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1.  Gene-centric Association Mapping of Chromosome 3p implicates MST1 in IBD pathogenesis 
Mucosal immunology  2008;1(2):131-138.
Association mapping and candidate gene studies within IBD linkage regions, as well as genome-wide association studies in CD have led to the discovery of multiple risk genes, but these only explain a fraction of the genetic susceptibility observed in IBD. We have thus been pursuing a region on chromosome 3p21-22 showing linkage to CD and UC using a gene-centric association mapping approach. We identified twelve functional candidate genes by searching for literature co-citations with relevant keywords and for gene expression patterns consistent with immune/intestinal function. We then performed an association study composed of a screening phase, where tagging SNPs were evaluated in 1020 IBD patients, and an independent replication phase in 745 IBD patients. These analyses identified and replicated significant association to IBD for four SNPs within a 1.2 Mb LD region. We then identified a non-synonymous coding variant (rs3197999, R689C) in the macrophage stimulating 1 (MST1) gene (p-value 3.62×10−6) that accounts for the association signal, and shows association to both CD and UC. MST1 encodes MSP, a protein regulating the innate immune responses to bacterial ligands. R689C is predicted to interfere with MSP binding to its receptor, suggesting a role for this gene in the pathogenesis of IBD.
PMCID: PMC4550306  PMID: 19079170
2.  Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility 
Wessel, Jennifer | Chu, Audrey Y. | Willems, Sara M. | Wang, Shuai | Yaghootkar, Hanieh | Brody, Jennifer A. | Dauriz, Marco | Hivert, Marie-France | Raghavan, Sridharan | Lipovich, Leonard | Hidalgo, Bertha | Fox, Keolu | Huffman, Jennifer E. | An, Ping | Lu, Yingchang | Rasmussen-Torvik, Laura J. | Grarup, Niels | Ehm, Margaret G. | Li, Li | Baldridge, Abigail S. | Stančáková, Alena | Abrol, Ravinder | Besse, Céline | Boland, Anne | Bork-Jensen, Jette | Fornage, Myriam | Freitag, Daniel F. | Garcia, Melissa E. | Guo, Xiuqing | Hara, Kazuo | Isaacs, Aaron | Jakobsdottir, Johanna | Lange, Leslie A. | Layton, Jill C. | Li, Man | Zhao, Jing Hua | Meidtner, Karina | Morrison, Alanna C. | Nalls, Mike A. | Peters, Marjolein J. | Sabater-Lleal, Maria | Schurmann, Claudia | Silveira, Angela | Smith, Albert V. | Southam, Lorraine | Stoiber, Marcus H. | Strawbridge, Rona J. | Taylor, Kent D. | Varga, Tibor V. | Allin, Kristine H. | Amin, Najaf | Aponte, Jennifer L. | Aung, Tin | Barbieri, Caterina | Bihlmeyer, Nathan A. | Boehnke, Michael | Bombieri, Cristina | Bowden, Donald W. | Burns, Sean M. | Chen, Yuning | Chen, Yii-Der I. | Cheng, Ching-Yu | Correa, Adolfo | Czajkowski, Jacek | Dehghan, Abbas | Ehret, Georg B. | Eiriksdottir, Gudny | Escher, Stefan A. | Farmaki, Aliki-Eleni | Frånberg, Mattias | Gambaro, Giovanni | Giulianini, Franco | III, William A. Goddard | Goel, Anuj | Gottesman, Omri | Grove, Megan L. | Gustafsson, Stefan | Hai, Yang | Hallmans, Göran | Heo, Jiyoung | Hoffmann, Per | Ikram, Mohammad K. | Jensen, Richard A. | Jørgensen, Marit E. | Jørgensen, Torben | Karaleftheri, Maria | Khor, Chiea C. | Kirkpatrick, Andrea | Kraja, Aldi T. | Kuusisto, Johanna | Lange, Ethan M. | Lee, I.T. | Lee, Wen-Jane | Leong, Aaron | Liao, Jiemin | Liu, Chunyu | Liu, Yongmei | Lindgren, Cecilia M. | Linneberg, Allan | Malerba, Giovanni | Mamakou, Vasiliki | Marouli, Eirini | Maruthur, Nisa M. | Matchan, Angela | McKean, Roberta | McLeod, Olga | Metcalf, Ginger A. | Mohlke, Karen L. | Muzny, Donna M. | Ntalla, Ioanna | Palmer, Nicholette D. | Pasko, Dorota | Peter, Andreas | Rayner, Nigel W. | Renström, Frida | Rice, Ken | Sala, Cinzia F. | Sennblad, Bengt | Serafetinidis, Ioannis | Smith, Jennifer A. | Soranzo, Nicole | Speliotes, Elizabeth K. | Stahl, Eli A. | Stirrups, Kathleen | Tentolouris, Nikos | Thanopoulou, Anastasia | Torres, Mina | Traglia, Michela | Tsafantakis, Emmanouil | Javad, Sundas | Yanek, Lisa R. | Zengini, Eleni | Becker, Diane M. | Bis, Joshua C. | Brown, James B. | Cupples, L. Adrienne | Hansen, Torben | Ingelsson, Erik | Karter, Andrew J. | Lorenzo, Carlos | Mathias, Rasika A. | Norris, Jill M. | Peloso, Gina M. | Sheu, Wayne H.-H. | Toniolo, Daniela | Vaidya, Dhananjay | Varma, Rohit | Wagenknecht, Lynne E. | Boeing, Heiner | Bottinger, Erwin P. | Dedoussis, George | Deloukas, Panos | Ferrannini, Ele | Franco, Oscar H. | Franks, Paul W. | Gibbs, Richard A. | Gudnason, Vilmundur | Hamsten, Anders | Harris, Tamara B. | Hattersley, Andrew T. | Hayward, Caroline | Hofman, Albert | Jansson, Jan-Håkan | Langenberg, Claudia | Launer, Lenore J. | Levy, Daniel | Oostra, Ben A. | O'Donnell, Christopher J. | O'Rahilly, Stephen | Padmanabhan, Sandosh | Pankow, James S. | Polasek, Ozren | Province, Michael A. | Rich, Stephen S. | Ridker, Paul M | Rudan, Igor | Schulze, Matthias B. | Smith, Blair H. | Uitterlinden, André G. | Walker, Mark | Watkins, Hugh | Wong, Tien Y. | Zeggini, Eleftheria | Scotland, Generation | Laakso, Markku | Borecki, Ingrid B. | Chasman, Daniel I. | Pedersen, Oluf | Psaty, Bruce M. | Tai, E. Shyong | van Duijn, Cornelia M. | Wareham, Nicholas J. | Waterworth, Dawn M. | Boerwinkle, Eric | Kao, WH Linda | Florez, Jose C. | Loos, Ruth J.F. | Wilson, James G. | Frayling, Timothy M. | Siscovick, David S. | Dupuis, Josée | Rotter, Jerome I. | Meigs, James B. | Scott, Robert A. | Goodarzi, Mark O.
Nature communications  2015;6:5897.
Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF=1.4%) with lower FG (β=-0.09±0.01 mmol L−1, p=3.4×10−12), T2D risk (OR[95%CI]=0.86[0.76-0.96], p=0.010), early insulin secretion (β=-0.07±0.035 pmolinsulin mmolglucose−1, p=0.048), but higher 2-h glucose (β=0.16±0.05 mmol L−1, p=4.3×10−4). We identify a gene-based association with FG at G6PC2 (pSKAT=6.8×10−6) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF=20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (β=0.02±0.004 mmol L−1, p=1.3×10−8). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.
PMCID: PMC4311266  PMID: 25631608
3.  A novel method for testing association of multiple genetic markers with a multinomial trait 
We developed a multinomial probit model with singular value decomposition for testing a large number of single nucleotide polymorphisms (SNPs) simultaneously, using maximum likelihood estimation and permutation. The method was validated by simulation. We simulated 1000 SNPs, including 9 associated with disease states, and 8 of the 9 were successfully identified. Applying the method to study 32 genes in our Mexican-American samples for association with prediabetes through either impaired glucose tolerance (IGT) or impaired fasting glucose (IFG), we found 3 genes (SORCS1, AMPD1, PPAR) associated with both IGT and IFG, while 5 genes (AMPD2, PRKAA2, C5, TCF7L2, ITR) with the IGT mechanism only and 6 genes (CAPN10, IL4,NOS3, CD14, GCG, SORT1) with the IFG mechanism only. These data suggest that IGT and IFG may indicate different physiological mechanism to prediabetes, via different genetic determinants.
PMCID: PMC4439253  PMID: 26005397
4.  Genome-Wide Association Study for Circulating Tissue Plasminogen Activator (tPA) Levels and Functional Follow-up Implicates Endothelial STXBP5 and STX2 
Huang, Jie | Huffman, Jennifer E. | Yamkauchi, Munekazu | Trompet, Stella | Asselbergs, Folkert W. | Sabater-Lleal, Maria | Trégouët, David-Alexandre | Chen, Wei-Min | Smith, Nicholas L. | Kleber, Marcus E. | Shin, So-Youn | Becker, Diane M. | Tang, Weihong | Dehghan, Abbas | Johnson, Andrew D. | Truong, Vinh | Folkersen, Lasse | Yang, Qiong | Oudot-Mellakh, Tiphaine | Buckley, Brendan M. | Moore, Jason H. | Williams, Frances M.K. | Campbell, Harry | Silbernagel, Günther | Vitart, Veronique | Rudan, Igor | Tofler, Geoffrey H. | Navis, Gerjan J. | DeStefano, Anita | Wright, Alan F. | Chen, Ming-Huei | de Craen, Anton J.M. | Worrall, Bradford B. | Rudnicka, Alicja R. | Rumley, Ann | Bookman, Ebony B. | Psaty, Bruce M. | Chen, Fang | Keene, Keith L. | Franco, Oscar H. | Böhm, Bernhard O. | Uitterlinden, Andre G. | Carter, Angela M. | Jukema, J. Wouter | Sattar, Naveed | Bis, Joshua C. | Ikram, Mohammad A. | Sale, Michèle M. | McKnight, Barbara | Fornage, Myriam | Ford, Ian | Taylor, Kent | Slagboom, P. Eline | McArdle, Wendy L. | Hsu, Fang-Chi | Franco-Cereceda, Anders | Goodall, Alison H. | Yanek, Lisa R. | Furie, Karen L. | Cushman, Mary | Hofman, Albert | Witteman, Jacqueline CM. | Folsom, Aaron R. | Basu, Saonli | Matijevic, Nena | van Gilst, Wiek H. | Wilson, James F. | Westendorp, Rudi G.J. | Kathiresan, Sekar | Reilly, Muredach P. | Tracy, Russell P. | Polasek, Ozren | Winkelmann, Bernhard R. | Grant, Peter J. | Hillege, Hans L. | Cambien, Francois | Stott, David J. | Lowe, Gordon D. | Spector, Timothy D. | Meigs, James B. | Marz, Winfried | Eriksson, Per | Becker, Lewis C. | Morange, Pierre-Emmanuel | Soranzo, Nicole | Williams, Scott M. | Hayward, Caroline | van der Harst, Pim | Hamsten, Anders | Lowenstein, Charles J. | Strachan, David P. | O'Donnell, Christopher J.
Tissue plasminogen activator (tPA), a serine protease, catalyzes the conversion of plasminogen to plasmin, the major enzyme responsible for endogenous fibrinolysis. In some populations, elevated plasma levels of tPA have been associated with myocardial infarction and other cardiovascular diseases (CVD). We conducted a meta-analysis of genome-wide association studies (GWAS) to identify novel correlates of circulating levels of tPA.
Approach and Results
Fourteen cohort studies with tPA measures (N=26,929) contributed to the meta-analysis. Three loci were significantly associated with circulating tPA levels (P <5.0×10−8). The first locus is on 6q24.3, with the lead SNP (rs9399599, P=2.9×10−14) within STXBP5. The second locus is on 8p11.21. The lead SNP (rs3136739, P=1.3×10−9) is intronic to POLB and less than 200kb away from the tPA encoding gene PLAT. We identified a non-synonymous SNP (rs2020921) in modest LD with rs3136739 (r2 = 0.50) within exon 5 of PLAT (P=2.0×10−8). The third locus is on 12q24.33, with the lead SNP (rs7301826, P=1.0×10−9) within intron 7 of STX2. We further found evidence for association of lead SNPs in STXBP5 and STX2 with expression levels of the respective transcripts. In in vitro cell studies, silencing STXBP5 decreased release of tPA from vascular endothelial cells, while silencing of STX2 increased tPA release. Through an in-silico lookup, we found no associations of the three lead SNPs with coronary artery disease or stroke.
We identified three loci associated with circulating tPA levels, the PLAT region, STXBP5 and STX2. Our functional studies implicate a novel role for STXBP5 and STX2 in regulating tPA release.
PMCID: PMC4009733  PMID: 24578379
tissue plasminogen activator; genome-wide association study; meta-analysis; cardiovascular disease risk; fibrinolysis; hemostasis
5.  A Genome-Wide Association Study Identifies IL23R as an Inflammatory Bowel Disease Gene 
Science (New York, N.Y.)  2006;314(5804):1461-1463.
The inflammatory bowel diseases Crohn's disease and ulcerative colitis are common, chronic disorders that cause abdominal pain, diarrhea, and gastrointestinal bleeding. To identify genetic factors that might contribute to these disorders, we performed a genome-wide association study. We found a highly significant association between Crohn's disease and the IL23R gene on chromosome 1p31, which encodes a subunit of the receptor for the proinflammatory cytokine interleukin-23. An uncommon coding variant (rs11209026, c.1142G>A, p.Arg381Gln) confers strong protection against Crohn's disease, and additional noncoding IL23R variants are independently associated. Replication studies confirmed IL23R associations in independent cohorts of patients with Crohn's disease or ulcerative colitis. These results and previous studies on the proinflammatory role of IL-23 prioritize this signaling pathway as a therapeutic target in inflammatory bowel disease.
PMCID: PMC4410764  PMID: 17068223
6.  Novel Genetic Markers Associate with Atrial Fibrillation Risk in Europeans and Japanese 
To identify non-redundant atrial fibrillation (AF) genetic susceptibility signals and examine their cumulative relations with AF risk.
AF-associated loci span broad genomic regions that may contain multiple susceptibility signals. Whether multiple signals exist at AF loci has not been systematically explored.
We performed association testing conditioned on the most significant, independently associated genetic markers at nine established AF loci using two complementary techniques in 64,683 individuals of European ancestry (3,869 incident and 3,302 prevalent AF cases). Genetic risk scores were created and tested for association with AF in Europeans and an independent sample of 11,309 individuals of Japanese ancestry (7,916 prevalent AF cases).
We observed at least four distinct AF susceptibility signals on chromosome 4q25 upstream of PITX2, but not at the remaining eight AF loci. A multilocus score comprised of 12 genetic markers demonstrated an estimated 5-fold gradient in AF risk. We observed a similar spectrum of risk associated with these markers in Japanese. Regions containing AF signals on chromosome 4q25 displayed a greater degree of evolutionary conservation than the remainder of the locus, suggesting that they may tag regulatory elements.
The chromosome 4q25 AF locus is architecturally complex and harbors at least four AF susceptibility signals in individuals of European ancestry. Similar polygenic AF susceptibility exists between Europeans and Japanese. Future work is necessary to identify causal variants, determine mechanisms by which associated loci predispose to AF, and explore whether AF susceptibility signals classify individuals at risk for AF and related morbidity.
PMCID: PMC4009240  PMID: 24486271
Atrial fibrillation; atrial flutter; genetic; risk; prognosis
7.  Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility 
Wessel, Jennifer | Chu, Audrey Y | Willems, Sara M | Wang, Shuai | Yaghootkar, Hanieh | Brody, Jennifer A | Dauriz, Marco | Hivert, Marie-France | Raghavan, Sridharan | Lipovich, Leonard | Hidalgo, Bertha | Fox, Keolu | Huffman, Jennifer E | An, Ping | Lu, Yingchang | Rasmussen-Torvik, Laura J | Grarup, Niels | Ehm, Margaret G | Li, Li | Baldridge, Abigail S | Stančáková, Alena | Abrol, Ravinder | Besse, Céline | Boland, Anne | Bork-Jensen, Jette | Fornage, Myriam | Freitag, Daniel F | Garcia, Melissa E | Guo, Xiuqing | Hara, Kazuo | Isaacs, Aaron | Jakobsdottir, Johanna | Lange, Leslie A | Layton, Jill C | Li, Man | Hua Zhao, Jing | Meidtner, Karina | Morrison, Alanna C | Nalls, Mike A | Peters, Marjolein J | Sabater-Lleal, Maria | Schurmann, Claudia | Silveira, Angela | Smith, Albert V | Southam, Lorraine | Stoiber, Marcus H | Strawbridge, Rona J | Taylor, Kent D | Varga, Tibor V | Allin, Kristine H | Amin, Najaf | Aponte, Jennifer L | Aung, Tin | Barbieri, Caterina | Bihlmeyer, Nathan A | Boehnke, Michael | Bombieri, Cristina | Bowden, Donald W | Burns, Sean M | Chen, Yuning | Chen, Yii-DerI | Cheng, Ching-Yu | Correa, Adolfo | Czajkowski, Jacek | Dehghan, Abbas | Ehret, Georg B | Eiriksdottir, Gudny | Escher, Stefan A | Farmaki, Aliki-Eleni | Frånberg, Mattias | Gambaro, Giovanni | Giulianini, Franco | Goddard, William A | Goel, Anuj | Gottesman, Omri | Grove, Megan L | Gustafsson, Stefan | Hai, Yang | Hallmans, Göran | Heo, Jiyoung | Hoffmann, Per | Ikram, Mohammad K | Jensen, Richard A | Jørgensen, Marit E | Jørgensen, Torben | Karaleftheri, Maria | Khor, Chiea C | Kirkpatrick, Andrea | Kraja, Aldi T | Kuusisto, Johanna | Lange, Ethan M | Lee, I T | Lee, Wen-Jane | Leong, Aaron | Liao, Jiemin | Liu, Chunyu | Liu, Yongmei | Lindgren, Cecilia M | Linneberg, Allan | Malerba, Giovanni | Mamakou, Vasiliki | Marouli, Eirini | Maruthur, Nisa M | Matchan, Angela | McKean-Cowdin, Roberta | McLeod, Olga | Metcalf, Ginger A | Mohlke, Karen L | Muzny, Donna M | Ntalla, Ioanna | Palmer, Nicholette D | Pasko, Dorota | Peter, Andreas | Rayner, Nigel W | Renström, Frida | Rice, Ken | Sala, Cinzia F | Sennblad, Bengt | Serafetinidis, Ioannis | Smith, Jennifer A | Soranzo, Nicole | Speliotes, Elizabeth K | Stahl, Eli A | Stirrups, Kathleen | Tentolouris, Nikos | Thanopoulou, Anastasia | Torres, Mina | Traglia, Michela | Tsafantakis, Emmanouil | Javad, Sundas | Yanek, Lisa R | Zengini, Eleni | Becker, Diane M | Bis, Joshua C | Brown, James B | Adrienne Cupples, L | Hansen, Torben | Ingelsson, Erik | Karter, Andrew J | Lorenzo, Carlos | Mathias, Rasika A | Norris, Jill M | Peloso, Gina M | Sheu, Wayne H.-H. | Toniolo, Daniela | Vaidya, Dhananjay | Varma, Rohit | Wagenknecht, Lynne E | Boeing, Heiner | Bottinger, Erwin P | Dedoussis, George | Deloukas, Panos | Ferrannini, Ele | Franco, Oscar H | Franks, Paul W | Gibbs, Richard A | Gudnason, Vilmundur | Hamsten, Anders | Harris, Tamara B | Hattersley, Andrew T | Hayward, Caroline | Hofman, Albert | Jansson, Jan-Håkan | Langenberg, Claudia | Launer, Lenore J | Levy, Daniel | Oostra, Ben A | O'Donnell, Christopher J | O'Rahilly, Stephen | Padmanabhan, Sandosh | Pankow, James S | Polasek, Ozren | Province, Michael A | Rich, Stephen S | Ridker, Paul M | Rudan, Igor | Schulze, Matthias B | Smith, Blair H | Uitterlinden, André G | Walker, Mark | Watkins, Hugh | Wong, Tien Y | Zeggini, Eleftheria | Laakso, Markku | Borecki, Ingrid B | Chasman, Daniel I | Pedersen, Oluf | Psaty, Bruce M | Shyong Tai, E | van Duijn, Cornelia M | Wareham, Nicholas J | Waterworth, Dawn M | Boerwinkle, Eric | Linda Kao, W H | Florez, Jose C | Loos, Ruth J.F. | Wilson, James G | Frayling, Timothy M | Siscovick, David S | Dupuis, Josée | Rotter, Jerome I | Meigs, James B | Scott, Robert A | Goodarzi, Mark O
Nature Communications  2015;6:5897.
Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF=1.4%) with lower FG (β=−0.09±0.01 mmol l−1, P=3.4 × 10−12), T2D risk (OR[95%CI]=0.86[0.76–0.96], P=0.010), early insulin secretion (β=−0.07±0.035 pmolinsulin mmolglucose−1, P=0.048), but higher 2-h glucose (β=0.16±0.05 mmol l−1, P=4.3 × 10−4). We identify a gene-based association with FG at G6PC2 (pSKAT=6.8 × 10−6) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF=20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (β=0.02±0.004 mmol l−1, P=1.3 × 10−8). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.
Both rare and common variants contribute to the aetiology of complex traits such as type 2 diabetes (T2D). Here, the authors examine the effect of coding variation on glycaemic traits and T2D, and identify low-frequency variation in GLP1R significantly associated with these traits.
PMCID: PMC4311266  PMID: 25631608
8.  Native American Ancestry Is Associated With Severe Diabetic Retinopathy in Latinos 
Diabetic retinopathy (DR) is a leading cause of blindness in working age adults. Studies have observed that Latinos have a higher prevalence of DR than whites. The purpose of this study is to test the association between genetic admixture and severe DR in Latinos with type 2 diabetes mellitus (T2DM).
We conducted a case–control study using 944 T2DM subjects from the Los Angeles Latino Eye Study. Cases (n = 135) were defined as proliferative or severe nonproliferative DR subjects. Controls (n = 809) were other diabetic subjects in the cohort. Genotyping was performed on the Illumina OmniExpress BeadChip. We estimated genetic ancestry in Latinos using STRUCTURE with the HapMap reference panels. Univariate and multivariate logistic regression analyses were used to test the relationship between the proportions of genetic ancestry and severe DR.
Native American ancestry (NAA) in Latino T2DM subjects is associated significantly with severe DR (P = 0.002). The association remained significant (P = 0.005) after adjusting for age, sex, duration of diabetes, hemoglobin A1c, body mass index, systolic blood pressure, education, and income. We also validated the NAA estimates in Latinos using ADMIXTURE with the 1000 Genomes Project reference panels and obtained consistent results.
Our results demonstrate for the first time to our knowledge that NAA is a significant risk factor for severe DR in Latinos.
Our results demonstrate for the first time to our knowledge that Native American ancestry is a significant risk factor for severe diabetic retinopathy in Latinos. Therefore, genetic ancestry should be included in the risk assessment of severe diabetic retinopathy in research studies of Latinos with type 2 diabetes mellitus.
PMCID: PMC4176415  PMID: 25146985
diabetic retinopathy; Latinos; genetic ancestry; Native American
9.  Genetic Variants Synthesize to Produce Paneth Cell Phenotypes that Define Subtypes of Crohn’s Disease 
Gastroenterology  2013;146(1):200-209.
Background & Aims
Genetic susceptibility loci for Crohn’s disease (CD) are numerous, complex, and likely interact with undefined components of the environment. It has been a challenge to link the effects of particular loci to phenotypes of cells associated with pathogenesis of CD, such as Paneth cells. We investigated whether specific phenotypes of Paneth cells associated with particular genetic susceptibility loci can be used to define specific subtypes of CD.
We performed a retrospective analysis of 119 resection specimens collected from patients with CD at 2 separate medical centers. Paneth cell phenotypes were classified as normal or abnormal (with disordered, diminished, diffuse, or excluded granule phenotypes) based on lysozyme-positive secretory granule morphology. To uncover the molecular basis of the Paneth cell phenotypes, we developed methods to determine transcriptional profiles from whole-thickness and laser-capture microdissected, formalin-fixed, paraffin-embedded tissue sections.
The proportion of abnormal Paneth cells was associated with the number of CD-associated NOD2 risk alleles. The cumulative number of NOD2 and ATG16L1 risk alleles had an additive effect on the proportion of abnormal Paneth cells. Unsupervised clustering analysis of demographic and Paneth cell data divided patients into 2 principal subgroups, defined by high and low proportions of abnormal Paneth cells. The disordered and diffuse abnormal Paneth cell phenotypes were associated with an altered transcriptional signature of immune system activation. We observed an inverse correlation between abnormal Paneth cells and the presence of granuloma. Moreover, high proportions of abnormal Paneth cells were associated with shorter time to disease recurrence after surgery.
Histologic analysis of Paneth cell phenotypes can be used to divide patients with CD into subgroups with distinct pathognomonic and clinical features.
PMCID: PMC3899786  PMID: 24076061
pathogenesis; prognostic factor; diagnosis; inflammatory bowel disease
10.  No Evidence for Genome-Wide Interactions on Plasma Fibrinogen by Smoking, Alcohol Consumption and Body Mass Index: Results from Meta-Analyses of 80,607 Subjects 
Baumert, Jens | Huang, Jie | McKnight, Barbara | Sabater-Lleal, Maria | Steri, Maristella | Chu, Audrey Y. | Trompet, Stella | Lopez, Lorna M. | Fornage, Myriam | Teumer, Alexander | Tang, Weihong | Rudnicka, Alicja R. | Mälarstig, Anders | Hottenga, Jouke-Jan | Kavousi, Maryam | Lahti, Jari | Tanaka, Toshiko | Hayward, Caroline | Huffman, Jennifer E. | Morange, Pierre-Emmanuel | Rose, Lynda M. | Basu, Saonli | Rumley, Ann | Stott, David J. | Buckley, Brendan M. | de Craen, Anton J. M. | Sanna, Serena | Masala, Marco | Biffar, Reiner | Homuth, Georg | Silveira, Angela | Sennblad, Bengt | Goel, Anuj | Watkins, Hugh | Müller-Nurasyid, Martina | Rückerl, Regina | Taylor, Kent | Chen, Ming-Huei | de Geus, Eco J. C. | Hofman, Albert | Witteman, Jacqueline C. M. | de Maat, Moniek P. M. | Palotie, Aarno | Davies, Gail | Siscovick, David S. | Kolcic, Ivana | Wild, Sarah H. | Song, Jaejoon | McArdle, Wendy L. | Ford, Ian | Sattar, Naveed | Schlessinger, David | Grotevendt, Anne | Franzosi, Maria Grazia | Illig, Thomas | Waldenberger, Melanie | Lumley, Thomas | Tofler, Geoffrey H. | Willemsen, Gonneke | Uitterlinden, André G. | Rivadeneira, Fernando | Räikkönen, Katri | Chasman, Daniel I. | Folsom, Aaron R. | Lowe, Gordon D. | Westendorp, Rudi G. J. | Slagboom, P. Eline | Cucca, Francesco | Wallaschofski, Henri | Strawbridge, Rona J. | Seedorf, Udo | Koenig, Wolfgang | Bis, Joshua C. | Mukamal, Kenneth J. | van Dongen, Jenny | Widen, Elisabeth | Franco, Oscar H. | Starr, John M. | Liu, Kiang | Ferrucci, Luigi | Polasek, Ozren | Wilson, James F. | Oudot-Mellakh, Tiphaine | Campbell, Harry | Navarro, Pau | Bandinelli, Stefania | Eriksson, Johan | Boomsma, Dorret I. | Dehghan, Abbas | Clarke, Robert | Hamsten, Anders | Boerwinkle, Eric | Jukema, J. Wouter | Naitza, Silvia | Ridker, Paul M. | Völzke, Henry | Deary, Ian J. | Reiner, Alexander P. | Trégouët, David-Alexandre | O'Donnell, Christopher J. | Strachan, David P. | Peters, Annette | Smith, Nicholas L.
PLoS ONE  2014;9(12):e111156.
Plasma fibrinogen is an acute phase protein playing an important role in the blood coagulation cascade having strong associations with smoking, alcohol consumption and body mass index (BMI). Genome-wide association studies (GWAS) have identified a variety of gene regions associated with elevated plasma fibrinogen concentrations. However, little is yet known about how associations between environmental factors and fibrinogen might be modified by genetic variation. Therefore, we conducted large-scale meta-analyses of genome-wide interaction studies to identify possible interactions of genetic variants and smoking status, alcohol consumption or BMI on fibrinogen concentration. The present study included 80,607 subjects of European ancestry from 22 studies. Genome-wide interaction analyses were performed separately in each study for about 2.6 million single nucleotide polymorphisms (SNPs) across the 22 autosomal chromosomes. For each SNP and risk factor, we performed a linear regression under an additive genetic model including an interaction term between SNP and risk factor. Interaction estimates were meta-analysed using a fixed-effects model. No genome-wide significant interaction with smoking status, alcohol consumption or BMI was observed in the meta-analyses. The most suggestive interaction was found for smoking and rs10519203, located in the LOC123688 region on chromosome 15, with a p value of 6.2×10−8. This large genome-wide interaction study including 80,607 participants found no strong evidence of interaction between genetic variants and smoking status, alcohol consumption or BMI on fibrinogen concentrations. Further studies are needed to yield deeper insight in the interplay between environmental factors and gene variants on the regulation of fibrinogen concentrations.
PMCID: PMC4281156  PMID: 25551457
11.  Large‐Scale Gene‐Centric Analysis Identifies Polymorphisms for Resistant Hypertension 
Resistant hypertension (RHTN), defined by lack of blood pressure (BP) control despite treatment with at least 3 antihypertensive drugs, increases cardiovascular risk compared with controlled hypertension. Yet, there are few data on genetic variants associated with RHTN.
Methods and Results
We used a gene‐centric array containing ≈50 000 single‐nucleotide polymorphisms (SNPs) to identify polymorphisms associated with RHTN in hypertensive participants with coronary artery disease (CAD) from INVEST‐GENES (the INnternational VErapamil‐SR Trandolapril STudy—GENEtic Substudy). RHTN was defined as BP≥140/90 on 3 drugs, or any BP on 4 or more drugs. Logistic regression analysis was performed in European Americans (n=904) and Hispanics (n=837), using an additive model adjusted for age, gender, randomized treatment assignment, body mass index, principal components for ancestry, and other significant predictors of RHTN. Replication of the top SNP was conducted in 241 European American women from WISE (Women's Ischemia Syndrome Evaluation), where RHTN was defined similarly. To investigate the functional effect of rs12817819, mRNA expression was measured in whole blood. We found ATP2B1 rs12817819 associated with RHTN in both INVEST European Americans (P‐value=2.44×10−3, odds ratio=1.57 [1.17 to 2.01]) and INVEST Hispanics (P=7.69×10−4, odds ratio=1.76 [1.27 to 2.44]). A consistent trend was observed at rs12817819 in WISE, and the INVEST‐WISE meta‐analysis result reached chip‐wide significance (P=1.60×10−6, odds ratio=1.65 [1.36 to 1.95]). Expression analyses revealed significant differences in ATP2B1 expression by rs12817819 genotype.
The ATP2B1 rs12817819 A allele is associated with increased risk for RHTN in hypertensive participants with documented CAD or suspected ischemic heart disease.
Clinical Trial Registration
URL:; Unique identifiers: NCT00133692 (INVEST), NCT00000554 (WISE).
PMCID: PMC4338734  PMID: 25385345
genetics; hypertension; pharmacology; resistant hypertension
12.  Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins 
Postmus, Iris | Trompet, Stella | Deshmukh, Harshal A. | Barnes, Michael R. | Li, Xiaohui | Warren, Helen R. | Chasman, Daniel I. | Zhou, Kaixin | Arsenault, Benoit J. | Donnelly, Louise A. | Wiggins, Kerri L. | Avery, Christy L. | Griffin, Paula | Feng, QiPing | Taylor, Kent D. | Li, Guo | Evans, Daniel S. | Smith, Albert V. | de Keyser, Catherine E. | Johnson, Andrew D. | de Craen, Anton J. M. | Stott, David J. | Buckley, Brendan M. | Ford, Ian | Westendorp, Rudi G. J. | Eline Slagboom, P. | Sattar, Naveed | Munroe, Patricia B. | Sever, Peter | Poulter, Neil | Stanton, Alice | Shields, Denis C. | O’Brien, Eoin | Shaw-Hawkins, Sue | Ida Chen, Y.-D. | Nickerson, Deborah A. | Smith, Joshua D. | Pierre Dubé, Marie | Matthijs Boekholdt, S. | Kees Hovingh, G. | Kastelein, John J. P. | McKeigue, Paul M. | Betteridge, John | Neil, Andrew | Durrington, Paul N. | Doney, Alex | Carr, Fiona | Morris, Andrew | McCarthy, Mark I. | Groop, Leif | Ahlqvist, Emma | Bis, Joshua C. | Rice, Kenneth | Smith, Nicholas L. | Lumley, Thomas | Whitsel, Eric A. | Stürmer, Til | Boerwinkle, Eric | Ngwa, Julius S. | O’Donnell, Christopher J. | Vasan, Ramachandran S. | Wei, Wei-Qi | Wilke, Russell A. | Liu, Ching-Ti | Sun, Fangui | Guo, Xiuqing | Heckbert, Susan R | Post, Wendy | Sotoodehnia, Nona | Arnold, Alice M. | Stafford, Jeanette M. | Ding, Jingzhong | Herrington, David M. | Kritchevsky, Stephen B. | Eiriksdottir, Gudny | Launer, Leonore J. | Harris, Tamara B. | Chu, Audrey Y. | Giulianini, Franco | MacFadyen, Jean G. | Barratt, Bryan J. | Nyberg, Fredrik | Stricker, Bruno H. | Uitterlinden, André G. | Hofman, Albert | Rivadeneira, Fernando | Emilsson, Valur | Franco, Oscar H. | Ridker, Paul M. | Gudnason, Vilmundur | Liu, Yongmei | Denny, Joshua C. | Ballantyne, Christie M. | Rotter, Jerome I. | Adrienne Cupples, L. | Psaty, Bruce M. | Palmer, Colin N. A. | Tardif, Jean-Claude | Colhoun, Helen M. | Hitman, Graham | Krauss, Ronald M. | Wouter Jukema, J | Caulfield, Mark J.
Nature Communications  2014;5:5068.
Statins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol response to statins, including up to 18,596 statin-treated subjects. We validate the most promising signals in a further 22,318 statin recipients and identify two loci, SORT1/CELSR2/PSRC1 and SLCO1B1, not previously identified in GWAS. Moreover, we confirm the previously described associations with APOE and LPA. Our findings advance the understanding of the pharmacogenetic architecture of statin response.
Statins are effectively used to prevent and manage cardiovascular disease, but patient response to these drugs is highly variable. Here, the authors identify two new genes associated with the response of LDL cholesterol to statins and advance our understanding of the genetic basis of drug response.
PMCID: PMC4220464  PMID: 25350695
13.  Associations of Candidate Genes to Age-related Macular Degeneration Among Racial/Ethnic Groups in the Multi-Ethnic Study of Atherosclerosis 
American journal of ophthalmology  2013;156(5):10.1016/j.ajo.2013.06.004.
To describe the relationships of selected candidate genes to the prevalence of early age-related macular degeneration (AMD) in a cohort of whites, blacks, Hispanics, and Chinese Americans.
Cross-sectional study.
Multicenter study.
Study Population
2456 persons aged 45–84 years with genotype information and fundus photographs.
Twelve of 2862 single nucleotide polymorphisms (SNPs) from 11 of 233 candidate genes for cardiovascular disease were selected for analysis based on screening with marginal unadjusted P value <0.001 within 1 or more racial/ethnic groups. Logistic regression models tested for association in case-control samples.
Main Outcome Measure
Prevalence of early AMD.
Early AMD was present in 4.0% of the cohort and varied from 2.4% in blacks to 6.0% in whites. The odds ratio increased from 2.3 for one to 10.0 for four risk alleles in a joint effect analysis of Age-Related Maculopathy Susceptibility 2 rs10490924 and Complement Factor H Y402H (P for trend=4.2×10−7). Frequencies of each SNP varied among the racial/ethnic groups. Adjusting for age and other factors, few statistically significant associations of the 12 SNPs with AMD were consistent across all groups. In a multivariate model, most candidate genes did not attenuate the comparatively higher odds of AMD in whites. The higher frequency of risk alleles for several SNPs in Chinese Americans may partially explain their AMD frequency approaching that of whites.
The relationships of 11 candidate genes to early AMD varied among 4 racial/ethnic groups, and partially explained the observed variations in early AMD prevalence among them.
PMCID: PMC3812928  PMID: 23938121
14.  No Association of 9p21 with Arterial Elasticity and Retinal Microvascular Findings 
Atherosclerosis  2013;230(2):301-303.
How 9p21 variation affects risk of cardiovascular disease is unclear, so we assessed whether 9p21 variants are associated with arterial elasticity or retinal microvascular findings.
In the prospective Multi-Ethnic Study of Atherosclerosis (MESA) we assessed 378 SNPs in the 9p21 locus. Within four ethnic groups, we used an additive genetic model to relate the 9p21 SNPs to five vascular phenotypes: small and large elasticity derived from radial diastolic pulse contour analysis; Young’s elastic modulus from carotid artery ultrasound measurements; and the diameter of the central retinal arteries and veins.
In neither ethnic-specific nor pooled data was there any statistically significant association between any of the 9p21 SNPs and any of the five vascular phenotypes.
Our study does not support an association of 9p21 variation with arterial elasticity or retinal microvascular abnormalities.
PMCID: PMC3787319  PMID: 24075760
Prospective study; 9p21 SNP; retinal microvascular abnormalities; arterial elasticity
15.  Association of NOD2 and IL23R with Inflammatory Bowel Disease in Puerto Rico 
PLoS ONE  2014;9(9):e108204.
The Puerto Rico population may be modeled as an admixed population with contributions from three continents: Sub-Saharan Africa, Ancient America, and Europe. Extending the study of the genetics of inflammatory bowel disease (IBD) to an admixed population such as Puerto Rico has the potential to shed light on IBD genes identified in studies of European populations, find new genes contributing to IBD susceptibility, and provide basic information on IBD for the care of US patients of Puerto Rican and Latino descent. In order to study the association between immune-related genes and Crohn’s disease (CD) and ulcerative colitis (UC) in Puerto Rico, we genotyped 1159 Puerto Rican cases, controls, and family members with the ImmunoChip. We also genotyped 832 subjects from the Human Genome Diversity Panel to provide data for estimation of global and local continental ancestry. Association of SNPs was tested by logistic regression corrected for global continental descent and family structure. We observed the association between Crohn’s disease and NOD2 (rs17313265, 0.28 in CD, 0.19 in controls, OR 1.5, p = 9×10−6) and IL23R (rs11209026, 0.026 in CD, 0.0.071 in controls, OR 0.4, p = 3.8×10−4). The haplotype structure of both regions resembled that reported for European populations and “local” continental ancestry of the IL23R gene was almost entirely of European descent. We also observed suggestive evidence for the association of the BAZ1A promoter SNP with CD (rs1200332, 0.45 in CD, 0.35 in controls, OR 1.5, p = 2×10−6). Our estimate of continental ancestry surrounding this SNP suggested an origin in Ancient America for this putative susceptibility region. Our observations underscored the great difference between global continental ancestry and local continental ancestry at the level of the individual gene, particularly for immune-related loci.
PMCID: PMC4178120  PMID: 25259511
16.  A Multi-Ethnic Meta-Analysis of Genome-Wide Association Studies in Over 100,000 Subjects Identifies 23 Fibrinogen-Associated Loci but no Strong Evidence of a Causal Association between Circulating Fibrinogen and Cardiovascular Disease 
Sabater-Lleal, Maria | Huang, Jie | Chasman, Daniel | Naitza, Silvia | Dehghan, Abbas | Johnson, Andrew D | Teumer, Alexander | Reiner, Alex P | Folkersen, Lasse | Basu, Saonli | Rudnicka, Alicja R | Trompet, Stella | Mälarstig, Anders | Baumert, Jens | Bis, Joshua C. | Guo, Xiuqing | Hottenga, Jouke J | Shin, So-Youn | Lopez, Lorna M | Lahti, Jari | Tanaka, Toshiko | Yanek, Lisa R | Oudot-Mellakh, Tiphaine | Wilson, James F | Navarro, Pau | Huffman, Jennifer E | Zemunik, Tatijana | Redline, Susan | Mehra, Reena | Pulanic, Drazen | Rudan, Igor | Wright, Alan F | Kolcic, Ivana | Polasek, Ozren | Wild, Sarah H | Campbell, Harry | Curb, J David | Wallace, Robert | Liu, Simin | Eaton, Charles B. | Becker, Diane M. | Becker, Lewis C. | Bandinelli, Stefania | Räikkönen, Katri | Widen, Elisabeth | Palotie, Aarno | Fornage, Myriam | Green, David | Gross, Myron | Davies, Gail | Harris, Sarah E | Liewald, David C | Starr, John M | Williams, Frances M.K. | Grant, P.J. | Spector, Timothy D. | Strawbridge, Rona J | Silveira, Angela | Sennblad, Bengt | Rivadeneira, Fernando | Uitterlinden, Andre G | Franco, Oscar H | Hofman, Albert | van Dongen, Jenny | Willemsen, G | Boomsma, Dorret I | Yao, Jie | Jenny, Nancy Swords | Haritunians, Talin | McKnight, Barbara | Lumley, Thomas | Taylor, Kent D | Rotter, Jerome I | Psaty, Bruce M | Peters, Annette | Gieger, Christian | Illig, Thomas | Grotevendt, Anne | Homuth, Georg | Völzke, Henry | Kocher, Thomas | Goel, Anuj | Franzosi, Maria Grazia | Seedorf, Udo | Clarke, Robert | Steri, Maristella | Tarasov, Kirill V | Sanna, Serena | Schlessinger, David | Stott, David J | Sattar, Naveed | Buckley, Brendan M | Rumley, Ann | Lowe, Gordon D | McArdle, Wendy L | Chen, Ming-Huei | Tofler, Geoffrey H | Song, Jaejoon | Boerwinkle, Eric | Folsom, Aaron R. | Rose, Lynda M. | Franco-Cereceda, Anders | Teichert, Martina | Ikram, M Arfan | Mosley, Thomas H | Bevan, Steve | Dichgans, Martin | Rothwell, Peter M. | Sudlow, Cathie L M | Hopewell, Jemma C. | Chambers, John C. | Saleheen, Danish | Kooner, Jaspal S. | Danesh, John | Nelson, Christopher P | Erdmann, Jeanette | Reilly, Muredach P. | Kathiresan, Sekar | Schunkert, Heribert | Morange, Pierre-Emmanuel | Ferrucci, Luigi | Eriksson, Johan G | Jacobs, David | Deary, Ian J | Soranzo, Nicole | Witteman, Jacqueline CM | de Geus, Eco JC | Tracy, Russell P. | Hayward, Caroline | Koenig, Wolfgang | Cucca, Francesco | Jukema, J Wouter | Eriksson, Per | Seshadri, Sudha | Markus, Hugh S. | Watkins, Hugh | Samani, Nilesh J | Wallaschofski, Henri | Smith, Nicholas L. | Tregouet, David | Ridker, Paul M. | Tang, Weihong | Strachan, David P. | Hamsten, Anders | O’Donnell, Christopher J.
Circulation  2013;128(12):10.1161/CIRCULATIONAHA.113.002251.
Estimates of the heritability of plasma fibrinogen concentration, an established predictor of cardiovascular disease (CVD), range from 34 to 50%. Genetic variants so far identified by genome-wide association (GWA) studies only explain a small proportion (< 2%) of its variation.
Methods and Results
We conducted a meta-analysis of 28 GWA studies, including more than 90,000 subjects of European ancestry, the first GWA meta-analysis of fibrinogen levels in 7 African Americans studies totaling 8,289 samples, and a GWA study in Hispanic-Americans totaling 1,366 samples. Evaluation for association of SNPs with clinical outcomes included a total of 40,695 cases and 85,582 controls for coronary artery disease (CAD), 4,752 cases and 24,030 controls for stroke, and 3,208 cases and 46,167 controls for venous thromboembolism (VTE). Overall, we identified 24 genome-wide significant (P<5×10−8) independent signals in 23 loci, including 15 novel associations, together accounting for 3.7% of plasma fibrinogen variation. Gene-set enrichment analysis highlighted key roles in fibrinogen regulation for the three structural fibrinogen genes and pathways related to inflammation, adipocytokines and thyrotrophin-releasing hormone signaling. Whereas lead SNPs in a few loci were significantly associated with CAD, the combined effect of all 24 fibrinogen-associated lead SNPs was not significant for CAD, stroke or VTE.
We identify 23 robustly associated fibrinogen loci, 15 of which are new. Clinical outcome analysis of these loci does not support a causal relationship between circulating levels of fibrinogen and CAD, stroke or VTE.
PMCID: PMC3842025  PMID: 23969696
Fibrinogen; cardiovascular disease; genome-wide association study
17.  Genome-wide association study in a Chinese population with diabetic retinopathy 
Human Molecular Genetics  2013;22(15):3165-3173.
Diabetic retinopathy (DR) is a leading cause of preventable blindness in adults. To identify genetic contributions in DR, we studied 2071 type 2 diabetics. We first conducted a genome-wide association study of 1007 individuals, comparing 570 subjects with ≥8 years duration without DR (controls) with 437 PDR (cases) in the Chinese discovery cohort. Cases and controls were similar for HbA1c, diabetes duration and body mass index. Association analysis with imputed data identified three novel loci: TBC1D4-COMMD6-UCHL3 (rs9565164, P = 1.3 × 10−7), LRP2-BBS5 (rs1399634, P = 2.0 × 10−6) and ARL4C-SH3BP4 (rs2380261, P = 2.1 × 10−6). Analysis of an independent cohort of 585 Hispanics diabetics with or without DR though did not confirm these signals. These genes are still of particular interest because they are involved in insulin regulation, inflammation, lipid signaling and apoptosis pathways, all of which are possibly involved with DR. Our finding nominates possible novel loci as potential DR susceptibility genes in the Chinese that are independent of the level of HbA1c and duration of diabetes and may provide insight into the pathophysiology of DR.
PMCID: PMC3699066  PMID: 23562823
18.  Multi-dimensional prognostic risk assessment identifies association between IL12B variation and surgery in Crohn’s disease 
Inflammatory bowel diseases  2013;19(8):10.1097/MIB.0b013e318281f275.
The ability to identify patients with Crohn’s disease (CD) at highest risk of surgery would be invaluable in guiding therapy. Genome-wide association (GWA) studies have identified multiple IBD loci with unknown phenotypic consequences.
1) to identify associations between known and novel CD loci with early resective CD surgery2) to develop the best predictive model for time to surgery using a combination of phenotypic, serologic and genetic variables.
Genotyping was performed on 1115 subjects using Illumina-based Genome-wide technology. Univariate and multivariate analyses tested genetic associations with need for surgery within 5 years. Analyses were performed by testing known CD loci (n=71) and by performing a GWA study. Time to surgery was analyzed using Cox regression modeling. Clinical and serologic variables were included along with genotype to build predictive models for time to surgery.
Surgery occurred within 5 years in 239 subjects at a median time of 12 months. Three CD susceptibility loci were independently associated with surgery within 5 years (IL12B, IL23R, C11orf30). GWA identified novel putative loci associated with early surgery; 7q21 (CACNA2D1) and 9q34 (RXRA, COL5A1). The most predictive models of time to surgery included genetic and clinical risk factors. More than a 20% difference in frequency of progression to surgery was seen between the lowest and highest risk groups.
Progression to surgery is faster in CD patients with both genetic and clinical risk factors. IL12B is independently associated with need and time to early surgery in CD patients and justifies the investigation of novel and existing therapies that affect this pathway.
PMCID: PMC3874388  PMID: 23665963
19.  Genetic Ancestry and the Relationship of Cigarette Smoking to Lung Function and Percent Emphysema in Four Race/Ethnic Groups: a Cross-sectional Study 
Thorax  2013;68(7):634-642.
Cigarette smoking is the major cause of chronic obstructive pulmonary disease and emphysema. Recent studies suggest that susceptibility to cigarette smoke may vary by race/ethnicity; however, they were generally small and relied on self-reported race/ethnicity.
To test the hypothesis that relationships of smoking to lung function and percent emphysema differ by genetic ancestry and self-reported race/ethnicity among Whites, African-Americans, Hispanics and Chinese-Americans.
Cross-sectional population-based study of adults age 45-84 years in the United States
Principal components of genetic ancestry and continental ancestry estimated from one-million genome-wide single nucleotide polymorphisms. Pack-years calculated as years smoking cigarettes-per-day/20. Spirometry measured for 3,344 and percent emphysema on computed tomography for 8,224 participants.
The prevalence of ever-smoking was: Whites, 57.6%; African-Americans, 56.4%; Hispanics, 46.7%; and Chinese-Americans, 26.8%. Every 10 pack-years was associated with −0.73% (95% CI −0.90%, −0.56%) decrement in the forced expiratory volume in one second to forced vital capacity (FEV1/FVC) and a 0.23% (95% CI 0.08%, 0.38%) increase in percent emphysema. There was no evidence that relationships of pack-years to the FEV1/FVC, airflow obstruction and percent emphysema varied by genetic ancestry (all p>0.10), self-reported race/ethnicity (all p>0.10) or, among African-Americans, African ancestry. There were small differences in relationships of pack-years to the FEV1 among male Chinese-Americans and to the FEV1/FVC with African and Native American ancestry among male Hispanics only.
In this large cohort, there was little-to-no evidence that the associations of smoking to lung function and percent emphysema differed by genetic ancestry or self-reported race/ethnicity.
PMCID: PMC4020409  PMID: 23585509
cigarette smoke; genetic ancestry; lung function; chronic obstructive pulmonary disease; COPD; emphysema; FVC; Forced Vital Capacity; FEV1; Forced Expiratory Volume in 1 second
20.  Relationship between proximal Crohn’s disease location and disease behavior and surgery: A cross-sectional study of the IBD Genetics Consortium 
In classifying Crohn’s disease (CD) location, proximal (L4) disease includes esophagogastroduodenal (EGD) and jejunal disease. Our aim was to determine the influence of proximal disease on outcomes of behavior and need for surgery and to determine if there was significant clinical heterogeneity between EGD and jejunal disease.
We performed a cross-sectional query of the NIDDK IBD Genetics Consortium (IBDGC) database of patients with a confirmed diagnosis of CD and phenotyped per the IBDGC manual. Presence of any L4, L4-EGD, L4-jejunal and non-L4 disease (L1-ileal, L2-colonic, and L3-ileocolonic) was compared with demographic features including age, race, ethnicity, smoking and IBD family history, diagnosis age, disease duration, clinical outcomes of inflammatory, stricturing or penetrating behavior, and CD abdominal surgeries. Univariate and multivariable analyses were performed with R.
Among 2105 patients with complete disease location data, 346 had L4 disease (175 L4-EGD, 115 L4-jejunal, and 56 EGD and jejunal) with 321 having concurrent L1-L3 disease. 1759 had only L1-L3 disease. L4 vs. non-L4 patients were more likely (p<0.001) to be younger at diagnosis, non-smokers, have co-existing ileal involvement and have stricturing disease. L4- jejunal vs. L4-EGD patients were at least twice as likely (p<0.001) to have had ileal disease, stricturing behavior, and any or multiple abdominal surgeries. Remarkably, L4-jejunal patients had more (p<0.001) stricturing behavior and multiple abdominal surgeries than non-L4 ileal disease patients. Logistic regression showed stricturing risks were ileal (without proximal) site (OR 3.18; 95% CI 2.23-4.64), longer disease duration (OR 1.33/decade; 1.19-1.49), jejunal site (OR 2.90; 1.89-4.45), and older age at diagnosis (OR 1.21/decade; 1.10-1.34). Multiple surgeries risks were disease duration (OR 3.74/decade; 3.05-4.64), penetrating disease (OR 2.60; 1.64-4.21), and jejunal site (OR 2.39; 1.36-4.20), with short duration from diagnosis to first surgery protective (OR 0.87/decade to 1st surgery; 0.84-0.90).
Jejunal disease is a significantly greater risk factor for stricturing disease and multiple abdominal surgeries than either EGD or ileal (without proximal) disease. The Montreal site classification should be revised to include separate designations for jejunal and EGD disease.
PMCID: PMC4059598  PMID: 23229423
21.  An association between the Calpastatin (CAST) gene and keratoconus 
Cornea  2013;32(5):696-701.
Keratoconus is a genetically heterogeneous corneal dystrophy. Previously, we performed two genome-wide linkage scans in a four generation autosomal dominant pedigree and repeatedly mapped a keratoconus locus to a genomic region located on chromosome 5q overlapping the gene encoding the inhibitor of calpains, calpastatin (CAST). To test whether variants in CAST gene are involved in genetic susceptibility to keratoconus we performed genetic testing of polymorphic markers in CAST gene in family and case-control panels of patients with keratoconus.
We genotyped SNPs (Single Nucleotide Polymorphisms) located in CAST gene in 262 patients in 40 Caucasian keratoconus families and in a Caucasian case-control panel with 304 cases and 518 controls. Generalized estimating equation models accounting for familial correlations implemented in GWAF program were used for association testing in families. Logistic regression models implemented in PLINK were performed to test associations in case-control samples.
Genetic testing of first set of seven SNPs in familial samples revealed two tentative nominally significant markers (rs4869307 p=0.03; rs27654: p=0.07). Additional genotyping of twelve tightly spaced SNPs identified CAST SNP rs4434401 to be associated with keratoconus in both familial and case-control panels with p values of 0.005 and 0.05, respectively; and with combined meta p value of familial and case-control cohorts of 0.002, or, after Bonferroni correction, 0.04.
Linkage analysis and genetic association support involvement of CAST gene in the genetic susceptibility to keratoconus. In-silico analysis of CAST expression suggests differential regulation of calpain/calpastatin system in cornea as a potential mechanism of functional defect.
PMCID: PMC3653445  PMID: 23449483
Linkage analysis; genetic association; common variation; keratoconus; calpains; calpastatin
22.  Genome-wide association analyses identify multiple loci associated with central corneal thickness and keratoconus 
Lu, Yi | Vitart, Veronique | Burdon, Kathryn P | Khor, Chiea Chuen | Bykhovskaya, Yelena | Mirshahi, Alireza | Hewitt, Alex W | Koehn, Demelza | Hysi, Pirro G | Ramdas, Wishal D | Zeller, Tanja | Vithana, Eranga N | Cornes, Belinda K | Tay, Wan-Ting | Tai, E Shyong | Cheng, Ching-Yu | Liu, Jianjun | Foo, Jia-Nee | Saw, Seang Mei | Thorleifsson, Gudmar | Stefansson, Kari | Dimasi, David P | Mills, Richard A | Mountain, Jenny | Ang, Wei | Hoehn, René | Verhoeven, Virginie J M | Grus, Franz | Wolfs, Roger | Castagne, Raphaële | Lackner, Karl J | Springelkamp, Henriët | Yang, Jian | Jonasson, Fridbert | Leung, Dexter Y L | Chen, Li J | Tham, Clement C Y | Rudan, Igor | Vatavuk, Zoran | Hayward, Caroline | Gibson, Jane | Cree, Angela J | MacLeod, Alex | Ennis, Sarah | Polasek, Ozren | Campbell, Harry | Wilson, James F | Viswanathan, Ananth C | Fleck, Brian | Li, Xiaohui | Siscovick, David | Taylor, Kent D | Rotter, Jerome I | Yazar, Seyhan | Ulmer, Megan | Li, Jun | Yaspan, Brian L | Ozel, Ayse B | Richards, Julia E | Moroi, Sayoko E | Haines, Jonathan L | Kang, Jae H | Pasquale, Louis R | Allingham, R Rand | Ashley-Koch, Allison | Mitchell, Paul | Wang, Jie Jin | Wright, Alan F | Pennell, Craig | Spector, Timothy D | Young, Terri L | Klaver, Caroline C W | Martin, Nicholas G | Montgomery, Grant W | Anderson, Michael G | Aung, Tin | Willoughby, Colin E | Wiggs, Janey L | Pang, Chi P | Thorsteinsdottir, Unnur | Lotery, Andrew J | Hammond, Christopher J | van Duijn, Cornelia M | Hauser, Michael A | Rabinowitz, Yaron S | Pfeiffer, Norbert | Mackey, David A | Craig, Jamie E | Macgregor, Stuart | Wong, Tien Y
Nature genetics  2013;45(2):155-163.
Central corneal thickness (CCT) is associated with eye conditions including keratoconus and glaucoma. We performed a meta-analysis on >20,000 individuals in European and Asian populations that identified 16 new loci associated with CCT at genome-wide significance (P < 5 × 10−8). We further showed that 2 CCT-associated loci, FOXO1 and FNDC3B, conferred relatively large risks for keratoconus in 2 cohorts with 874 cases and 6,085 controls (rs2721051 near FOXO1 had odds ratio (OR) = 1.62, 95% confidence interval (CI) = 1.4–1.88, P = 2.7 × 10−10, and rs4894535 in FNDC3B had OR = 1.47, 95% CI = 1.29–1.68, P = 4.9 × 10−9). FNDC3B was also associated with primary open-angle glaucoma (P = 5.6 × 10−4; tested in 3 cohorts with 2,979 cases and 7,399 controls). Further analyses implicate the collagen and extracellular matrix pathways in the regulation of CCT.
PMCID: PMC3720123  PMID: 23291589
23.  Combination of Innate and Adaptive Immune Alterations Increased the Likelihood of Fibrostenosis in Crohn’s Disease 
Inflammatory bowel diseases  2010;16(8):10.1002/ibd.21196.
Mutations in the nucleotide oligomerization domain-2 (NOD2) gene and positive antibodies to microbial antigens have been found to be associated with the Crohn’s disease (CD) phenotype, fibrostenosis. The aim of this study was to confirm these relationships in a large cohort of CD patients and to determine the correlation between the presence of NOD2 variants and antibodies to oligomannan, CBir, outer membrane porin-C (OmpC), and I2 in CD patients with fibrostenosis.
Sera and DNA from 731 unrelated CD patients were tested for NOD2 variants (SNP 8, 12, and 13) and the antibodies. The results were correlated with CD phenotypes, fibrostenosis, internal penetrating, perianal penetrating, and ulcerative colitis (UC)-like as well as other clinical features.
The presence of NOD2 allelic variants was primarily associated with fibrostenosis, secondarily with small bowel disease and small bowel surgery, and was inversely associated with UC-like disease. This association was present in patients with a fibrostenosis only (Vienna B2) and those with both stricturing and penetrating disease. The presence and level of antibodies to microbial antigens was also associated with the fibrostenosis phenotype. In the 316 patients with fibrostenosis the prevalence of NOD2 variants was significantly correlated with the antibody titer by quartile sum score. Further, when these patients with fibrostenosis were clustered by quartile sum score, the odds ratio for fibrostenosis was significantly higher in the patients with NOD2 variant alleles within each cluster, indicating synergy.
Defects of innate (NOD2 variants) and adaptive (antibodies to microbial antigens) immunity act synergistically to increase the risk of the fibrostenosis phenotype.
PMCID: PMC3875376  PMID: 20027650
NOD2; Crohn’s disease; fibrostenosis; phenotype
24.  Contribution of higher risk genes and European admixture to Crohn's disease in African Americans 
Inflammatory bowel diseases  2012;18(12):10.1002/ibd.22931.
Background & Aims
African Americans (AA) are an admixed population of West African (WA) and European ancestry (EA). Crohn's disease (CD) susceptibility genes have not been established. We therefore evaluated the contribution of European admixture and major established risk genes to AA CD.
Ninety-seven admixture informative markers were genotyped for ancestry estimates using STRUCTURE. 354 AA CD cases and 354 ethnicity-matched controls were genotyped for total 21 SNPs in ATG16L1, NOD2, IBD5, IL23R and IRGM by TaqMan or direct sequencing. Association was evaluated by logistic regression, adjusted for ancestry.
Mean EA was similar among the CD cases and controls (20.9% and 20.4, respectively, p=0.58). No significant admixture differences were observed among cases (211 to 227) stratified by phenotypic sub-classifications including onset, surgery, site, and behavior. CD was associated with NOD2 carrier (6.93% CD, 2.15% Controls, p = 0.007), ATG16L1 Thr300Ala (36.1% CD, 29.3% Controls, p=0.003), SLC22A4 and SLC22A5 (IBD5 locus) functional SNPs (L503F [10.6% CD, 7.6% Controls, p=0.05] and g-207c [41.3% CD, 35.7% Controls, p=0.03], respectively) and IL23R rs2201841 (18.2% CD, 13.8% Controls, p=0.03), but not IRGM variants nor three African ancestral NOD2 nonsynonymous variants. IBD5 risk was recessive. An all-minor allele IBD5 haplotype from EA was associated (p=0.05), whereas a more common haplotype isolating g-207c was not.
Specific functional gene variations significantly contribute to AA CD risk. Established NOD2, SLC22A4-A5, and ATG16L1 variants show increased CD risk, with IBD5 in recessive. Although CD is more common in whites, European admixture is similar among AA cases and controls.
PMCID: PMC3810419  PMID: 22411504
genetics; epidemiology; Crohn's disease
25.  A Genome-Wide Association Study of Central Corneal Thickness in Latinos 
Central corneal thickness (CCT) is a clinically important risk factor for primary open-angle glaucoma and keratoconus. Genetic factors controlling CCT in Latinos, the most populous minority population in the United States, are unclear. Here we describe the first genome-wide association study (GWAS) report of CCT in Latinos.
We performed a GWAS for CCT on 1768 Latinos recruited in the Los Angeles Latino Eye Study (LALES) using Illumina's HumanOmniExpress BeadChip (∼730K markers). To discover additional associated single-nucleotide polymorphisms (SNPs), we imputed SNPs based on the 1000 Genomes Project reference panels. All subjects were 40 years of age and older. We used linear regression with adjustment for age, sex, and principal components of genetic ancestry.
We replicated the involvement of several previously reported loci, such as RXRA-COL5A1, FOXO1, and ZNF469, for CCT in Latinos (P < 0.002). Moreover, we discovered novel SNPs, rs3118515, rs943423, rs3118594, and rs3132307, that reached GWAS significance (P < 5 × 10−8) in the uncharacterized LOC100506532 (gene type: miscRNA) for CCT in Latinos. By conditional analysis, we demonstrate that rs3118515 in this gene is responsible for the GWAS signal in the chromosome 9 RXRA-COL5A1 region in Latinos. Moreover, multiple sources of ENCODE evidence suggest that rs3118515 is in a regulatory region. Reverse-transcription PCR products indicated that transcripts of LOC100506532 surrounding rs3118515 were expressed in human corneas.
We discovered novel SNPs for CCT in Latinos and provided the first reported evidence of the corneal expression of LOC100506532. These results help to further increase our understanding of the genetic architecture of CCT.
In this first GWAS of central corneal thickness in Latinos, we discovered the involvement of novel SNPs, both directly genotyped and imputed, that reached genome-wide significance. This study provided the first reported evidence of the corneal expression of LOC100506532.
PMCID: PMC3621577  PMID: 23493294
central corneal thickness; Latino; GWAS; rs3118515; LOC100506532

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