were defined by the National Cholesterol Education Program (NCEP) criteria for MetS in pairwise combinations. Individuals exceeding the NCEP thresholds for both traits of a pair were considered affected. RESULTS Twenty-nine common variants were associated with MetS or a pair of traits. Variants in the genes LPL, CETP, APOA5 (and its cluster), GCKR (and its cluster), LIPC, TRIB1, LOC100128354/MTNR1B, ABCB11, and LOC100129150 were further tested for their association with individual qualitative and quantitative traits. None of the 16 top SNPs (one per gene) associated simultaneously with more than two individual traits. Of them 11 variants showed nominal associations with MetS per se. The effects of 16 top SNPs on the quantitative traits were relatively small, together explaining from ∼9% of the variance in triglycerides, 5.8% of high-density lipoprotein cholesterol, 3.6% of fasting glucose, and 1.4% of systolic blood pressure. CONCLUSIONS Qualitative and quantitative pleiotropic tests on pairs of traits indicate that a small portion of the covariation in these traits can be explained by the reported common genetic variants.

Association of genetic variation with systolic and diastolic blood pressure among African Americans: the Candidate Gene Association Resource study

The prevalence of hypertension in African Americans (AAs) is higher than in other US groups; yet, few have performed genome-wide association studies (GWASs) in AA. Among people of European descent, GWASs have identified genetic variants at 13 loci that are associated with blood pressure. It is unknown if these variants confer susceptibility in people of African ancestry. Here, we examined genome-wide and candidate gene associations with systolic blood pressure (SBP) and diastolic blood pressure (DBP) using the Candidate Gene Association Resource (CARe) consortium consisting of 8591 AAs. Genotypes included genome-wide single-nucleotide polymorphism (SNP) data utilizing the Affymetrix 6.0 array with imputation to 2.5 million HapMap SNPs and candidate gene SNP data utilizing a 50K cardiovascular gene-centric array (ITMAT-Broad-CARe [IBC] array). For Affymetrix data, the strongest signal for DBP was rs10474346 (P= 3.6 × 10−8) located near GPR98 and ARRDC3. For SBP, the strongest signal was rs2258119 in C21orf91 (P= 4.7 × 10−8). The top IBC association for SBP was rs2012318 (P= 6.4 × 10−6) near SLC25A42 and for DBP was rs2523586 (P= 1.3 × 10−6) near HLA-B. None of the top variants replicated in additional AA (n = 11 882) or European-American (n = 69 899) cohorts. We replicated previously reported European-American blood pressure SNPs in our AA samples (SH2B3, P= 0.009; TBX3-TBX5, P= 0.03; and CSK-ULK3, P= 0.0004). These genetic loci represent the best evidence of genetic influences on SBP and DBP in AAs to date. More broadly, this work supports that notion that blood pressure among AAs is a trait with genetic underpinnings but also with significant complexity.

A Bivariate Genome-Wide Approach to Metabolic Syndrome STAMPEED Consortium

OBJECTIVE The metabolic syndrome (MetS) is defined as concomitant disorders of lipid and glucose metabolism, central obesity, and high blood pressure, with an increased risk of type 2 diabetes and cardiovascular disease. This study tests whether common genetic variants with pleiotropic effects account for some of the correlated architecture among five metabolic phenotypes that define MetS. RESEARCH DESIGN AND METHODS Seven studies of the STAMPEED consortium, comprising 22,161 participants of European ancestry, underwent genome-wide association analyses of metabolic traits using a panel of ∼2.5 million imputed single nucleotide polymorphisms (SNPs). Phenotypes were defined by the National Cholesterol Education Program (NCEP) criteria for MetS in pairwise combinations. Individuals exceeding the NCEP thresholds for both traits of a pair were considered affected. RESULTS Twenty-nine common variants were associated with MetS or a pair of traits. Variants in the genes LPL, CETP, APOA5 (and its cluster), GCKR (and its cluster), LIPC, TRIB1, LOC100128354/MTNR1B, ABCB11, and LOC100129150 were further tested for their association with individual qualitative and quantitative traits. None of the 16 top SNPs (one per gene) associated simultaneously with more than two individual traits. Of them 11 variants showed nominal associations with MetS per se. The effects of 16 top SNPs on the quantitative traits were relatively small, together explaining from ∼9% of the variance in triglycerides, 5.8% of high-density lipoprotein cholesterol, 3.6% of fasting glucose, and 1.4% of systolic blood pressure. CONCLUSIONS Qualitative and quantitative pleiotropic tests on pairs of traits indicate that a small portion of the covariation in these traits can be explained by the reported common genetic variants.

APOL1 Variants Associate with Increased Risk of CKD among African Americans

Although case-control studies suggest that African Americans with common coding variants in the APOL1 gene are 5-29 times more likely than those individuals without such variants to have focal segmental glomerulosclerosis, HIV-associated nephropathy, or ESRD, prospective studies have not yet evaluated the impact of these variants on CKD in a community-based sample of African Americans. Here, we studied whether the APOL1 G1 and G2 risk alleles associate with the development of CKD and progression to ESRD by analyzing data from 3067 African Americans in the Atherosclerosis Risk in Communities Study who did not have CKD at baseline. Carrying two risk alleles associated with a 1.49-fold increased risk of CKD (95% CI=1.02 to 2.17) and a 1.88-fold increased risk of ESRD (95% CI=1.20 to 2.93) compared with zero or one risk allele; associations persisted after adjusting for European ancestry. Among participants who developed CKD, those participants with two risk alleles were more likely to progress to ESRD than their counterparts with zero or one risk allele (HR=2.22, 95% CI=1.01 to 4.84). In conclusion, APOL1 risk variants are risk factors for the development of CKD and progression from CKD to ESRD among African Americans in the general population.

Genome-Wide Association Study Identifies Novel Loci Associated with Circulating Phospho- and Sphingolipid Concentrations

Phospho- and sphingolipids are crucial cellular and intracellular compounds. These lipids are required for active transport, a number of enzymatic processes, membrane formation, and cell signalling. Disruption of their metabolism leads to several diseases, with diverse neurological, psychiatric, and metabolic consequences. A large number of phospholipid and sphingolipid species can be detected and measured in human plasma. We conducted a meta-analysis of five European family-based genome-wide association studies (N = 4034) on plasma levels of 24 sphingomyelins (SPM), 9 ceramides (CER), 57 phosphatidylcholines (PC), 20 lysophosphatidylcholines (LPC), 27 phosphatidylethanolamines (PE), and 16 PE-based plasmalogens (PLPE), as well as their proportions in each major class. This effort yielded 25 genome-wide significant loci for phospholipids (smallest P-value = 9.88×10−204) and 10 loci for sphingolipids (smallest P-value = 3.10×10−57). After a correction for multiple comparisons (P-value<2.2×10−9), we observed four novel loci significantly associated with phospholipids (PAQR9, AGPAT1, PKD2L1, PDXDC1) and two with sphingolipids (PLD2 and APOE) explaining up to 3.1% of the variance. Further analysis of the top findings with respect to within class molar proportions uncovered three additional loci for phospholipids (PNLIPRP2, PCDH20, and ABDH3) suggesting their involvement in either fatty acid elongation/saturation processes or fatty acid specific turnover mechanisms. Among those, 14 loci (KCNH7, AGPAT1, PNLIPRP2, SYT9, FADS1-2-3, DLG2, APOA1, ELOVL2, CDK17, LIPC, PDXDC1, PLD2, LASS4, and APOE) mapped into the glycerophospholipid and 12 loci (ILKAP, ITGA9, AGPAT1, FADS1-2-3, APOA1, PCDH20, LIPC, PDXDC1, SGPP1, APOE, LASS4, and PLD2) to the sphingolipid pathways. In large meta-analyses, associations between FADS1-2-3 and carotid intima media thickness, AGPAT1 and type 2 diabetes, and APOA1 and coronary artery disease were observed. In conclusion, our study identified nine novel phospho- and sphingolipid loci, substantially increasing our knowledge of the genetic basis for these traits.