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1.  A Genome-Wide Association Study of Central Corneal Thickness in Latinos 
Purpose.
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.
Methods.
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.
Results.
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.
Conclusions.
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.
doi:10.1167/iovs.13-11692
PMCID: PMC3621577  PMID: 23493294
central corneal thickness; Latino; GWAS; rs3118515; LOC100506532
2.  Genetic Association of COL5A1 Variants in Keratoconus Patients Suggests a Complex Connection between Corneal Thinning and Keratoconus 
Purpose.
Single nucleotide polymorphisms (SNPs) located near or within the COL5A1 gene, at 9q34.2-q34.3 chromosomal region have been reported in association with central corneal thickness (CCT). Using family linkage analysis, we identified a keratoconus susceptibility locus at 9q34. These findings led us to perform an association study between COL5A1 variation and keratoconus susceptibility.
Methods.
A Caucasian case–control cohort of 222 keratoconus patients and 3324 controls was selected as the discovery panel. An independent case–control panel of 304 cases and 518 controls and a family panel of 186 subjects were replicated for genotyping and association. Forty-four SNPs (21 for discovery and 23 for fine-mapping) spanning 300 kilobases in and around COL5A1 were genotyped and tested for genetic association. Logistic regression models implemented in PLINK were used to test for association in case controls. Generalized estimating equation models accounting for familial correlations implemented in genome-wide interaction analyses with family data were used for association testing in families.
Results.
Two CCT associated SNPs (rs1536482 and rs7044529 near and within COL5A1) were identified in the keratoconus discovery cohort (P values of 6.5 × 10−3 and 7.4 × 10−3). SNP rs1536482 was replicated in the second case–control sample (P = 0.02), and SNP rs7044529 was replicated in a keratoconus family panel (P = 0.03). Meta P values of rs1536482 and rs7044529 in the keratoconus cohorts were 1.5 × 10−4 (odds ratio [OR] = 1.30) and 2.9 × 10−3 (OR = 1.39). After Bonferroni correction, the association of SNP rs1536482 remained significant (P = 6.5 × 10−3).
Conclusions.
SNPs in the COL5A1 region, which regulate normal variation in CCT, may play a role in the thinning associated with keratoconus.
Variants in the COL5A1 gene may contribute to genetic susceptibility to corneal thinning associated with keratoconus, in addition to their role in genetic regulation of normal variation in central corneal thickness.
doi:10.1167/iovs.13-11601
PMCID: PMC3630822  PMID: 23513063
keratoconus; association; COL5A1
3.  Increased Immune Reactivity Predicts Aggressive Complicating Crohn’s disease in Children 
Background and Aim
The ability to identify children with Crohn’s disease who are at highest risk for rapid progression from uncomplicated to complicated phenotypes would be invaluable in guiding initial therapy. Aim: To determine whether immune responses and/or CARD15 variants are associated with complicated disease phenotypes and predict disease progression.
Methods
Sera were collected from 796 pediatric CD cases and tested for anti-Cbir1 (flagellin), anti-outer membrane protein C (anti-OmpC), anti-Saccharomyces-cerevisiae (ASCA) and perinuclear anti-neutrophil cytoplasmic antibody (pANCA) using ELISA. Genotyping (TaqmanMGB) was performed for 3 CARD15 variants (SNPs 8, 12, 13). Associations between immune responses (antibody sum (AS) and quartile sum score (QSS), CARD15, and clinical phenotype were evaluated.
Results
32% of patients developed at least one disease complication within a median of 32 months and 18% underwent surgery. The frequency of internal penetrating (IP), stricturing (S) and surgery significantly increased (p trend < 0.0001 for all 3 outcomes) with increasing AS and QSS. 9% of seropositive groups had IP/S vs. 2.9% in the seronegative group (p=0.01). 12% of seropositive groups underwent surgery vs. 2% in the seronegative group (p=0.0001). The highest AS group (3) and QSS group (4) demonstrated the most rapid disease progression (p < 0.0001). Increased hazard ratio was observed for AS group 3 (7.8 [2.2–28.7] p < 0.002 and QSS group 4 (11.0 [1.5,83.0] p < 0.02).
Conclusions
The rate of complicated CD increases in children as the number and magnitude of immune reactivity increases. Disease progression is significantly faster in children expressing immune reactivity.
doi:10.1016/j.cgh.2008.04.032
PMCID: PMC3745777  PMID: 18619921
4.  Metabolic and cardiovascular genes in polycystic ovary syndrome: A candidate-wide association study (CWAS) 
Steroids  2011;77(4):317-322.
The role of metabolic disturbance in polycystic ovary syndrome (PCOS) has been well established, with insulin resistance and the resulting compensatory hyperinsulinemia thought to promote hyperandrogenemia. Genome-wide association studies (GWAS) have established a large number of loci for metabolic conditions such as type 2 diabetes and obesity. A subset of these loci has been investigated for a role in PCOS; these studies generally have not revealed a confirmed role for these loci in PCOS risk. However, a large scale investigation of genes related to these pathways has not previously been performed. We conducted a two stage case control association study of 121,715 single nucleotide polymorphisms (SNPs) selected to represent susceptibility loci associated with traits such as type 2 diabetes, obesity measures, lipid levels and cardiovascular function using the Cardio-Metabochip in 847 PCOS cases and 845 controls. Several hypothesis-generating associations with PCOS were observed (top SNP rs2129107, P = 3.8 × 10−6). We did not find any loci definitively associated with PCOS after strict correction for multiple testing, suggesting that cardio-metabolic loci are not major risk factors underlying the susceptibility to PCOS.
doi:10.1016/j.steroids.2011.12.005
PMCID: PMC3689580  PMID: 22178785
Candidate-wide association study; Polycystic ovary syndrome; Cardio-Metabochip; Single nucleotide polymorphism; Genetic association
5.  RGS6 Variants Are Associated With Dietary Fat Intake in Hispanics: The IRAS Family Study 
Obesity (Silver Spring, Md.)  2011;19(7):1433-1438.
Recently, a genome-wide association scan was completed in the IRAS (Insulin Resistance Atherosclerosis Study) Family Study (IRASFS) Hispanic-American cohort. Multiple single-nucleotide polymorphisms (SNPs) in the G-protein signaling 6 (RGS6) gene were found to be associated with adiposity phenotypes. RGS6 has shown downstream antagonistic interplay with opioid receptors, targets of fatty/sugary food agonists. The possibility that RGS6 promotes tolerance and tachyphylaxis among the opioid receptor is a plausible pathway for overconsuming fat/sugar-laden food. Therefore, we hypothesized that RGS6 variants are associated with intake of fatty/sugary foods. In 932 Hispanics from San Antonio and San Luis Valley, CO, the following dietary intake variables were assessed using the Block Brief 2000 food frequency questionnaire: total calories, total fat, % calories from fat, % calories from saturated fat, protein, % calories from protein, carbohydrates, % calories from carbohydrates, and daily frequency of servings of fats/oils/sweets. We tested for association between 23 SNPs in RGS6 and dietary intake using a variance components measured genotype approach. All models were adjusted for gender, recruitment site, admixture, BMI, and age. Using an additive genetic model, rs1402064 was associated with higher intake of fats/oils/sweets, total calories, total fat and saturated fat (P = 0.0007, 0.026, 0.023, and 0.024). SNPs rs847330 and rs847354 were associated with higher intake of fats/oils/sweets (P = 0.002 and 0.018), total fat (P = 0.040 and 0.048) and saturated fat (P = 0.044 and 0.041). Finally, rs769148 was associated with higher intake of fats/oils/sweets (P = 0.002). RGS6 is a new candidate gene for adiposity traits that may be associated with a behavioral tendency toward fat-laden food intake.
doi:10.1038/oby.2010.333
PMCID: PMC3683650  PMID: 21233807
6.  IL23R Haplotypes Provide A Large Population Attributable Risk for Crohn’s Disease 
Inflammatory bowel diseases  2008;14(9):1185-1191.
The IL-23 pathway plays a pivotal role in the development of chronic mucosal inflammation seen in the inflammatory bowel diseases. Multiple studies have now established the contribution of the interleukin 23 receptor gene (IL23R) to Crohn’s Disease (CD) risk in general and of the IL23R R381Q variant in particular. The aim of this work was to estimate the total contribution of this gene to CD risk test using a haplotype approach.
Methods
763 CD subjects and 254 controls were genotyped for single nucleotide polymorphisms in the IL23R gene using Illumina and ABI methods. Haplotypes were assigned using PHASEv2 and tested for association with CD by chi-square and permutation.
Results
Haplotypes with both increased and decreased risk for CD were observed in 2 of the 4 observed blocks (Block 2 H1: 55.4% control, 64% CD, p=0.019; H2: 64.5% control, 54.4% CD, p=0.006; Block 3 H1: 55.8% control, 64.4% CD, p=0.013; H2: 47.0% control, 36.6% CD, p=0.001). The population attributable risk for these haplotypes was substantially larger than that estimated for the IL23R R381Q variant (Block 2 H1 and block 3 H1 ~20%, compared with ~4% for Block 3 H6, containing the variant).
Discussion
These observations suggest that IL23R makes a substantial contribution to Crohn’s disease susceptibility, larger than that estimated from the population frequency of the R381Q variant. These observations also support the expectation that finding “hits” from genome wide association studies will be but an important chapter in the story of unraveling the genetic contribution to Crohn’s disease, rather than the final chapter that brings clarity to all the plot twists of a complicated story.
doi:10.1002/ibd.20478
PMCID: PMC2574614  PMID: 18470928
7.  A genome-wide association study identifies a potential novel gene locus for keratoconus, one of the commonest causes for corneal transplantation in developed countries 
Human Molecular Genetics  2011;21(2):421-429.
Keratoconus is a condition in which the cornea progressively thins over time, and is a major cause for cornea transplantation. To identify keratoconus susceptibility regions, we performed a comprehensive genome-wide association study (GWAS) using a discovery and replication design. A discovery panel of 222 keratoconus Caucasian patients and 3324 Caucasian controls was genotyped using Illumina 370K beadchips. Further associated and fine-mapping single nucleotide polymorphisms (SNPs) (n= 4905) were genotyped in an independent replication case–control panel of 304 cases and 518 controls and a family panel of 307 subjects in 70 families. Logistic regression models implemented in PLINK were performed to test associations in case–control samples with and without principal component (PC) adjustments. Generalized estimation equation models accounting for familial correlations implemented in GWAF were used for association testing in families. No genome-wide associations were identified in the discovery GWAS panel. From the initial testing without adjustments for PCs, the top three SNPs located at 3p26 (rs6442925), 2q21.3 (rs4954218) and 19q13.3 (rs1428642) were identified with unadjusted P-values of 6.5 × 10−8, 2.4 × 10−7 and 3.1 × 10−7, respectively. After adjustments for PCs, rs1428642 became the most significant through the genome with a P-value of 1.4 × 10−6, while rs6442925 and rs4954218 were less significant (P= 1.9 × 10−5 and 2.6 × 10−4). SNP rs4954218 was confirmed in two independent replication panels with P-values of 0.004 and 0.009, respectively. Meta-analysis revealed a highest association at rs4954218 with adjusted P= 1.6 × 10−7 (unadjusted P= 1.2 × 10−9). These findings suggest SNP rs4954218, located near the RAB3GAP1 gene, previously reported to be associated with corneal malformation, is a potential susceptibility locus for keratoconus.
doi:10.1093/hmg/ddr460
PMCID: PMC3276283  PMID: 21979947
8.  Interactions between commensal fungi and the C-type lectin receptor Dectin-1 influence colitis 
Science (New York, N.Y.)  2012;336(6086):1314-1317.
The intestinal microflora, typically equated with bacteria, influences diseases such as obesity and inflammatory bowel disease (IBD). Here we show that the mammalian gut contains a rich fungal community that interacts with the immune system through the innate immune receptor Dectin-1. Mice lacking Dectin-1 exhibited increased susceptibility t chemically-induced colitis, which was the result of altered responses to indigenous fungi. In humans we identified a polymorphism in the gene for Dectin-1 (CLEC7A) that is strongly linked to a severe form of ulcerative colitis. Together our findings reveal a novel eukaryotic fungal community in the gut (the “mycobiome”) that coexists with bacteria and substantially expands the repertoire of organisms interacting with the intestinal immune system to influence health and disease.
doi:10.1126/science.1221789
PMCID: PMC3432565  PMID: 22674328
9.  Genes Linked to Energy Metabolism and Immunoregulatory Mechanisms are Associated with Subcutaneous Adipose Tissue Distribution in HIV-infected Men 
Pharmacogenetics and genomics  2011;21(12):798-807.
Objective
Genetic studies may help explain abnormalities of fat distribution in HIV-infected patients treated with antiretroviral therapy (ARV).
Methods
Subcutaneous adipose tissue (SAT) volume measured by magnetic resonance imaging (MRI) in leg, lower trunk, upper trunk, and arm was examined in 192 HIV-infected Caucasian men, ARV-treated from the Fat Redistribution and Metabolic Change in HIV infection (FRAM) study. Single nucleotide polymorphisms (SNPs) were assayed using the Illumina HumanCNV370-quad beadchip. Multivariate and univariate genome wide association analyses of the four SAT depots were implemented in PLINK software adjusted for age and ARV duration. Functional annotation analysis (FAA) using Ingenuity Systems Pathway Analysis tool (IPA) was carried out for markers with P<10-3 near known genes identified by multivariate analysis.
Results
Loci (rs10504906, rs13267998, rs921231) in or near the anion exchanger solute carrier family 26, member 7 isoform a (SLC26A7) were strongly associated with upper trunk and arm SAT (9.8*10-7≤P<7.8*10-6). Loci (rs193139, rs7523050, rs1761621) in and near a gene rich region including G-protein-signaling modulator 2 (GPSM2) and syntaxin binding protein 3 (STXBP3) were significantly associated with lower body SAT depots (9.9*10-7≤P<9.5*10-6). GPSM2 is associated with cell division and cancer while STXBP3 is associated with glucose metabolism in adipoctyes. IPA identified atherosclerosis, mitochondrial function and T-Cell mediated apoptosis as processes related to SAT volume in HIV-infected individuals (P<5*10-3).
Conclusions
Our results are limited by the small sample size and replication is needed, however this genomic scan uncovered new genes associated with metabolism and inflammatory pathways that may affect SAT volume in ARV-treated HIV-infected patients.
doi:10.1097/FPC.0b013e32834b68f9
PMCID: PMC3210910  PMID: 21897333
HIV; HAART; GWAS; Subcutaneous Fat; SAT
10.  Variation in the Lysyl Oxidase (LOX) Gene Is Associated with Keratoconus in Family-Based and Case-Control Studies 
Purpose.
Keratoconus is a bilateral noninflammatory progressive corneal disorder with complex genetic inheritance and a common cause for cornea transplantation in young adults. A genomewide linkage scan in keratoconus families identified a locus at 5q23.2, overlapping the gene coding for the lysyl oxidase (LOX). LOX encodes an enzyme responsible for collagen cross-linking in a variety of tissues including the cornea. Corneal collagen cross-linking with long-wave ultraviolet light and riboflavin is a promising new treatment for keratoconus. To determine whether LOX is a genetic determinant of the pathogenesis of keratoconus, we analyzed association results of LOX polymorphisms in two independent case-control samples and in keratoconus families.
Methods.
Association results were analyzed of single-nucleotide polymorphisms (SNPs) in the LOX gene from a Genome-Wide Association Study (GWAS) investigation in two independent panels of patients with keratoconus and controls and in keratoconus families.
Results.
Evidence of association was found at SNPs rs10519694 and rs2956540 located in intron 4 of LOX in the GWAS discovery case-control panel with P values of 2.3 × 10−3 and 7 × 10−3, respectively. The same two SNPs were found to be associated with keratoconus by family-based association testing with P values of 2.7 × 10−3 and 7.7 × 10−4, respectively. Meta P values of 4.0 × 10−5 and 4.0 × 10−7 were calculated for SNPs rs10519694 and rs2956540 by analyzing case-control and family samples simultaneously. Sequencing of LOX exons in a subset of keratoconus patients identified two polymorphisms, rs1800449 and rs2288393, located in LOX transcripts I and II, associated with keratoconus in case-control and family samples with a meta P value of 0.02.
Conclusions.
Results provided strong genetic evidence that LOX variants lead to increased susceptibility to developing of keratoconus.
Keratoconus is a progressive disorder of the cornea with complex genetic inheritance, which can lead to severe visual impairment or blindness. Here we describe the association between variation in the lysyl oxidase gene and keratoconus susceptibility in case-control and family studies.
doi:10.1167/iovs.11-9268
PMCID: PMC3760233  PMID: 22661479
11.  Associations of SNPs in ADIPOQ and subclinical cardiovascular disease in the Multi-Ethnic Study of Atherosclerosis (MESA) 
Obesity (Silver Spring, Md.)  2010;19(4):840-847.
Circulating adiponectin has been associated with both clinical and subclinical cardiovascular disease (CVD). Variants of the adiponectin gene (ADIPOQ) are associated with clinical CVD, but little is known about associations with subclinical CVD. We studied the association of 11 ADIPOQ SNPs with common and internal carotid intima media thickness (cIMT), presence of coronary artery calcification (CAC), and CAC scores (in those with CAC) in 2847 participants in the Multi-Ethnic Study of Atherosclerosis (MESA). Participants were Caucasian (n=712), African-American (n=712), Chinese (n=718), and Hispanic (n=705). All models were adjusted for age, sex, and field site, and stratified by race/ethnic group. African-Americans with genotypes AG/GG of rs2241767 had 36% greater (95% CI (16%, 59%), p=0.0001) CAC prevalence; they also had a larger common cIMT (p=0.0043). Also in African-Americans, genotypes AG/AA of rs1063537 were associated with a 35% (95% CI (14%, 59%), p=0.0005) greater CAC prevalence. Hispanics with the AA genotype of rs11711353 had a 37% (95% CI (14%, 66%), p=0.0011), greater CAC prevalence compared to those with the GG genotype. Additional adjustment for ancestry in African-American and Hispanic participants did not change the results. No single SNP was associated with subclinical CVD phenotypes in Chinese or Caucasian participants. There appears to be an association between ADIPOQ SNPs and subclinical CVD in African-American and Hispanics. Replication as well as assessment of other ADIPOQ SNPs appears warranted.
doi:10.1038/oby.2010.229
PMCID: PMC3510267  PMID: 20930713
12.  A Multinomial Ordinal Probit Model with Singular Value Decomposition Method for a Multinomial Trait 
We developed a multinomial ordinal probit model with singular value decomposition for testing a large number of single nucleotide polymorphisms SNPs simultaneously for association with multidisease status when sample size is much smaller than the number of SNPs. The validity and performance of the method was evaluated via simulation. We applied the method to our real study sample recruited through the Mexican-American Coronary Artery Disease study. We found 3 genes SORCS1, AMPD1, and PPARα to be associated with the development of both IGT and IFG, while 5 genes AMPD2, PRKAA2, C5, TCF7L2, and ITR with the IGT mechanism only and 6 genes CAPN10, IL4, NOS3, CD14, GCG, and SORT1 with the IFG mechanism only. These data suggest that IGT and IFG may indicate different physiological mechanism to prediabetes, via different genetic determinants.
doi:10.1155/2012/419832
PMCID: PMC3440186  PMID: 22984364
13.  Genotype Imputation for Latinos Using the HapMap and 1000 Genomes Project Reference Panels 
Frontiers in Genetics  2012;3:117.
Genotype imputation is a vital tool in genome-wide association studies (GWAS) and meta-analyses of multiple GWAS results. Imputation enables researchers to increase genomic coverage and to pool data generated using different genotyping platforms. HapMap samples are often employed as the reference panel. More recently, the 1000 Genomes Project resource is becoming the primary source for reference panels. Multiple GWAS and meta-analyses are targeting Latinos, the most populous, and fastest growing minority group in the US. However, genotype imputation resources for Latinos are rather limited compared to individuals of European ancestry at present, largely because of the lack of good reference data. One choice of reference panel for Latinos is one derived from the population of Mexican individuals in Los Angeles contained in the HapMap Phase 3 project and the 1000 Genomes Project. However, a detailed evaluation of the quality of the imputed genotypes derived from the public reference panels has not yet been reported. Using simulation studies, the Illumina OmniExpress GWAS data from the Los Angles Latino Eye Study and the MACH software package, we evaluated the accuracy of genotype imputation in Latinos. Our results show that the 1000 Genomes Project AMR + CEU + YRI reference panel provides the highest imputation accuracy for Latinos, and that also including Asian samples in the panel can reduce imputation accuracy. We also provide the imputation accuracy for each autosomal chromosome using the 1000 Genomes Project panel for Latinos. Our results serve as a guide to future imputation based analysis in Latinos.
doi:10.3389/fgene.2012.00117
PMCID: PMC3384355  PMID: 22754564
genotype imputation; Latino; HapMap Project; 1000 Genomes Project
14.  Genome-Wide Association of Pericardial Fat Identifies a Unique Locus for Ectopic Fat 
PLoS Genetics  2012;8(5):e1002705.
Pericardial fat is a localized fat depot associated with coronary artery calcium and myocardial infarction. We hypothesized that genetic loci would be associated with pericardial fat independent of other body fat depots. Pericardial fat was quantified in 5,487 individuals of European ancestry from the Framingham Heart Study (FHS) and the Multi-Ethnic Study of Atherosclerosis (MESA). Genotyping was performed using standard arrays and imputed to ∼2.5 million Hapmap SNPs. Each study performed a genome-wide association analysis of pericardial fat adjusted for age, sex, weight, and height. A weighted z-score meta-analysis was conducted, and validation was obtained in an additional 3,602 multi-ethnic individuals from the MESA study. We identified a genome-wide significant signal in our primary meta-analysis at rs10198628 near TRIB2 (MAF 0.49, p = 2.7×10-08). This SNP was not associated with visceral fat (p = 0.17) or body mass index (p = 0.38), although we observed direction-consistent, nominal significance with visceral fat adjusted for BMI (p = 0.01) in the Framingham Heart Study. Our findings were robust among African ancestry (n = 1,442, p = 0.001), Hispanic (n = 1,399, p = 0.004), and Chinese (n = 761, p = 0.007) participants from the MESA study, with a combined p-value of 5.4E-14. We observed TRIB2 gene expression in the pericardial fat of mice. rs10198628 near TRIB2 is associated with pericardial fat but not measures of generalized or visceral adiposity, reinforcing the concept that there are unique genetic underpinnings to ectopic fat distribution.
Author Summary
Pericardial fat is a localized fat depot associated with coronary artery calcium and myocardial infarction. To test whether genetic loci are associated with pericardial fat independent of other body fat depots, we measured pericardial fat in 5,487 individuals of European ancestry. After performing an unbiased screen using genome-wide association, we identified a genome-wide significant signal in our primary meta-analysis at rs10198628 near TRIB2 (MAF 0.49, p = 2.7×10-08). This SNP was not associated with visceral fat (p = 0.17) or body mass index (p = 0.38). Our findings were robust among multi-ethnic participants from the MESA study, with a combined p-value of 5.4E-14. We observed TRIB2 gene expression in the pericardial fat of mice. rs10198628 near TRIB2 is associated with pericardial fat but not measures of generalized or visceral adiposity, reinforcing the concept that there are unique genetic underpinnings to ectopic fat distribution.
doi:10.1371/journal.pgen.1002705
PMCID: PMC3349742  PMID: 22589742
15.  Population Structure of Hispanics in the United States: The Multi-Ethnic Study of Atherosclerosis 
PLoS Genetics  2012;8(4):e1002640.
Using ∼60,000 SNPs selected for minimal linkage disequilibrium, we perform population structure analysis of 1,374 unrelated Hispanic individuals from the Multi-Ethnic Study of Atherosclerosis (MESA), with self-identification corresponding to Central America (n = 93), Cuba (n = 50), the Dominican Republic (n = 203), Mexico (n = 708), Puerto Rico (n = 192), and South America (n = 111). By projection of principal components (PCs) of ancestry to samples from the HapMap phase III and the Human Genome Diversity Panel (HGDP), we show the first two PCs quantify the Caucasian, African, and Native American origins, while the third and fourth PCs bring out an axis that aligns with known South-to-North geographic location of HGDP Native American samples and further separates MESA Mexican versus Central/South American samples along the same axis. Using k-means clustering computed from the first four PCs, we define four subgroups of the MESA Hispanic cohort that show close agreement with self-identification, labeling the clusters as primarily Dominican/Cuban, Mexican, Central/South American, and Puerto Rican. To demonstrate our recommendations for genetic analysis in the MESA Hispanic cohort, we present pooled and stratified association analysis of triglycerides for selected SNPs in the LPL and TRIB1 gene regions, previously reported in GWAS of triglycerides in Caucasians but as yet unconfirmed in Hispanic populations. We report statistically significant evidence for genetic association in both genes, and we further demonstrate the importance of considering population substructure and genetic heterogeneity in genetic association studies performed in the United States Hispanic population.
Author Summary
Using genotype data from about 60,000 distinct genetic markers, we examined population structure in 1,374 unrelated Hispanic individuals from the Multi-Ethnic Study of Atherosclerosis (MESA), with self-identification corresponding to Central America (n = 93), Cuba (n = 50), the Dominican Republic (n = 203), Mexico (n = 708), Puerto Rico (n = 192), and South America (n = 111). By comparing genetic ancestry of MESA Hispanic participants to reference samples representing worldwide diversity, we show major differences in ancestry of MESA Hispanics reflecting their Caucasian, African, and Native American origins, with finer differences corresponding to North-South geographic origins that separate MESA Mexican versus Central/South American samples. Based on our analysis, we define four subgroups of the MESA Hispanic cohort that show close agreement with the following self-identified regions of origin: Dominican/Cuban, Mexican, Central/South American, and Puerto Rican. We examine association of triglycerides with selected genetic markers, and we further demonstrate the importance of considering differences in genetic ancestry (or factors associated with genetic ancestry) when performing genetic studies of the United States Hispanic population.
doi:10.1371/journal.pgen.1002640
PMCID: PMC3325201  PMID: 22511882
16.  Replication of Association of a Novel Insulin Receptor Gene Polymorphism with Polycystic Ovary Syndrome 
Fertility and sterility  2011;95(5):1736-1741.e11.
Objective
To evaluate association with polycystic ovary syndrome (PCOS) of 295 variants in 39 genes central to metabolic insulin signaling and glycogen synthase kinase-3β (GSK-3β) regulation, followed by replication efforts.
Design
Case-control association study, with discovery and replication cohorts.
Setting
Subjects were recruited from reproductive endocrinology clinics, controls were recruited from communities surrounding the University of Alabama at Birmingham and Erasmus Medical Center.
Patients
273 cases with PCOS and 173 controls in the discovery cohort; 526 cases and 3585 controls in the replication cohort. All subjects were Caucasian.
Interventions
Phenotypic and genotypic assessment.
Main Outcome Measures
295 SNPs, PCOS status.
Results
Several SNPs were associated with PCOS in the discovery cohort. Four insulin receptor (INSR) SNPs and three insulin receptor substrate 2 (IRS2) SNPs associated with PCOS (P<0.05) were genotyped in the replication cohort. One INSR SNP (rs2252673) replicated association with PCOS. The minor allele conferred increased odds of PCOS in both cohorts, independent of body mass index (BMI).
Conclusions
A pathway-based, tagging SNP approach allowed us to identify novel INSR SNPs associated with PCOS, one of which confirmed association in a large replication cohort.
doi:10.1016/j.fertnstert.2011.01.015
PMCID: PMC3062664  PMID: 21300347
PCOS; INSR; replication; SNP
17.  The CREB Coactivator CRTC3 Links Catecholamine Signaling to Energy Balance 
Nature  2010;468(7326):933-939.
Under lean conditions, the adipose-derived hormone leptin maintains energy balance in part through CNS-mediated increases in sympathetic outflow that enhance fat burning 1,2. Triggering of beta adrenergic receptors in adipocytes stimulates energy expenditure via cAMP-dependent increases in lipolysis and fatty acid oxidation 3. Although the underlying mechanism is unclear, catecholamine signaling in fat cells is thought to be disrupted in obesity 4, where it may contribute to the ectopic accumulation of lipid in liver and to the development of insulin resistance 5,6. Here we show that the cAMP responsive CREB coactivator CRTC3 promotes obesity by attenuating beta adrenergic receptor signaling in adipose; mice with a knockout of the CRTC3 gene have increased energy expenditure, are resistant to diet induced obesity, and are protected from the development of hepatic steatosis under high fat diet feeding conditions. CRTC3 was activated in response to catecholamine signals, when it reduced adenyl cyclase activity by upregulating the expression of RGS2 7–9, a metabolic syndrome susceptibility gene 10, which we show here is also a direct target of CREB and CRTC3. RGS2 expression was down-regulated in adipocytes from CRTC3−/− mice, leading to increases in insulin and catecholamine signaling that enhanced glucose and fatty acid oxidation. As a common human CRTC3 variant (Ser72Asn), with increased transcriptional activity, is associated with several anthropometric indices of adiposity in two distinct Mexican-American cohorts, our results suggest that adipocyte CRTC3 may play a role in the development of obesity in this population.
doi:10.1038/nature09564
PMCID: PMC3025711  PMID: 21164481
18.  Genetic Predictors of Medically Refractory Ulcerative Colitis 
Inflammatory bowel diseases  2010;16(11):1830-1840.
Background
Acute severe ulcerative colitis (UC) remains a significant clinical challenge and the ability to predict, at an early stage, those individuals at risk of colectomy for medically refractory UC (MR-UC) would be a major clinical advance. The aim of this study was to use a genome-wide association study (GWAS) in a well-characterized cohort of UC patients to identify genetic variation that contributes to MR-UC.
Methods
A GWAS comparing 324 MR-UC patients with 537 Non-MR-UC patients was analyzed using logistic regression and Cox proportional hazards methods. In addition, the MR-UC patients were compared with 2601 healthy controls.
Results
MR-UC was associated with more extensive disease (p= 2.7×10−6) and a positive family history of UC (p= 0.004). A risk score based on the combination of 46 SNPs associated with MR-UC explained 48% of the variance for colectomy risk in our cohort. Risk scores divided into quarters showed the risk of colectomy to be 0%, 17%, 74% and 100% in the four groups. Comparison of the MR-UC subjects with healthy controls confirmed the contribution of the major histocompatibility complex to severe UC (peak association: rs17207986, p= 1.4×10−16) and provided genome-wide suggestive association at the TNFSF15 (TL1A) locus (peak association: rs11554257, p= 1.4×10−6).
Conclusions
A SNP-based risk scoring system, identified here by GWAS analyses, may provide a useful adjunct to clinical parameters for predicting natural history in UC. Furthermore, discovery of genetic processes underlying disease severity may help to identify pathways for novel therapeutic intervention in severe UC.
doi:10.1002/ibd.21293
PMCID: PMC2959149  PMID: 20848476
Ulcerative colitis; Natural History; Genetics
19.  Genome-Wide Association Study Identifies Variants Associated with Histologic Features of Nonalcoholic Fatty Liver Disease 
Gastroenterology  2010;139(5):1567-1576.e6.
Background & Aims
There is little data available from genome-wide association studies (GWAS) of liver histology in patients with non-alcoholic fatty liver disease (NAFLD). We conducted a pilot GWAS in patients with NAFLD, characterized by histology, who were enrolled in the NASH CRN Database Study.
Methods
We studied clinical, laboratory, and histological data from 236 non-Hispanic Caucasian women with NAFLD. We analyzed 324,623 single nucleotide polymorphisms (SNPs) from the 22 autosomal chromosomes. Multivariate-adjusted logistic regression analyses were conducted for binary outcomes and linear regression analysis was applied for quantitative traits. A P-value < 1×10−6 was considered to be significant.
Results
In multivariate models adjusted for age, body mass index, diabetes, waist:hip ratios, and levels of hemoglobin A1c, the NAFLD activity score was associated with the SNP rs2645424 on chromosome 8 in farnesyl diphosphate farnesyl transferase 1 (FDFT1) (P=6.8×10−7). The degree of fibrosis was associated with the SNP rs343062 on chromosome 7 (P=2.7×10−8). SNPs associated with lobular inflammation included SNP rs1227756 on chromosome 10 in COL13A1 (P=2.0×10−7), rs6591182 on chromosome 11 (P=8.6×10−7), and rs887304 on chromosome 12 in EFCAB4B (P=7.7×10−7). SNPs associated with serum levels of alanine aminotransferase included rs2499604 on chromosome 1 (P=2.2×10−6), rs6487679 on chromosome 12 in PZP (P=1.3×10−6), rs1421201 on chromosome 18 (P=1.0×10−5), and rs2710833 on chromosome 4 (P=6.3×10−7). There were no significant associations between genotypes and steatosis, ballooning degeneration, portal inflammation, or other features of NAFLD.
Conclusions
A GWAS significantly associated genetic variants with features of hepatic histology in patients with NAFLD. These findings should be validated in larger and more diverse cohorts.
doi:10.1053/j.gastro.2010.07.057
PMCID: PMC2967576  PMID: 20708005
GWAS; NASH; NAS; NASH CRN; FDFT1; AST
20.  Genome-wide association study of vitamin D concentrations in Hispanic Americans: The IRAS Family Study 
Vitamin D deficiency is associated with many adverse health outcomes. There are several well established environmental predictors of vitamin D concentrations, yet studies of the genetic determinants of vitamin D concentrations are in their infancy. Our objective was to conduct a pilot genome-wide association (GWA) study of 25-hydroxyvitamin D (25[OH]D) and 1,25-dihydroxyvitamin D (1,25[OH]2D) concentrations in a subset of 229 Hispanic subjects, followed by replication genotyping of 50 single nucleotide polymorphisms (SNPs) in the entire sample of 1,190 Hispanics from San Antonio, Texas and San Luis Valley, Colorado. Of the 309,200 SNPs that met all quality control criteria, three SNPs in high linkage disequilibrium (LD) with each other were significantly associated with 1,25[OH]2D (rs6680429, rs9970802, and rs10889028) at a Bonferroni corrected P-value threshold of 1.62 × 10−7, however none met the threshold for 25[OH]D. Of the 50 SNPs selected for replication genotyping, five for 25[OH]D (rs2806508, rs10141935, rs4778359, rs1507023, and rs9937918) and eight for 1,25[OH]2D (rs6680429, rs1348864, rs4559029, rs12667374, rs7781309, rs10505337, rs2486443, and rs2154175) were replicated in the entire sample of Hispanics (P < 0.01). In conclusion, we identified several SNPs that were associated with vitamin D metabolite concentrations in Hispanics. These candidate polymorphisms merit further investigation in independent populations and other ethnicities.
doi:10.1016/j.jsbmb.2010.06.013
PMCID: PMC2949505  PMID: 20600896
Vitamin D; 25-hydroxyvitamin D; 1,25-dihydroxyvitamin D; genome-wide association study; Hispanic
21.  Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47 
Anderson, Carl A. | Boucher, Gabrielle | Lees, Charlie W. | Franke, Andre | D’Amato, Mauro | Taylor, Kent D. | Lee, James C. | Goyette, Philippe | Imielinski, Marcin | Latiano, Anna | Lagacé, Caroline | Scott, Regan | Amininejad, Leila | Bumpstead, Suzannah | Baidoo, Leonard | Baldassano, Robert N. | Barclay, Murray | Bayless, Theodore M. | Brand, Stephan | Büning, Carsten | Colombel, Jean-Frédéric | Denson, Lee A. | De Vos, Martine | Dubinsky, Marla | Edwards, Cathryn | Ellinghaus, David | Fehrmann, Rudolf S.N. | Floyd, James A.B. | Florin, Tim | Franchimont, Denis | Franke, Lude | Georges, Michel | Glas, Jürgen | Glazer, Nicole L. | Guthery, Stephen L. | Haritunians, Talin | Hayward, Nicholas K. | Hugot, Jean-Pierre | Jobin, Gilles | Laukens, Debby | Lawrance, Ian | Lémann, Marc | Levine, Arie | Libioulle, Cecile | Louis, Edouard | McGovern, Dermot P. | Milla, Monica | Montgomery, Grant W. | Morley, Katherine I. | Mowat, Craig | Ng, Aylwin | Newman, William | Ophoff, Roel A | Papi, Laura | Palmieri, Orazio | Peyrin-Biroulet, Laurent | Panés, Julián | Phillips, Anne | Prescott, Natalie J. | Proctor, Deborah D. | Roberts, Rebecca | Russell, Richard | Rutgeerts, Paul | Sanderson, Jeremy | Sans, Miquel | Schumm, Philip | Seibold, Frank | Sharma, Yashoda | Simms, Lisa | Seielstad, Mark | Steinhart, A. Hillary | Targan, Stephan R. | van den Berg, Leonard H. | Vatn, Morten | Verspaget, Hein | Walters, Thomas | Wijmenga, Cisca | Wilson, David C. | Westra, Harm-Jan | Xavier, Ramnik J. | Zhao, Zhen Z. | Ponsioen, Cyriel Y. | Andersen, Vibeke | Torkvist, Leif | Gazouli, Maria | Anagnou, Nicholas P. | Karlsen, Tom H. | Kupcinskas, Limas | Sventoraityte, Jurgita | Mansfield, John C. | Kugathasan, Subra | Silverberg, Mark S. | Halfvarson, Jonas | Rotter, Jerome I. | Mathew, Christopher G. | Griffiths, Anne M. | Gearry, Richard | Ahmad, Tariq | Brant, Steven R. | Chamaillard, Mathias | Satsangi, Jack | Cho, Judy H. | Schreiber, Stefan | Daly, Mark J. | Barrett, Jeffrey C. | Parkes, Miles | Annese, Vito | Hakonarson, Hakon | Radford-Smith, Graham | Duerr, Richard H. | Vermeire, Séverine | Weersma, Rinse K. | Rioux, John D.
Nature genetics  2011;43(3):246-252.
Genome-wide association studies (GWAS) and candidate gene studies in ulcerative colitis (UC) have identified 18 susceptibility loci. We conducted a meta-analysis of 6 UC GWAS, comprising 6,687 cases and 19,718 controls, and followed-up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P<5×10-8), increasing the number of UC associated loci to 47. After annotating associated regions using GRAIL, eQTL data and correlations with non-synonymous SNPs, we identified many candidate genes providing potentially important insights into disease pathogenesis, including IL1R2, IL8RA/B, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease (IBD) risk loci is now 99, including a minimum of 28 shared association signals between Crohn’s disease (CD) and UC.
doi:10.1038/ng.764
PMCID: PMC3084597  PMID: 21297633
22.  Fucosyltransferase 2 (FUT2) non-secretor status is associated with Crohn's disease 
Human Molecular Genetics  2010;19(17):3468-3476.
Genetic variation in both innate and adaptive immune systems is associated with Crohn's disease (CD) susceptibility, but much of the heritability to CD remains unknown. We performed a genome-wide association study (GWAS) in 896 CD cases and 3204 healthy controls all of Caucasian origin as defined by multidimensional scaling. We found supportive evidence for 21 out of 40 CD loci identified in a recent CD GWAS meta-analysis, including two loci which had only nominally achieved replication (rs4807569, 19p13; rs991804, CCL2/CCL7). In addition, we identified associations with genes involved in tight junctions/epithelial integrity (ASHL, ARPC1A), innate immunity (EXOC2), dendritic cell biology [CADM1 (IGSF4)], macrophage development (MMD2), TGF-β signaling (MAP3K7IP1) and FUT2 (a physiological trait that regulates gastrointestinal mucosal expression of blood group A and B antigens) (rs602662, P = 3.4 × 10−5). Twenty percent of Caucasians are ‘non-secretors’ who do not express ABO antigens in saliva as a result of the FUT2 W134X allele. We demonstrated replication in an independent cohort of 1174 CD cases and 357 controls between the four primary FUT2 single nucleotide polymorphisms (SNPs) and CD (rs602662, combined P-value 4.90 × 10−8) and also association with FUT2 W143X (P = 2.6 × 10−5). Further evidence of the relevance of this locus to CD pathogenesis was demonstrated by the association of the original four SNPs and CD in the recently published CD GWAS meta-analysis (rs602662, P = 0.001). These findings strongly implicate this locus in CD susceptibility and highlight the role of the mucus layer in the development of CD.
doi:10.1093/hmg/ddq248
PMCID: PMC2916706  PMID: 20570966
23.  Genome Wide Association (GWA) Predictors Of Anti-TNFα Therapeutic Responsiveness In Pediatric Inflammatory Bowel Disease (IBD) 
Inflammatory bowel diseases  2010;16(8):1357-1366.
Background
Inter-individual variation in response to anti-TNFα therapy may be explained by genetic variability in disease pathogenesis or mechanism of action. Recent genome wide association studies (GWAS) in IBD have increased our understanding of the genetic susceptibility to IBD.
Aim
Test associations of known IBD susceptibility loci and novel “pharmacogenetic” GWAS identified loci with primary non-response to anti-TNFα in pediatric IBD patients and develop a predictive model of primary non-response.
Methods
Primary non response was defined using the HBI for CD and partial Mayo score for UC. Genotyping was performed using the Illumina Infinium platform. Chi square analysis tested associations of phenotype and genotype with primary non-response. Genetic associations were identified by testing known IBD susceptibility loci and by performing a GWAS for primary non-response. Step-wise multiple logistic regression was performed to build predictive models.
Results
Non-response occurred in 22 of 94 subjects. Six known susceptibility loci were associated with primary non-response (p < 0.05). Only the 21q22.2/BRWDI loci remained significant in the predictive model. The most predictive model included 3 novel “pharmacogenetic” GWAS loci, the previously identified BRWD1, pANCA and a UC diagnosis (R2 =0.82 and AUC = 0.98%). The relative risk of non-response increased 15 fold when number of risk factors increased from 0–2 to ≥ 3.
Conclusion
The combination of phenotype and genotype is most predictive of primary non response to anti-TNFα in pediatric IBD. Defining predictors of response to anti-TNFα may allow the identification of patients who will not benefit from this class of therapy.
doi:10.1002/ibd.21174
PMCID: PMC2889173  PMID: 20014019
24.  Variants in the HMG-CoA Reductase (HMGCR) Gene Influence Component Phenotypes in Polycystic Ovary Syndrome 
Fertility and sterility  2009;94(1):255-60.e1-2.
Objective
To study the role of genetic variation in the HMG-CoA reductase (HMGCR) gene in PCOS.
Design
Women with and without PCOS were genotyped for seven single nucleotide polymorphisms (SNPs) in HMGCR. SNPs and haplotypes were determined and tested for association with PCOS and its component traits.
Setting
Subjects were recruited from the reproductive endocrinology clinic at the University of Alabama at Birmingham; controls were recruited from the surrounding community. Genotyping took place at Cedars-Sinai Medical Center in Los Angeles.
Patient(s)
A total of 287 white PCOS women and 187 controls were studied.
Intervention(s)
Phenotypic and genotypic assessment.
Main outcome measure(s)
HMGCR genotype, PCOS diagnosis, androgen levels, metabolic traits.
Result(s)
No association with PCOS was observed. SNP rs4629571 was associated with increased HOMA-IR. Haplotype 3 was associated with increased HOMA-IR; Haplotype 5 was associated with higher sex hormone binding globulin (SHBG) and lower free testosterone.
Conclusion
Variation in the HMGCR gene may influence component features of PCOS including insulin resistance, SHBG, and free testosterone. HMGCR may thus act as a modifier gene in PCOS.
doi:10.1016/j.fertnstert.2009.01.158
PMCID: PMC3032056  PMID: 19327767
polycystic ovary syndrome; HMGCR; insulin resistance; SHBG; androgens
25.  A Genome-wide Association Study of Carotid Atherosclerosis in HIV-infected Men 
AIDS (London, England)  2010;24(4):583-592.
Background
The role of host genetics in the development of subclinical atherosclerosis in the context of HIV infected persons who are being treated with highly active antiretroviral therapy (HAART) is not well understood.
Methods
The present genome-wide association study (GWAS) is based on 177 HIV-positive Caucasian males receiving HAART who participated in the Fat Redistribution and Metabolic Change in HIV Infection (FRAM) Study. Common and internal carotid intima-media thicknesses (cIMT) measured by B-mode ultrasound were used as a subclinical measure of atherosclerosis. Single nucleotide polymorphisms (SNPs) were assayed using the Illumina HumanCNV370-quad beadchip. Copy Number Variants (CNV) were inferred using a hidden Markov Model (PennCNV). Regression analyses were used to assess the association of common and internal cIMT with individual SNPs and CNVs, adjusting for age, duration of antiretroviral treatment, and principal components to account for potential population stratification.
Results
Two SNPs in tight linkage disequilibrium, rs2229116 (a missense, nonsynonymous polymorphism (IIe to Val)) and rs7177922, located in the Ryanodine receptor (RYR3) gene on chromosome 15 were significantly associated with common cIMT (p-value<1.61×10−7). The RYR gene family has been known to play a role in the etiology of cardiovascular disease and has been shown to be regulated by HIV TAT protein.
Conclusions
These results suggest that in the context of HIV infection and HAART, a functional SNP in a biologically plausible candidate gene, RYR3, is associated with increased common carotid IMT, which is a surrogate for atherosclerosis.
doi:10.1097/QAD.0b013e3283353c9e
PMCID: PMC3072760  PMID: 20009918
HIV; HAART; atherosclerosis; GWAS; intima-media thickness

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