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1.  Human metabolic individuality in biomedical and pharmaceutical research 
Nature  2011;477(7362):10.1038/nature10354.
Genome-wide association studies (GWAS) have identified many risk loci for complex diseases, but effect sizes are typically small and information on the underlying biological processes is often lacking. Associations with metabolic traits as functional intermediates can overcome these problems and potentially inform individualized therapy. Here we report a comprehensive analysis of genotype-dependent metabolic phenotypes using a GWAS with non-targeted metabolomics. We identified 37 genetic loci associated with blood metabolite concentrations, of which 25 exhibit effect sizes that are unusually high for GWAS and account for 10-60% of metabolite levels per allele copy. Our associations provide new functional insights for many disease-related associations that have been reported in previous studies, including cardiovascular and kidney disorders, type 2 diabetes, cancer, gout, venous thromboembolism, and Crohn’s disease. Taken together our study advances our knowledge of the genetic basis of metabolic individuality in humans and generates many new hypotheses for biomedical and pharmaceutical research.
PMCID: PMC3832838  PMID: 21886157
2.  Meta-Analysis of Genome-Wide Association Studies Identifies Six New Loci for Serum Calcium Concentrations 
O'Seaghdha, Conall M. | Wu, Hongsheng | Yang, Qiong | Kapur, Karen | Guessous, Idris | Zuber, Annie Mercier | Köttgen, Anna | Stoudmann, Candice | Teumer, Alexander | Kutalik, Zoltán | Mangino, Massimo | Dehghan, Abbas | Zhang, Weihua | Eiriksdottir, Gudny | Li, Guo | Tanaka, Toshiko | Portas, Laura | Lopez, Lorna M. | Hayward, Caroline | Lohman, Kurt | Matsuda, Koichi | Padmanabhan, Sandosh | Firsov, Dmitri | Sorice, Rossella | Ulivi, Sheila | Brockhaus, A. Catharina | Kleber, Marcus E. | Mahajan, Anubha | Ernst, Florian D. | Gudnason, Vilmundur | Launer, Lenore J. | Mace, Aurelien | Boerwinckle, Eric | Arking, Dan E. | Tanikawa, Chizu | Nakamura, Yusuke | Brown, Morris J. | Gaspoz, Jean-Michel | Theler, Jean-Marc | Siscovick, David S. | Psaty, Bruce M. | Bergmann, Sven | Vollenweider, Peter | Vitart, Veronique | Wright, Alan F. | Zemunik, Tatijana | Boban, Mladen | Kolcic, Ivana | Navarro, Pau | Brown, Edward M. | Estrada, Karol | Ding, Jingzhong | Harris, Tamara B. | Bandinelli, Stefania | Hernandez, Dena | Singleton, Andrew B. | Girotto, Giorgia | Ruggiero, Daniela | d'Adamo, Adamo Pio | Robino, Antonietta | Meitinger, Thomas | Meisinger, Christa | Davies, Gail | Starr, John M. | Chambers, John C. | Boehm, Bernhard O. | Winkelmann, Bernhard R. | Huang, Jie | Murgia, Federico | Wild, Sarah H. | Campbell, Harry | Morris, Andrew P. | Franco, Oscar H. | Hofman, Albert | Uitterlinden, Andre G. | Rivadeneira, Fernando | Völker, Uwe | Hannemann, Anke | Biffar, Reiner | Hoffmann, Wolfgang | Shin, So–Youn | Lescuyer, Pierre | Henry, Hughes | Schurmann, Claudia | Munroe, Patricia B. | Gasparini, Paolo | Pirastu, Nicola | Ciullo, Marina | Gieger, Christian | März, Winfried | Lind, Lars | Spector, Tim D. | Smith, Albert V. | Rudan, Igor | Wilson, James F. | Polasek, Ozren | Deary, Ian J. | Pirastu, Mario | Ferrucci, Luigi | Liu, Yongmei | Kestenbaum, Bryan | Kooner, Jaspal S. | Witteman, Jacqueline C. M. | Nauck, Matthias | Kao, W. H. Linda | Wallaschofski, Henri | Bonny, Olivier | Fox, Caroline S. | Bochud, Murielle | Abecasis, Gonçalo R.
PLoS Genetics  2013;9(9):e1003796.
Calcium is vital to the normal functioning of multiple organ systems and its serum concentration is tightly regulated. Apart from CASR, the genes associated with serum calcium are largely unknown. We conducted a genome-wide association meta-analysis of 39,400 individuals from 17 population-based cohorts and investigated the 14 most strongly associated loci in ≤21,679 additional individuals. Seven loci (six new regions) in association with serum calcium were identified and replicated. Rs1570669 near CYP24A1 (P = 9.1E-12), rs10491003 upstream of GATA3 (P = 4.8E-09) and rs7481584 in CARS (P = 1.2E-10) implicate regions involved in Mendelian calcemic disorders: Rs1550532 in DGKD (P = 8.2E-11), also associated with bone density, and rs7336933 near DGKH/KIAA0564 (P = 9.1E-10) are near genes that encode distinct isoforms of diacylglycerol kinase. Rs780094 is in GCKR. We characterized the expression of these genes in gut, kidney, and bone, and demonstrate modulation of gene expression in bone in response to dietary calcium in mice. Our results shed new light on the genetics of calcium homeostasis.
Author Summary
Calcium is vital to many biological processes and its serum concentration is tightly regulated. Family studies have shown that serum calcium is under strong genetic control. Apart from CASR, the genes associated with serum calcium are largely unknown. We conducted a genome-wide association meta-analysis of 39,400 individuals from 17 population-based cohorts and investigated the 14 most strongly associated loci in ≤21,679 additional individuals. We identified seven loci (six new regions) as being robustly associated with serum calcium. Three loci implicate regions involved in rare monogenic diseases including disturbances of serum calcium levels. Several of the newly identified loci harbor genes linked to the hormonal control of serum calcium. In mice experiments, we characterized the expression of these genes in gut, kidney, and bone, and explored the influence of dietary calcium intake on the expression of these genes in these organs. Our results shed new light on the genetics of calcium homeostasis and suggest a role for dietary calcium intake in bone-specific gene expression.
PMCID: PMC3778004  PMID: 24068962
3.  Neutrophil Gelatinase-Associated Lipocalin (NGAL) and Kidney Injury Molecule 1 (KIM-1) as Predictors of Incident CKD Stage 3: The Atherosclerosis Risk in Communities (ARIC) Study 
Identifying individuals at risk for chronic kidney disease (CKD) is critical for timely treatment initiation to slow progression of the disease. Neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule 1 (KIM-1) are known biomarkers of acute kidney injury, but it is unknown whether these markers are associated with incident CKD stage 3 in the general population.
Study Design
Matched case-control study
Setting and Participants
African American and Caucasian participants from the Atherosclerosis Risk in Communities (ARIC) study who at baseline had an estimated glomerular filtration rate ≥ 60 ml/min/1.73 m2 and urinary albumin-creatinine ratio (UACR) ≤ 30 mg/g. A total of 143 controls were matched on age, sex and race to 143 cases of incident CKD stage 3 after 8.6 years of follow-up.
Quartile of NGAL and KIM-1.
Outcomes & Measurements
Incident CKD stage 3 (eGFR < 60 ml/min/1.73 m2 at follow-up and a decrease in eGFR from baseline to follow-up of ≥25%)
Both NGAL (p=0.05) and KIM-1 (p<0.001) were positively correlated with baseline UACR; neither was associated with baseline eGFR. Participants with NGAL concentrations in the fourth quartile had more than 2-fold higher odds (adjusted OR, 2.11, 95% CI, 0.96–4.64) of incident CKD stage 3 compared to participants in the first quartile after multivariable adjustment (p-trend=0.03). Adjustment for urinary creatinine and albumin resulted in a non-significant association (highest quartile adjusted OR. 1.52; 95% CI, 0.64–3.58; p=0.2). No significant association between KIM-1 levels and incident CKD was observed in crude or adjusted models.
The relatively small sample size of the study limits precision and power to detect weak associations.
Higher NGAL levels, but not KIM-1 levels, were associated with incident CKD stage 3. Adjustment for urinary creatinine and albumin concentration attenuated this association. Additional studies are needed to confirm these findings and assess the utility of urinary NGAL as a marker of CKD risk.
PMCID: PMC3399971  PMID: 22542304
4.  Genome-wide association analyses identify 18 new loci associated with serum urate concentrations 
Köttgen, Anna | Albrecht, Eva | Teumer, Alexander | Vitart, Veronique | Krumsiek, Jan | Hundertmark, Claudia | Pistis, Giorgio | Ruggiero, Daniela | O’Seaghdha, Conall M | Haller, Toomas | Yang, Qiong | Tanaka, Toshiko | Johnson, Andrew D | Kutalik, Zoltán | Smith, Albert V | Shi, Julia | Struchalin, Maksim | Middelberg, Rita P S | Brown, Morris J | Gaffo, Angelo L | Pirastu, Nicola | Li, Guo | Hayward, Caroline | Zemunik, Tatijana | Huffman, Jennifer | Yengo, Loic | Zhao, Jing Hua | Demirkan, Ayse | Feitosa, Mary F | Liu, Xuan | Malerba, Giovanni | Lopez, Lorna M | van der Harst, Pim | Li, Xinzhong | Kleber, Marcus E | Hicks, Andrew A | Nolte, Ilja M | Johansson, Asa | Murgia, Federico | Wild, Sarah H | Bakker, Stephan J L | Peden, John F | Dehghan, Abbas | Steri, Maristella | Tenesa, Albert | Lagou, Vasiliki | Salo, Perttu | Mangino, Massimo | Rose, Lynda M | Lehtimäki, Terho | Woodward, Owen M | Okada, Yukinori | Tin, Adrienne | Müller, Christian | Oldmeadow, Christopher | Putku, Margus | Czamara, Darina | Kraft, Peter | Frogheri, Laura | Thun, Gian Andri | Grotevendt, Anne | Gislason, Gauti Kjartan | Harris, Tamara B | Launer, Lenore J | McArdle, Patrick | Shuldiner, Alan R | Boerwinkle, Eric | Coresh, Josef | Schmidt, Helena | Schallert, Michael | Martin, Nicholas G | Montgomery, Grant W | Kubo, Michiaki | Nakamura, Yusuke | Tanaka, Toshihiro | Munroe, Patricia B | Samani, Nilesh J | Jacobs, David R | Liu, Kiang | D’Adamo, Pio | Ulivi, Sheila | Rotter, Jerome I | Psaty, Bruce M | Vollenweider, Peter | Waeber, Gerard | Campbell, Susan | Devuyst, Olivier | Navarro, Pau | Kolcic, Ivana | Hastie, Nicholas | Balkau, Beverley | Froguel, Philippe | Esko, Tõnu | Salumets, Andres | Khaw, Kay Tee | Langenberg, Claudia | Wareham, Nicholas J | Isaacs, Aaron | Kraja, Aldi | Zhang, Qunyuan | Wild, Philipp S | Scott, Rodney J | Holliday, Elizabeth G | Org, Elin | Viigimaa, Margus | Bandinelli, Stefania | Metter, Jeffrey E | Lupo, Antonio | Trabetti, Elisabetta | Sorice, Rossella | Döring, Angela | Lattka, Eva | Strauch, Konstantin | Theis, Fabian | Waldenberger, Melanie | Wichmann, H-Erich | Davies, Gail | Gow, Alan J | Bruinenberg, Marcel | Study, LifeLines Cohort | Stolk, Ronald P | Kooner, Jaspal S | Zhang, Weihua | Winkelmann, Bernhard R | Boehm, Bernhard O | Lucae, Susanne | Penninx, Brenda W | Smit, Johannes H | Curhan, Gary | Mudgal, Poorva | Plenge, Robert M | Portas, Laura | Persico, Ivana | Kirin, Mirna | Wilson, James F | Leach, Irene Mateo | van Gilst, Wiek H | Goel, Anuj | Ongen, Halit | Hofman, Albert | Rivadeneira, Fernando | Uitterlinden, Andre G | Imboden, Medea | von Eckardstein, Arnold | Cucca, Francesco | Nagaraja, Ramaiah | Piras, Maria Grazia | Nauck, Matthias | Schurmann, Claudia | Budde, Kathrin | Ernst, Florian | Farrington, Susan M | Theodoratou, Evropi | Prokopenko, Inga | Stumvoll, Michael | Jula, Antti | Perola, Markus | Salomaa, Veikko | Shin, So-Youn | Spector, Tim D | Sala, Cinzia | Ridker, Paul M | Kähönen, Mika | Viikari, Jorma | Hengstenberg, Christian | Nelson, Christopher P | Consortium, CARDIoGRAM | Consortium, DIAGRAM | Consortium, ICBP | Consortium, MAGIC | Meschia, James F | Nalls, Michael A | Sharma, Pankaj | Singleton, Andrew B | Kamatani, Naoyuki | Zeller, Tanja | Burnier, Michel | Attia, John | Laan, Maris | Klopp, Norman | Hillege, Hans L | Kloiber, Stefan | Choi, Hyon | Pirastu, Mario | Tore, Silvia | Probst-Hensch, Nicole M | Völzke, Henry | Gudnason, Vilmundur | Parsa, Afshin | Schmidt, Reinhold | Whitfield, John B | Fornage, Myriam | Gasparini, Paolo | Siscovick, David S | Polašek, Ozren | Campbell, Harry | Rudan, Igor | Bouatia-Naji, Nabila | Metspalu, Andres | Loos, Ruth J F | van Duijn, Cornelia M | Borecki, Ingrid B | Ferrucci, Luigi | Gambaro, Giovanni | Deary, Ian J | Wolffenbuttel, Bruce H R | Chambers, John C | März, Winfried | Pramstaller, Peter P | Snieder, Harold | Gyllensten, Ulf | Wright, Alan F | Navis, Gerjan | Watkins, Hugh | Witteman, Jacqueline C M | Sanna, Serena | Schipf, Sabine | Dunlop, Malcolm G | Tönjes, Anke | Ripatti, Samuli | Soranzo, Nicole | Toniolo, Daniela | Chasman, Daniel I | Raitakari, Olli | Kao, W H Linda | Ciullo, Marina | Fox, Caroline S | Caulfield, Mark | Bochud, Murielle | Gieger, Christian
Nature genetics  2012;45(2):145-154.
Elevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SFMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout.
PMCID: PMC3663712  PMID: 23263486
5.  Validated SNPs for eGFR and their associations with albuminuria 
Human Molecular Genetics  2012;21(14):3293-3298.
Albuminuria and reduced glomerular filtration rate are manifestations of chronic kidney disease (CKD) that predict end-stage renal disease, acute kidney injury, cardiovascular disease and death. We hypothesized that SNPs identified in association with the estimated glomerular filtration rate (eGFR) would also be associated with albuminuria. Within the CKDGen Consortium cohort (n= 31 580, European ancestry), we tested 16 eGFR-associated SNPs for association with the urinary albumin-to-creatinine ratio (UACR) and albuminuria [UACR >25 mg/g (women); 17 mg/g (men)]. In parallel, within the CARe Renal Consortium (n= 5569, African ancestry), we tested seven eGFR-associated SNPs for association with the UACR. We used a Bonferroni-corrected P-value of 0.003 (0.05/16) in CKDGen and 0.007 (0.05/7) in CARe. We also assessed whether the 16 eGFR SNPs were associated with the UACR in aggregate using a beta-weighted genotype score. In the CKDGen Consortium, the minor A allele of rs17319721 in the SHROOM3 gene, known to be associated with a lower eGFR, was associated with lower ln(UACR) levels (beta = −0.034, P-value = 0.0002). No additional eGFR-associated SNPs met the Bonferroni-corrected P-value threshold of 0.003 for either UACR or albuminuria. In the CARe Renal Consortium, there were no associations between SNPs and UACR with a P< 0.007. Although we found the genotype score to be associated with albuminuria (P= 0.0006), this result was driven almost entirely by the known SHROOM3 variant, rs17319721. Removal of rs17319721 resulted in a P-value 0.03, indicating a weak residual aggregate signal. No alleles, previously demonstrated to be associated with a lower eGFR, were associated with the UACR or albuminuria, suggesting that there may be distinct genetic components for these traits.
PMCID: PMC3491918  PMID: 22492995
6.  Incident Gout in Women and Association with Obesity in the Atherosclerosis Risk in Communities (ARIC) Study 
The American Journal of Medicine  2012;125(7):717.e9-717.e17.
We hypothesized that women with early- and mid-adult life obesity, as well as high mid-adult life waist-to-hip ratios, and high weight gain during adulthood, experience a greater incidence of gout.
We examined the incidence of gout in the Atherosclerosis Risk in Communities (ARIC) Study, a population-based biracial cohort comprised of individuals aged 45–65 years of age at baseline (1987–1989). A total of 6,263 women without prior history of gout were identified. We examined the association of BMI and obesity at cohort entry and at age 25 years, waist-to-hip ratio and weight change, with gout incidence (1996–1998).
Over 9 years of follow-up, 103 women developed gout. The cumulative incidence of gout, by age 70 years, according to BMI category at baseline of <25, 25–29.9, 30–34.9, and ≥ 35 kg/m2, was 1.9, 3.6, 7.9, and 11.8%, respectively (P <0.001). Obese women (BMI≥30) at baseline had an adjusted 2.4-fold greater risk of developing gout than non-obese women (95% confidence interval (CI) 1.53, 3.68). This association was attenuated after further adjustment for urate levels. Further, early adult obesity in women was associated with a 2.8-fold increased risk of gout compared to non-obese women (95% CI 1.33, 6.09), which remained statistically significant after baseline urate adjustment. There was a graded association between each anthropometric measure, including weight gain, with incident gout (each P for trend <0.001). The results were similar in black and white women.
In a large cohort of African American and Caucasian women, obesity in early and mid-adulthood, and weight gain during this interval, were each independent risk factors for incident gout in women.
PMCID: PMC3383456  PMID: 22571781
Gout; Women; Obesity; Weight; Arthritis
7.  Association of apolipoprotein A1 and B with kidney function and chronic kidney disease in two multiethnic population samples 
Nephrology Dialysis Transplantation  2012;27(7):2839-2847.
lipoprotein risk factors for atherosclerosis, i.e., increased LDL cholesterol, increased triglycerides and decreased HDL cholesterol, also are associated with progression of loss of kidney function...Goek and coworkers describe the association of the apoliproteins A1 and B and eGFR in two large cohorts derived from the general polulation [the NHANES III (N=7,023) and the ARIC study (n=10,292)]. The results were similar in both cohorts...
Circulating lipoproteins and their protein constituents, apolipoproteins, are risk factors for chronic kidney disease (CKD). The associations between apolipoprotein A1, apolipoprotein B and their ratio with glomerular filtration rate estimated from the new CKD Epidemiology Collaboration (CKD-EPI) equation (eGFR) are not well studied in the general population.
Associations between apolipoprotein A1, B and their ratio with the outcomes of eGFR, CKD (eGFR <60 mL/min/1.73m2) and albuminuria were examined in the Atherosclerosis Risk in Communities study (ARIC, n = 10 292, 1996–98) and the Third National Health and Nutrition Examination Survey (NHANES III, n = 7023, 1988–91). Cross-sectional multivariable-adjusted analyses were performed using linear and logistic regression. Prospective analyses related baseline apolipoprotein levels to subsequent CKD incidence over 10 years using the ARIC Carotid MRI follow-up cohort (n = 1659).
Higher apolipoprotein A1 quartiles were associated with a lower prevalence of CKD [Q4 versus Q1: odds ratio (OR) 0.73, P-trend = 0.02 in ARIC; Q4 versus Q1: OR 0.53, P-trend <0.01 in NHANES III] as well as with higher eGFR (P-trend <0.01 in ARIC and NHANES III). No consistent significant associations were found for apolipoprotein B in either study. The apolipoprotein B/A1 ratio was significantly associated with eGFR across quartiles in both studies (P-trend <0.01) and with CKD in ARIC (Q4 versus Q1: OR 1.23, P-trend = 0.01). Prospectively, there were trends for the association of apolipoproteins with incident CKD [Q4 versus Q1: incidence rate ratio (IRR) = 0.68 for apolipoprotein A1, P-trend = 0.1; Q4 versus Q1: IRR = 1.35 for apolipoprotein B, P-trend = 0.2]. Associations were not systematically stronger when comparing traditional lipids (total cholesterol, low-density lipoprotein or high-density lipoprotein) to apolipoproteins.
Higher serum apolipoprotein A1 was associated with lower prevalence of CKD and higher eGFR estimated by the CKD-EPI equation in two large multiethnic population-based samples. While apolipoprotein B showed no consistent associations, a higher apolipoprotein B/A1 ratio was significantly associated with lower eGFR in both studies. The direction and magnitude of the longitudinal associations between apolipoproteins and CKD incidence were overall similar to those observed cross-sectionally. No consistent differences became apparent between traditional lipids and apolipoproteins.
PMCID: PMC3471548  PMID: 22287661
apolipoprotein; ARIC; chronic kidney disease; epidemiology; NHANES
8.  Genome-wide association study for serum urate concentrations and gout among African Americans identifies genomic risk loci and a novel URAT1 loss-of-function allele 
Human Molecular Genetics  2011;20(20):4056-4068.
Serum urate concentrations are highly heritable and elevated serum urate is a key risk factor for gout. Genome-wide association studies (GWAS) of serum urate in African American (AA) populations are lacking. We conducted a meta-analysis of GWAS of serum urate levels and gout among 5820 AA and a large candidate gene study among 6890 AA and 21 708 participants of European ancestry (EA) within the Candidate Gene Association Resource Consortium. Findings were tested for replication among 1996 independent AA individuals, and evaluated for their association among 28 283 EA participants of the CHARGE Consortium. Functional studies were conducted using 14C-urate transport assays in mammalian Chinese hamster ovary cells. In the discovery GWAS of serum urate, three loci achieved genome-wide significance (P< 5.0 × 10−8): a novel locus near SGK1/SLC2A12 on chromosome 6 (rs9321453, P= 1.0 × 10−9), and two loci previously identified in EA participants, SLC2A9 (P= 3.8 × 10−32) and SLC22A12 (P= 2.1 × 10−10). A novel rare non-synonymous variant of large effect size in SLC22A12, rs12800450 (minor allele frequency 0.01, G65W), was identified and replicated (beta −1.19 mg/dl, P= 2.7 × 10−16). 14C-urate transport assays showed reduced urate transport for the G65W URAT1 mutant. Finally, in analyses of 11 loci previously associated with serum urate in EA individuals, 10 of 11 lead single-nucleotide polymorphisms showed direction-consistent association with urate among AA. In summary, we identified and replicated one novel locus in association with serum urate levels and experimentally characterize the novel G65W variant in URAT1 as a functional allele. Our data support the importance of multi-ethnic GWAS in the identification of novel risk loci as well as functional variants.
PMCID: PMC3177647  PMID: 21768215
9.  Trefoil Factor 3 Predicts Incident Chronic Kidney Disease: A Case-Control Study Nested within the Atherosclerosis Risk in Communities (ARIC) Study 
American Journal of Nephrology  2011;34(4):291-297.
Early detection of individuals at high risk for chronic kidney disease (CKD) may aid prevention. Urinary levels of trefoil factor 3 (TFF3) are associated with acute kidney injury in animal models, but the association of TFF3 levels with incident CKD in humans is unknown.
We conducted a case-control study nested within the Atherosclerosis Risk in Communities (ARIC) Study and the ARIC Carotid MRI Study to determine whether urinary TFF3 levels predict incident CKD over 8.6 years of follow-up. A total of 143 participants with incident CKD (eGFR decreasing by ≥25% to <60 ml/min/1.73 m2) were matched on age, sex and race to 143 non-cases.
Higher TFF3 levels at baseline were strongly associated with Black race, diabetes (both p = 0.002), and antihypertensive medication use (p = 0.02). Compared to participants with TFF3 levels in the lowest quartile, the odds ratio (OR) of incident CKD was 1.84 (95% confidence interval (CI): 0.80, 4.22) for individuals with TFF3 levels in the second quartile, 2.43 (95% CI: 1.06, 5.53) for the third quartile, and 2.77 (95% CI: 1.22, 6.28) for the fourth quartile (p trend = 0.02). Adjustment for covariates, including urinary albumin: creatinine ratio, did not markedly change the associations. Twofold higher TFF3 levels were strongly associated with incident CKD after adjustment for CKD risk factors (adjusted OR = 1.35; 95% CI: 1.11, 1.64).
Higher urinary TFF3 levels may indicate ongoing repair of damage in the kidney. Additional studies are needed to confirm whether TFF3 can be useful as a marker of increased risk for CKD.
PMCID: PMC3169359  PMID: 21829008
Kidney disease; Tubulointerstitual disease; Biomarkers
10.  Younger age at gout onset is related to obesity in a community-based cohort 
Arthritis care & research  2011;63(8):1108-1114.
Obesity is associated with gout risk. It is unclear whether obesity is associated with a younger age of gout onset. We examined whether obesity is related to age at gout onset and quantified the risk of incident gout by obesity status in the Campaign Against Cancer and Heart Disease (CLUE II) study, a longitudinal community-based cohort.
CLUE II began in 1989 as a cohort study of residents living within or surrounding Washington County, Maryland. Follow-up questionnaires queried whether each participant had been diagnosed with gout by a healthcare professional. Among participants with gout, we assessed whether obesity was related to age at disease onset. We also ascertained the eighteen-year risk of incident gout according to obesity status (BMI ≥30 kg/m2) at baseline with cumulative incidence ratios (RR) and 95% confidence intervals (CI) from Poisson regression.
Among the study population (n=15,533), 517 developed incident gout. The prevalence of obesity at baseline was 16.2%. The overall mean age at gout onset was 59.3 years. The onset of gout was 3.1 years (95% CI: 0.3, 5.8) earlier in those who were obese at baseline and 11.0 years earlier (95% CI: 5.8, 16.1) in participants who were obese at age 21, compared to their non-obese participants. The 18-year adjusted RR of gout in obese participants compared to non-obese participants was 1.92 (95% CI: 1.55, 2.37).
Obesity is not only a risk factor for incident gout but was associated with an earlier age at gout onset.
PMCID: PMC3149749  PMID: 21485022
Gout; Obesity; Epidemiology; Age
11.  High-Normal Albuminuria and Risk of Heart Failure in the Community 
Albuminuria has been associated with cardiovascular risk, but the relationship of high-normal albuminuria to subsequent heart failure has not been well established.
Study Design
Prospective observational study, the Atherosclerosis Risk in Communities (ARIC) Study.
Setting & Participants
10,975 individuals free from heart failure were followed up from the fourth ARIC Study visit (1996–1998) through January 2006.
Urinary albumin-creatinine ratio (UACR), analyzed continuously and categorically as optimal (<5 mg/g), intermediate-normal (5–9 mg/g), high-normal (10–29 mg/g), microalbuminuria (30–299 mg/g), and macroalbuminuria (≥300 mg/g).
Outcomes & Measurements
Incident heart failure was defined as a heart failure–related hospitalization or death. Cox proportional hazard models were used to calculate the HR of heart failure after adjustment for age, race, sex, estimated glomerular filtration rate (eGFR), and other cardiovascular risk factors.
Individuals were followed up for a median of 8.3 years and experienced 344 heart failure events. Compared with normal UACR, albuminuria was associated with a progressively increased risk of heart failure from intermediate-normal (adjusted HR, 1.54; 95% CI, 1.12–2.11) and high-normal UACR (adjusted HR, 1.91; 95% CI, 1.38–2.66) to microalbuminuria (adjusted HR, 2.49; 95% CI, 1.77–3.50) and macroalbuminuria (adjusted HR, 3.47; 95% CI, 2.10–5.72). Results were similar in secondary analyses of participants censored at the time of coronary heart disease event and along a range of eGFRs.
UACR was measured as a single random sample.
Albuminuria is associated with subsequent heart failure, even in individuals with few cardiovascular risk factors and UACR within the normal range. Our results suggest that the association between albuminuria and heart failure may not be mediated fully by ischemic heart disease or kidney disease, measured using eGFR.
PMCID: PMC3119712  PMID: 21549463
Albuminuria; urinary albumin-creatinine ratio; heart failure; epidemiology
12.  The MYH9/APOL1 region and chronic kidney disease in European-Americans 
Human Molecular Genetics  2011;20(12):2450-2456.
Polymorphisms in the MYH9 and adjacent APOL1 gene region demonstrate a strong association with non-diabetic kidney disease in African-Americans. However, it is not known to what extent these polymorphisms are present in other ethnic groups. To examine the association of genetic polymorphisms in this region with chronic kidney disease (CKD; estimated glomerular filtration rate <60 ml/min/1.73 m2) in individuals of European ancestry, we examined rs4821480, an MYH9 single-nucleotide polymorphism (SNP) recently identified as associated with kidney disease in African-Americans, in 13 133 participants from the Framingham Heart Study (FHS) and Atherosclerosis Risk in Communities (ARIC) Study. In addition, we further interrogated the MYH9/APOL1 gene region using 282 SNPs for association with CKD using age-, sex- and center-adjusted models and performed a meta-analysis of the results from both studies. Because of prior data linking rs4821480 and kidney disease, we used a P-value of <0.05 to test the association with CKD. In the meta-analysis, rs4821480 (minor allele frequency 4.45 and 3.96% in FHS and ARIC, respectively) was associated with higher CKD prevalence in participants free of diabetes (odds ratio 1.44; 95% confidence interval 1.15–1.80; P = 0.001). No other SNPs achieved significance after adjusting for multiple testing. Results utilizing directly genotyped data confirmed the results of the primary analysis. Recently identified APOL1 risk variants were also directly genotyped, but did not account for the observed MYH9 signal. These data suggest that the MYH9 polymorphism rs4821480 is associated with an increased risk of non-diabetic CKD in individuals of European ancestry.
PMCID: PMC3098737  PMID: 21429915
13.  Multiple Genetic Loci Influence Serum Urate and Their Relationship with Gout and Cardiovascular Disease Risk Factors 
Elevated serum urate levels can lead to gout and are associated with cardiovascular risk factors. We performed genome-wide association to search for genetic susceptibility loci for serum urate and gout, and investigated the causal nature of the associations of serum urate with gout and selected cardiovascular risk factors and coronary heart disease (CHD).
Methods and Results
Meta-analyses of genome-wide association studies (GWAS) were performed in 5 population-based cohorts of the CHARGE consortium for serum urate and gout in 28,283 white individuals. The effect of the most significant SNP at all genome-wide significant loci on serum urate was added to create a genetic urate score. Findings were replicated in the Women’s Genome Health Study (WGHS; n=22,054). SNPs at 8 genetic loci achieved genome-wide significance with serum urate levels (p-values 4×10−8 to 2×10−242; SLC22A11, GCKR, R3HDM2-INHBC region, RREB1, PDZK1, SLC2A9, ABCG2, SLC17A1). Only two loci [SLC2A9, ABCG2] showed genome-wide significant association with gout. The genetic urate score was strongly associated with serum urate and gout (odds ratio 12.4 per 100 umol/L; p-value=3×10−39), but not with blood pressure, glucose, eGFR, chronic kidney disease, or CHD. The lack of association between the genetic score and the latter phenotypes was also observed in WGHS.
The genetic urate score analysis suggested a causal relationship between serum urate and gout but did not provide evidence for one between serum urate and cardiovascular risk factors and CHD.
PMCID: PMC3371395  PMID: 20884846
urate; gout; cardiovascular disease risk factors; genome-wide association study; Mendelian randomization
14.  Lower Urinary Connective Tissue Growth Factor Levels and Incident CKD Stage 3 in the General Population 
Connective tissue growth factor (CTGF) is involved in the development and progression of kidney diseases including diabetic nephropathy and kidney fibrosis, but may also play a role in mesangial repair following injury. It is unknown whether, in the general population, urinary CTGF levels are associated with reduction of estimated glomerular filtration rate (eGFR) to less than 60 ml/min/1.73m2 (ie, development of chronic kidney disease [CKD] stage 3).
Study Design
Nested case-control.
Setting & Participants
100 cases of incident CKD stage 3 and 100 age-and sex-matched controls in the Framingham Heart Study (FHS); 141 cases and 135 age-, sexand race-matched controls in the Atherosclerosis Risk in Communities (ARIC) Study. Controls had eGFR ≥60 ml/min/1.73m2 at follow-up in both studies.
Urinary CTGF concentrations.
Incident CKD stage 3, defined as eGFR <60 ml/min/1.73m2.
Stored urine samples from Framingham Heart Study and ARIC were measured for CTGF. Covariates were obtained from Framingham Heart Study and ARIC participant examinations.
In Framingham Heart Study, the median baseline urinary CTGF concentration was lower among cases (1.35 ng/mL) than controls (2.35 ng/mL; paired t-test P<0.0001). The multivariable-adjusted OR for incident CKD stage 3 was 0.33 (95% confidence interval [CI] 0.17–0.64; P<0.001) per 1-standard deviation increase in log urinary CTGF after adjustment for CKD risk factors, baseline eGFR and baseline log urinary albumin-creatinine ratio, with similar results among participants without diabetes (n=184). Results were not materially different when urinary CTGF was indexed to urinary creatinine (multivariable-adjusted OR, 0.34; 95% CI, 0.21–0.56; P<0.001). A similar, but non-significant, trend of risk of incident CKD stage 3 with lower baseline urinary CTGF concentration was observed in an independent case-control study conducted in the ARIC Study, with the strongest results observed among participants free of diabetes. This inverse relationship was robust in meta-analysis of both the overall and diabetes-free groups.
Observational study; causality cannot be inferred.
Lower urinary CTGF concentrations precede the onset of CKD stage 3 in the general population. Further work is required to fully characterize how CTGF influences risk of CKD.
PMCID: PMC3100386  PMID: 21292366
15.  Association of Estimated Glomerular Filtration Rate and Urinary Uromodulin Concentrations with Rare Variants Identified by UMOD Gene Region Sequencing 
PLoS ONE  2012;7(5):e38311.
Recent genome-wide association studies (GWAS) have identified common variants in the UMOD region associated with kidney function and disease in the general population. To identify novel rare variants as well as common variants that may account for this GWAS signal, the exons and 4 kb upstream region of UMOD were sequenced.
Methodology/Principal Findings
Individuals (n = 485) were selected based on presence of the GWAS risk haplotype and chronic kidney disease (CKD) in the ARIC Study and on the extremes of of the UMOD gene product, uromodulin, in urine (Tamm Horsfall protein, THP) in the Framingham Heart Study (FHS). Targeted sequencing was conducted using capillary based Sanger sequencing (3730 DNA Analyzer). Variants were tested for association with THP concentrations and estimated glomerular filtration rate (eGFR), and identified non-synonymous coding variants were genotyped in up to 22,546 follow-up samples. Twenty-four and 63 variants were identified in the 285 ARIC and 200 FHS participants, respectively. In both studies combined, there were 33 common and 54 rare (MAF<0.05) variants. Five non-synonymous rare variants were identified in FHS; borderline enrichment of rare variants was found in the extremes of THP (SKAT p-value = 0.08). Only V458L was associated with THP in the FHS general-population validation sample (p = 9*10−3, n = 2,522), but did not show direction-consistent and significant association with eGFR in both the ARIC (n = 14,635) and FHS (n = 7,520) validation samples. Pooling all non-synonymous rare variants except V458L together showed non-significant associations with THP and eGFR in the FHS validation sample. Functional studies of V458L revealed no alternations in protein trafficking.
Multiple novel rare variants in the UMOD region were identified, but none were consistently associated with eGFR in two independent study samples. Only V458L had modest association with THP levels in the general population and thus could not account for the observed GWAS signal.
PMCID: PMC3365030  PMID: 22693617
16.  Common variants in 22 loci are associated with QRS duration and cardiac ventricular conduction 
Sotoodehnia, Nona | Isaacs, Aaron | de Bakker, Paul I.W. | Dörr, Marcus | Newton-Cheh, Christopher | Nolte, Ilja M. | van der Harst, Pim | Müller, Martina | Eijgelsheim, Mark | Alonso, Alvaro | Hicks, Andrew A. | Padmanabhan, Sandosh | Hayward, Caroline | Smith, Albert Vernon | Polasek, Ozren | Giovannone, Steven | Fu, Jingyuan | Magnani, Jared W. | Marciante, Kristin D. | Pfeufer, Arne | Gharib, Sina A. | Teumer, Alexander | Li, Man | Bis, Joshua C. | Rivadeneira, Fernando | Aspelund, Thor | Köttgen, Anna | Johnson, Toby | Rice, Kenneth | Sie, Mark P.S. | Wang, Amanda Ying | Klopp, Norman | Fuchsberger, Christian | Wild, Sarah H. | Leach, Irene Mateo | Estrada, Karol | Völker, Uwe | Wright, Alan F. | Asselbergs, Folkert W. | Qu, Jiaxiang | Chakravarti, Aravinda | Sinner, Moritz F. | Kors, Jan A. | Petersmann, Astrid | Harris, Tamara B. | Soliman, Elsayed Z. | Munroe, Patricia B. | Psaty, Bruce M. | Oostra, Ben A. | Cupples, L. Adrienne | Perz, Siegfried | de Boer, Rudolf A. | Uitterlinden, André G. | Vözke, Henry | Spector, Timothy D. | Liu, Fang-Yu | Boerwinkle, Eric | Dominiczak, Anna F. | Rotter, Jerome I. | van Herpen, Gé | Levy, Daniel | Wichmann, H.-Erich | van Gilst, Wiek H. | Witteman, Jacqueline C.M. | Kroemer, Heyo K. | Kao, W.H. Linda | Heckbert, Susan R. | Meitinger, Thomas | Hofman, Albert | Campbell, Harry | Folsom, Aaron R. | van Veldhuisen, Dirk J. | Schwienbacher, Christine | O’Donnell, Christopher J. | Volpato, Claudia Beu | Caulfield, Mark J. | Connell, John M. | Launer, Lenore | Lu, Xiaowen | Franke, Lude | Fehrmann, Rudolf S.N. | Meerman, Gerard te | Groen, Harry J.M. | Weersma, Rinse K. | van den Berg, Leonard H. | Wijmenga, Cisca | Ophoff, Roel A. | Navis, Gerjan | Rudan, Igor | Snieder, Harold | Wilson, James F. | Pramstaller, Peter P. | Siscovick, David S. | Wang, Thomas J. | Gudnason, Vilmundur | van Duijn, Cornelia M. | Felix, Stephan B. | Fishman, Glenn I. | Jamshidi, Yalda | Stricker, Bruno H Ch | Samani, Nilesh J. | Kääb, Stefan | Arking, Dan E.
Nature Genetics  2010;42(12):1068-1076.
QRS interval on the electrocardiogram reflects ventricular depolarization and conduction time, and is a risk factor for mortality, sudden death, and heart failure. We performed a genome-wide association meta-analysis in 40,407 European-descent individuals from 14 studies, with further genotyping in 7170 additional Europeans, and identified 22 loci associated with QRS duration (P < 5 × 10−8). These loci map in or near genes in pathways with established roles in ventricular conduction such as sodium channels, transcription factors, and calcium-handling proteins, but also point to novel biologic processes, such as kinase inhibitors and genes related to tumorigenesis. We demonstrate that SCN10A, a gene at our most significant locus, is expressed in the mouse ventricular conduction system, and treatment with a selective SCN10A blocker prolongs QRS duration. These findings extend our current knowledge of ventricular depolarization and conduction.
PMCID: PMC3338195  PMID: 21076409
QRS interval; ECG; quantitative trait; genome-wide association study
17.  Genome-Wide Association and Functional Follow-Up Reveals New Loci for Kidney Function 
Pattaro, Cristian | Köttgen, Anna | Teumer, Alexander | Garnaas, Maija | Böger, Carsten A. | Fuchsberger, Christian | Olden, Matthias | Chen, Ming-Huei | Tin, Adrienne | Taliun, Daniel | Li, Man | Gao, Xiaoyi | Gorski, Mathias | Yang, Qiong | Hundertmark, Claudia | Foster, Meredith C. | O'Seaghdha, Conall M. | Glazer, Nicole | Isaacs, Aaron | Liu, Ching-Ti | Smith, Albert V. | O'Connell, Jeffrey R. | Struchalin, Maksim | Tanaka, Toshiko | Li, Guo | Johnson, Andrew D. | Gierman, Hinco J. | Feitosa, Mary | Hwang, Shih-Jen | Atkinson, Elizabeth J. | Lohman, Kurt | Cornelis, Marilyn C. | Johansson, Åsa | Tönjes, Anke | Dehghan, Abbas | Chouraki, Vincent | Holliday, Elizabeth G. | Sorice, Rossella | Kutalik, Zoltan | Lehtimäki, Terho | Esko, Tõnu | Deshmukh, Harshal | Ulivi, Sheila | Chu, Audrey Y. | Murgia, Federico | Trompet, Stella | Imboden, Medea | Kollerits, Barbara | Pistis, Giorgio | Harris, Tamara B. | Launer, Lenore J. | Aspelund, Thor | Eiriksdottir, Gudny | Mitchell, Braxton D. | Boerwinkle, Eric | Schmidt, Helena | Cavalieri, Margherita | Rao, Madhumathi | Hu, Frank B. | Demirkan, Ayse | Oostra, Ben A. | de Andrade, Mariza | Turner, Stephen T. | Ding, Jingzhong | Andrews, Jeanette S. | Freedman, Barry I. | Koenig, Wolfgang | Illig, Thomas | Döring, Angela | Wichmann, H.-Erich | Kolcic, Ivana | Zemunik, Tatijana | Boban, Mladen | Minelli, Cosetta | Wheeler, Heather E. | Igl, Wilmar | Zaboli, Ghazal | Wild, Sarah H. | Wright, Alan F. | Campbell, Harry | Ellinghaus, David | Nöthlings, Ute | Jacobs, Gunnar | Biffar, Reiner | Endlich, Karlhans | Ernst, Florian | Homuth, Georg | Kroemer, Heyo K. | Nauck, Matthias | Stracke, Sylvia | Völker, Uwe | Völzke, Henry | Kovacs, Peter | Stumvoll, Michael | Mägi, Reedik | Hofman, Albert | Uitterlinden, Andre G. | Rivadeneira, Fernando | Aulchenko, Yurii S. | Polasek, Ozren | Hastie, Nick | Vitart, Veronique | Helmer, Catherine | Wang, Jie Jin | Ruggiero, Daniela | Bergmann, Sven | Kähönen, Mika | Viikari, Jorma | Nikopensius, Tiit | Province, Michael | Ketkar, Shamika | Colhoun, Helen | Doney, Alex | Robino, Antonietta | Giulianini, Franco | Krämer, Bernhard K. | Portas, Laura | Ford, Ian | Buckley, Brendan M. | Adam, Martin | Thun, Gian-Andri | Paulweber, Bernhard | Haun, Margot | Sala, Cinzia | Metzger, Marie | Mitchell, Paul | Ciullo, Marina | Kim, Stuart K. | Vollenweider, Peter | Raitakari, Olli | Metspalu, Andres | Palmer, Colin | Gasparini, Paolo | Pirastu, Mario | Jukema, J. Wouter | Probst-Hensch, Nicole M. | Kronenberg, Florian | Toniolo, Daniela | Gudnason, Vilmundur | Shuldiner, Alan R. | Coresh, Josef | Schmidt, Reinhold | Ferrucci, Luigi | Siscovick, David S. | van Duijn, Cornelia M. | Borecki, Ingrid | Kardia, Sharon L. R. | Liu, Yongmei | Curhan, Gary C. | Rudan, Igor | Gyllensten, Ulf | Wilson, James F. | Franke, Andre | Pramstaller, Peter P. | Rettig, Rainer | Prokopenko, Inga | Witteman, Jacqueline C. M. | Hayward, Caroline | Ridker, Paul | Parsa, Afshin | Bochud, Murielle | Heid, Iris M. | Goessling, Wolfram | Chasman, Daniel I. | Kao, W. H. Linda | Fox, Caroline S. | Gibson, Greg
PLoS Genetics  2012;8(3):e1002584.
Chronic kidney disease (CKD) is an important public health problem with a genetic component. We performed genome-wide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR), the primary clinical measure of CKD, in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. Morpholino knockdown of mpped2 and casp9 in zebrafish embryos revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. By providing new insights into genes that regulate renal function, these results could further our understanding of the pathogenesis of CKD.
Author Summary
Chronic kidney disease (CKD) is an important public health problem with a hereditary component. We performed a new genome-wide association study in up to 130,600 European ancestry individuals to identify genes that may influence kidney function, specifically genes that may influence kidney function differently depending on sex, age, hypertension, and diabetes status of individuals. We uncovered 6 new loci associated with estimated glomerular filtration rate (eGFR), the primary measure of renal function, in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. CDK12 effect was stronger in younger and absent in older individuals. MPPED2, DDX1, SLC47A1, and CDK12 loci were associated with eGFR in African ancestry samples as well, highlighting the cross-ethnicity validity of our findings. Using the zebrafish model, we performed morpholino knockdown of mpped2 and casp9 in zebrafish embryos and revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. These results further our understanding of the pathogenesis of CKD and provide insights into potential novel mechanisms of disease.
PMCID: PMC3315455  PMID: 22479191
18.  Race differences in access to health care and disparities in incident chronic kidney disease in the US 
Background. The contribution of race differences in access to health care to disparities in chronic kidney disease (CKD) incidence in the United States is unknown.
Methods. We examined race differences in usual source of health care, health insurance and CKD incidence among 3883 Whites and 1607 Blacks with hypertension or diabetes enrolled in the Atherosclerosis Risk in Communities Study. In multivariable analyses, we explored the incremental contribution of access to health care in explaining Blacks’ excess CKD incidence above and beyond other socioeconomic, lifestyle and clinical factors.
Results. Compared with Whites, Blacks had poorer access to health care (3 vs 0.3% with no usual source of health care or health insurance, P < 0.001) and experienced greater CKD incidence (14.7 vs 12.0 cases per 1000 person-years, P < 0.001). Blacks’ excess risk of CKD persisted after adjusting for demographic, socioeconomic, lifestyle and clinical factors [hazard ratio (HR) (95% confidence interval (95% CI)) = 1.21 (1.01–1.47)]. Adjustment for these factors explained 64% of the excess risk among Blacks. The increased risk for CKD among Blacks was attenuated after additional adjustment for race differences in access to health care [HR (95% CI) = 1.19 (0.99–1.45)], which explained an additional 10% of the disparity.
Conclusions. In this population at risk for developing CKD, we found that poorer access to health care among Blacks explained some of Blacks’ excess risk of CKD, beyond the excess risk explained by demographic, socioeconomic, lifestyle and clinical factors. Improved access to health care for high-risk individuals could narrow disparities in CKD incidence.
PMCID: PMC3108345  PMID: 20688771
access to health care; chronic kidney disease; disparities
19.  Reliability and Sensitivity of the Self-report of Physician-diagnosed Gout in the Campaign Against Cancer and Heart Disease and the Atherosclerosis Risk in the Community Cohorts 
The Journal of Rheumatology  2010;38(1):135-141.
Gout is often defined by self-report in epidemiologic studies. Yet the validity of self-reported gout is uncertain. We evaluated the reliability and sensitivity of the self-report of physician-diagnosed gout in the Campaign Against Cancer and Heart Disease (CLUE II) and the Atherosclerosis Risk in the Community (ARIC) cohorts.
The CLUE II cohort comprises 12,912 individuals who self-reported gout status on either the 2000, 2003, or 2007 questionnaires. We calculated reliability as the percentage of participants reporting having gout on more than 1 questionnaire using Cohen’s κ statistic. The ARIC cohort comprises 11,506 individuals who self-reported gout status at visit 4. We considered a hospital discharge diagnosis of gout or use of a gout-specific medication as the standard against which to calculate the sensitivity of self-reported, physician-diagnosed gout.
Of the 437 CLUE II participants who self-reported physician-diagnosed gout in 2000, and subsequently answered the 2003 questionnaire, 75% reported gout in 2003 (κ = 0.73). Of the 271 participants who reported gout in 2000, 73% again reported gout at the 2007 followup questionnaire (κ = 0.63). In ARIC, 196 participants met the definition for gout prior to visit 4 and self-reported their gout status at visit 4. The sensitivity of a self-report of physician-diagnosed gout was 84%. Accuracy was similar across sex and race subgroups, but differed across hyperuricemia and education strata.
These 2 population-based US cohorts suggest that self-report of physician-diagnosed gout has good reliability and sensitivity. Thus, self-report of a physician diagnosis of gout is appropriate for epidemiologic studies.
PMCID: PMC3285109  PMID: 21123328
20.  Common variants in the calcium-sensing receptor gene are associated with total serum calcium levels 
Human Molecular Genetics  2010;19(21):4296-4303.
Serum calcium levels are tightly regulated. We performed genome-wide association studies (GWAS) in population-based studies participating in the CHARGE Consortium to uncover common genetic variations associated with total serum calcium levels. GWAS of serum calcium concentrations was performed in 20 611 individuals of European ancestry for ∼2.5 million genotyped and imputed single-nucleotide polymorphisms (SNPs). The SNP with the lowest P-value was rs17251221 (P = 2.4 * 10−22, minor allele frequency 14%) in the calcium-sensing receptor gene (CASR). This lead SNP was associated with higher serum calcium levels [0.06 mg/dl (0.015 mmol/l) per copy of the minor G allele] and accounted for 0.54% of the variance in serum calcium concentrations. The identification of variation in CASR that influences serum calcium concentration confirms the results of earlier candidate gene studies. The G allele of rs17251221 was also associated with higher serum magnesium levels (P = 1.2 * 10−3), lower serum phosphate levels (P = 2.8 * 10−7) and lower bone mineral density at the lumbar spine (P = 0.038), but not the femoral neck. No additional genomic loci contained SNPs associated at genome-wide significance (P < 5 * 10−8). These associations resemble clinical characteristics of patients with familial hypocalciuric hypercalcemia, an autosomal-dominant disease arising from rare inactivating mutations in the CASR gene. We conclude that common genetic variation in the CASR gene is associated with similar but milder features in the general population.
PMCID: PMC2951868  PMID: 20705733
21.  Impact of repeated measures and sample selection on genome-wide association studies of fasting glucose 
Genetic epidemiology  2010;34(7):665-673.
Although GWAS have been performed in longitudinal studies, most used only a single trait measure. GWAS of fasting glucose have generally included only normoglycemic individuals. We examined the impact of both repeated measures and sample selection on GWAS in ARIC, a study which obtained four longitudinal measures of fasting glucose and included both individuals with and without prevalent diabetes. The sample included Caucasians and the Affymetrix 6.0 chip was used for genotyping. Sample sizes for GWAS analyses ranged from 8372 (first study visit) to 5782 (average fasting glucose). Candidate SNP analyses with SNPs identified through fasting glucose or diabetes GWAS were conducted in 9133 individuals, including 761 with prevalent diabetes. For a constant sample size, smaller p-values were obtained for the average measure of fasting glucose compared to values at any single visit, and two additional significant GWAS signals were detected. For four candidate SNPs (rs780094, rs10830963, rs7903146, and rs4607517), the strength of association between genotype and glucose was significantly (p-interaction < .05) different in those with and without prevalent diabetes and for all five fasting glucose candidate SNPs (rs780094, rs10830963, rs560887, rs4607517, rs13266634) the association with measured fasting glucose was more significant in the smaller sample without prevalent diabetes than in the larger combined sample of those with and without diabetes. This analysis demonstrates the potential utility of averaging trait values in GWAS studies and explores the advantage of using only individuals without prevalent diabetes in GWAS of fasting glucose.
PMCID: PMC2964401  PMID: 20839289
GWAS; fasting glucose; type 2 diabetes; sample selection
22.  Correlates of kidney stone disease differ by race in a multi-ethnic middle aged population: The ARIC Study 
Preventive medicine  2010;51(5):416-420.
To identify correlates of kidney stone disease in white and African American men and women in a population-based longitudinal study starting in four US communities, and to assess differences in correlates across racial groups.
12,161 middle-aged participants of the ARIC Study provided information on history of kidney stone disease between 1993–1995. Information on incident kidney stone-related hospitalizations was obtained from ICD-codes on hospital discharge records.
Kidney stone disease was reported by 12.0% of men and 4.8% of women. After multivariable adjustment, prevalent kidney stone disease was significantly (p<0.05) associated with male gender (PR=2.50), increased serum triglycerides (PR=1.07 per SD increase), diabetes (PR=1.27), gallstone disease (PR=1.54), white race (PR= 1.67), and region of residence. Male gender (HR=1.70), diabetes (HR=1.98) and hypertension (HR=1.69) were significantly associated (p<0.05) with incident kidney stone-related hospitalizations (n=94). Race-stratified analyses showed stronger associations of prevalent kidney stone disease with increased triglycerides, older age, and gallstone disease in African Americans compared to whites, whereas male gender showed stronger association in whites (all p-interaction<0.05).
We identified novel correlates of kidney stone disease (triglycerides, gallstone disease) and risk factor interactions by race (age, male gender, triglycerides, gallstone disease).
PMCID: PMC2964449  PMID: 20801154
Kidney stones; risk factors; epidemiology
23.  Association of eGFR-Related Loci Identified by GWAS with Incident CKD and ESRD 
PLoS Genetics  2011;7(9):e1002292.
Family studies suggest a genetic component to the etiology of chronic kidney disease (CKD) and end stage renal disease (ESRD). Previously, we identified 16 loci for eGFR in genome-wide association studies, but the associations of these single nucleotide polymorphisms (SNPs) for incident CKD or ESRD are unknown. We thus investigated the association of these loci with incident CKD in 26,308 individuals of European ancestry free of CKD at baseline drawn from eight population-based cohorts followed for a median of 7.2 years (including 2,122 incident CKD cases defined as eGFR <60ml/min/1.73m2 at follow-up) and with ESRD in four case-control studies in subjects of European ancestry (3,775 cases, 4,577 controls). SNPs at 11 of the 16 loci (UMOD, PRKAG2, ANXA9, DAB2, SHROOM3, DACH1, STC1, SLC34A1, ALMS1/NAT8, UBE2Q2, and GCKR) were associated with incident CKD; p-values ranged from p = 4.1e-9 in UMOD to p = 0.03 in GCKR. After adjusting for baseline eGFR, six of these loci remained significantly associated with incident CKD (UMOD, PRKAG2, ANXA9, DAB2, DACH1, and STC1). SNPs in UMOD (OR = 0.92, p = 0.04) and GCKR (OR = 0.93, p = 0.03) were nominally associated with ESRD. In summary, the majority of eGFR-related loci are either associated or show a strong trend towards association with incident CKD, but have modest associations with ESRD in individuals of European descent. Additional work is required to characterize the association of genetic determinants of CKD and ESRD at different stages of disease progression.
Author Summary
Chronic kidney disease (CKD) affects about 6%–11% of the general population, and progression to end stage renal disease (ESRD) has a significant public health impact. Family studies suggest that the risk for CKD and ESRD is heritable. Unraveling the genetic underpinning of risk for these diseases may lead to the identification of novel mechanisms and thus diagnostic and therapeutic tools. We have previously identified 16 genetic markers in association with kidney function and prevalent CKD in general population studies. However, little is known about the relevance of these SNPs to the initial development of CKD or to ESRD risk. Therefore, we have now analyzed the association of these markers with the initiation of CKD in more than 26,000 individuals from the general population using serial estimations of kidney function, and with ESRD in four case-control studies in subjects of European ancestry (3,775 cases, 4,577 controls). We show that many of the 16 markers are also associated or show a strong trend towards association with initiation of CKD, while only 2 markers are nominally associated with ESRD. Further work is required to characterize the association of genetic determinants of different stages of CKD progression.
PMCID: PMC3183079  PMID: 21980298
24.  Prevalence of kidney disease in anaemia differs by GFR-estimating method: The Third National Health and Nutrition Examination Survey (1988–94) 
Nephrology Dialysis Transplantation  2010;25(8):2542-2548.
Background. Anaemia worsens as kidney function declines. Both conditions are associated with increased mortality. Serum cystatin C is purportedly a more sensitive marker of kidney disease and a better predictor of mortality than serum creatinine. However, studies suggest that extrarenal factors also influence cystatin C levels.
Methods. We determined whether estimates of glomerular filtration rate [estimated glomerular filtration rate (eGFR)] based on serum cystatin C alone or in combination with serum creatinine were superior to those based on serum creatinine in recognizing impaired kidney function in the setting of anaemia in a sub-sample of the Third National Health and Nutrition Examination Survey of the USA consisting of 6734 participants, 20 years or older.
Results. The prevalence of moderate to severe kidney disease (eGFR 15–59 mL/min/1.73 m2) among anaemic persons was 15–16% when based on serum creatinine alone (eGFRSCR) or combined with cystatin C (eGFRSCR + CYSC); this estimate increased to nearly 25% when kidney function was estimated by cystatin C (eGFRCYSC). The adjusted odds ratios of kidney disease in anaemic versus non-anaemic persons were slightly higher with eGFRCYSC than eGFRSCR and eGFRSCR + CYSC in younger adults [odds ratio (OR) = 5.22, 95% confidence interval (CI): 2.23, 12.17], women (OR = 5.34, 95% CI: 2.36, 12.06) and those with elevated C-reactive protein (CRP) (OR = 7.36, 95% CI: 1.98–27.36).
Conclusions. Impaired kidney function was common in individuals with anaemia. Among anaemic individuals, the prevalence estimate for kidney disease was notably higher when kidney function was estimated by cystatin C alone compared with the estimations by serum creatinine alone or in combination with serum cystatin C. eGFRCYSC may be particularly helpful in identifying kidney disease in the setting of anaemia among younger persons, women and those with elevated CRP. Regardless of which renal biomarker is used, our study suggests that an evaluation for underlying kidney disease should be considered in the standard workup of anaemia.
PMCID: PMC2910334  PMID: 20176612
anaemia; chronic kidney failure; creatinine; cystatin C; glomerular filtration rate
25.  Identification of a Sudden Cardiac Death Susceptibility Locus at 2q24.2 through Genome-Wide Association in European Ancestry Individuals 
PLoS Genetics  2011;7(6):e1002158.
Sudden cardiac death (SCD) continues to be one of the leading causes of mortality worldwide, with an annual incidence estimated at 250,000–300,000 in the United States and with the vast majority occurring in the setting of coronary disease. We performed a genome-wide association meta-analysis in 1,283 SCD cases and >20,000 control individuals of European ancestry from 5 studies, with follow-up genotyping in up to 3,119 SCD cases and 11,146 controls from 11 European ancestry studies, and identify the BAZ2B locus as associated with SCD (P = 1.8×10−10). The risk allele, while ancestral, has a frequency of ∼1.4%, suggesting strong negative selection and increases risk for SCD by 1.92–fold per allele (95% CI 1.57–2.34). We also tested the role of 49 SNPs previously implicated in modulating electrocardiographic traits (QRS, QT, and RR intervals). Consistent with epidemiological studies showing increased risk of SCD with prolonged QRS/QT intervals, the interval-prolonging alleles are in aggregate associated with increased risk for SCD (P = 0.006).
Author Summary
Family studies have clearly demonstrated a role for genes in modifying risk for sudden cardiac death (SCD), however genetic studies have been limited by available samples. Here we have assembled over 4,400 SCD cases with >30,000 controls, all of European ancestry, and utilize a two-stage study design. In the first stage, we conducted an unbiased genome-wide scan in 1,283 SCD cases and >20,000 controls, and then performed follow-up genotyping in the remainder of the samples. We demonstrate strong association to a region of the genome not previously implicated in SCD, the BAZ2B locus, which contains 3 genes not previously known to play a role in cardiac biology. In addition, we used the genome-wide scan data to test a focused hypothesis that genetic variants that modulate ECG traits associated with SCD (QT, QRS, and RR intervals) also modify risk for SCD, and we demonstrate that QT- and QRS-prolonging alleles are, as a group, associated with increased risk of SCD. Taken together, these findings begin to elucidate the genetic contribution to SCD susceptibility and provide important targets for functional studies to investigate the etiology and pathogenesis of SCD.
PMCID: PMC3128111  PMID: 21738491

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