Publications by authors named "Hannah C Ainsworth"

16 Publications

  • Page 1 of 1

Intrinsic DNA topology as a prioritization metric in genomic fine-mapping studies.

Nucleic Acids Res 2020 11;48(20):11304-11321

Department of Biostatistics and Data Science, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.

In genomic fine-mapping studies, some approaches leverage annotation data to prioritize likely functional polymorphisms. However, existing annotation resources can present challenges as many lack information for novel variants and/or may be uninformative for non-coding regions. We propose a novel annotation source, sequence-dependent DNA topology, as a prioritization metric for fine-mapping. DNA topology and function are well-intertwined, and as an intrinsic DNA property, it is readily applicable to any genomic region. Here, we constructed and applied Minor Groove Width (MGW) as a prioritization metric. Using an established MGW-prediction method, we generated a MGW census for 199 038 197 SNPs across the human genome. Summarizing a SNP's change in MGW (ΔMGW) as a Euclidean distance, ΔMGW exhibited a strongly right-skewed distribution, highlighting the infrequency of SNPs that generate dissimilar shape profiles. We hypothesized that phenotypically-associated SNPs can be prioritized by ΔMGW. We tested this hypothesis in 116 regions analyzed by a Massively Parallel Reporter Assay and observed enrichment of large ΔMGW for functional polymorphisms (P = 0.0007). To illustrate application in fine-mapping studies, we applied our MGW-prioritization approach to three non-coding regions associated with systemic lupus erythematosus. Together, this study presents the first usage of sequence-dependent DNA topology as a prioritization metric in genomic association studies.
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http://dx.doi.org/10.1093/nar/gkaa877DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7672465PMC
November 2020

Genetic and Clinical Predictors of Age of ESKD in Individuals With Autosomal Dominant Tubulointerstitial Kidney Disease Due to Mutations.

Kidney Int Rep 2020 Sep 3;5(9):1472-1485. Epub 2020 Jul 3.

Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.

Introduction: Autosomal dominant tubulo-interstitial kidney disease due to mutations (ADTKD-) is a rare condition associated with high variability in the age of end-stage kidney disease (ESKD). The minor allele of rs4293393, located in the promoter of the gene, is present in 19% of the population and downregulates uromodulin production by approximately 50% and might affect the age of ESKD. The goal of this study was to better understand the genetic and clinical characteristics of ADTKD- and to perform a Mendelian randomization study to determine if the minor allele of rs4293393 was associated with better kidney survival.

Methods: An international group of collaborators collected clinical and genetic data on 722 affected individuals from 249 families with 125 mutations, including 28 new mutations. The median age of ESKD was 47 years. Men were at a much higher risk of progression to ESKD (hazard ratio 1.78,  < 0.001).

Results: The allele frequency of the minor rs4293393 allele was only 11.6% versus the 19% expected ( < 0.01), resulting in Hardy-Weinberg disequilibrium and precluding a Mendelian randomization experiment. An score reflecting the severity of the trafficking defect of uromodulin mutants was found to be a promising predictor of the age of ESKD.

Conclusion: We report the clinical characteristics associated with 125 mutations. Male gender and a new score predict age of ESKD.
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http://dx.doi.org/10.1016/j.ekir.2020.06.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7486199PMC
September 2020

Kidney-Risk Variants Induce Mitochondrial Fission.

Kidney Int Rep 2020 Jun 30;5(6):891-904. Epub 2020 Mar 30.

Department of Internal Medicine, Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.

Introduction: G1 and G2 nephropathy-risk variants cause mitochondrial dysfunction and contribute to kidney disease. Analyses were performed to determine the genetic regulation of and elucidate potential mechanisms in -nephropathy.

Methods: A global gene expression analysis was performed in human primary renal tubule cell lines derived from 50 African American individuals. Follow-up gene knock out, cell-based rescue, and microscopy experiments were performed.

Results: genotypes did not alter expression levels in the global gene expression analysis. Expression quantitative trait locus (eQTL) analysis in polyinosinic-polycytidylic acid (poly IC)-stimulated renal tubule cells revealed that single nucleotide polymorphism (SNP) rs513349 adjacent to was a eQTL for and a eQTL for ; and were co-expressed in cells. knockout in a human podocyte cell line resulted in diminished APOL1 protein, supporting a pivotal effect for BAK1 on expression. Because BAK1 is involved in mitochondrial dynamics, mitochondrial morphology was examined in primary renal tubule cells and HEK293 Tet-on cells of various genotypes. Mitochondria in wild-type (G0G0) tubule cells maintained elongated morphology when stimulated by low-dose poly IC, whereas those with G1G1, G2G2, and G1G2 genotypes appeared to fragment. HEK293 Tet-on cells overexpressing G0, G1, and G2 were created; G0 cells appeared to promote mitochondrial fusion, whereas G1 and G2 induced mitochondrial fission. The mitochondrial dynamic regulator Mdivi-1 significantly preserved cell viability and mitochondrial cristae structure and reversed mitochondrial fission induced by overexpression of G1 and G2.

Conclusion: Results suggest the mitochondrial fusion/fission pathway may be a therapeutic target in -nephropathy.
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http://dx.doi.org/10.1016/j.ekir.2020.03.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7271005PMC
June 2020

A plausibly causal functional lupus-associated risk variant in the STAT1-STAT4 locus.

Hum Mol Genet 2018 07;27(13):2392-2404

Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.

Systemic lupus erythematosus (SLE or lupus) (OMIM: 152700) is a chronic autoimmune disease with debilitating inflammation that affects multiple organ systems. The STAT1-STAT4 locus is one of the first and most highly replicated genetic loci associated with lupus risk. We performed a fine-mapping study to identify plausible causal variants within the STAT1-STAT4 locus associated with increased lupus disease risk. Using complementary frequentist and Bayesian approaches in trans-ancestral Discovery and Replication cohorts, we found one variant whose association with lupus risk is supported across ancestries in both the Discovery and Replication cohorts: rs11889341. In B cell lines from patients with lupus and healthy controls, the lupus risk allele of rs11889341 was associated with increased STAT1 expression. We demonstrated that the transcription factor HMGA1, a member of the HMG transcription factor family with an AT-hook DNA-binding domain, has enriched binding to the risk allele compared with the non-risk allele of rs11889341. We identified a genotype-dependent repressive element in the DNA within the intron of STAT4 surrounding rs11889341. Consistent with expression quantitative trait locus (eQTL) analysis, the lupus risk allele of rs11889341 decreased the activity of this putative repressor. Altogether, we present a plausible molecular mechanism for increased lupus risk at the STAT1-STAT4 locus in which the risk allele of rs11889341, the most probable causal variant, leads to elevated STAT1 expression in B cells due to decreased repressor activity mediated by increased binding of HMGA1.
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http://dx.doi.org/10.1093/hmg/ddy140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6005081PMC
July 2018

Allele-specific methylation in the genomic region in DNA from human saliva, CD4+ cells, and total leukocytes.

Clin Epigenetics 2018 6;10:46. Epub 2018 Apr 6.

3Department of Physiology and Pharmacology, Wake Forest School of Medicine, 575 N. Patterson Ave. Suite 310, Winston-Salem, NC 27101 USA.

Background: Genetic variants within the fatty acid desaturase () gene cluster (human Chr11) are important regulators of long-chain (LC) polyunsaturated fatty acid (PUFA) biosynthesis in the liver and consequently have been associated with circulating LC-PUFA levels. More recently, epigenetic modifications such as DNA methylation, particularly within the cluster, have been shown to affect LC-PUFA levels. Our lab previously demonstrated strong associations of allele-specific methylation (ASM) between a single nucleotide polymorphism (SNP) rs174537 and CpG sites across the region in human liver tissues. Given that epigenetic signatures are tissue-specific, we aimed to evaluate the methylation status and ASM associations between rs174537 and DNA methylation obtained from human saliva, CD4+ cells and total leukocytes derived from whole blood. The goals were to (1) determine if DNA methylation from these peripheral samples would display similar ASM trends as previously observed in human liver tissues and (2) evaluate the associations between DNA methylation and circulating LC-PUFAs.

Results: DNA methylation at six CpG sites spanning and promoter regions and a putative enhancer region were determined in two Caucasian cohorts of healthy volunteers: leukocytes in cohort 1 ( = 89, median age = 43, 35% male) and saliva and CD4+ cells in cohort 2 ( = 32, median age = 41, 41% male). Significant ASM between rs174537 and DNA methylation at three CpG sites located in the promoter region (i.e., chr11:61594865, chr11:61594876, chr11:61594907) and one CpG site in the putative enhancer region (chr11:61587979) were observed with leukocytes. In CD4+ cells, significant ASM was observed at CpG sites chr11:61594876 and chr11:61584894. Genotype at rs174537 was significantly associated with DNA methylation from leukocytes. Similar trends were observed with CD4+ cells, but not with saliva. DNA methylation from leukocytes and CD4+ cells also significantly correlated with circulating omega-6 LC-PUFAs.

Conclusions: We observed significant ASM between rs174537 and DNA methylation at key regulatory regions in the region from leukocyte and CD4+ cells. DNA methylation from leukocytes also correlated with circulating omega-6 LC-PUFAs. These results support the use of peripheral whole blood samples, with leukocytes showing the most promise for future nutrigenomic studies evaluating epigenetic modifications affecting LC-PUFA biosynthesis in humans.
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http://dx.doi.org/10.1186/s13148-018-0480-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5889567PMC
February 2019

Brief Report: The Genetic Profile of Rheumatoid Factor-Positive Polyarticular Juvenile Idiopathic Arthritis Resembles That of Adult Rheumatoid Arthritis.

Arthritis Rheumatol 2018 06 21;70(6):957-962. Epub 2018 Apr 21.

Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, Georgia.

Objective: Juvenile idiopathic arthritis (JIA) comprises 7 heterogeneous categories of chronic childhood arthritides. Approximately 5% of children with JIA have rheumatoid factor (RF)-positive arthritis, which phenotypically resembles adult rheumatoid arthritis (RA). Our objective was to compare and contrast the genetics of RF-positive polyarticular JIA with those of RA and selected other JIA categories, to more fully understand the pathophysiologic relationships of inflammatory arthropathies.

Methods: Patients with RF-positive polyarticular JIA (n = 340) and controls (n = 14,412) were genotyped using the Immunochip array. Single-nucleotide polymorphisms were tested for association using a logistic regression model adjusting for admixture proportions. We calculated weighted genetic risk scores (wGRS) of reported RA and JIA risk loci, and we compared the ability of these wGRS to predict RF-positive polyarticular JIA.

Results: As expected, the HLA region was strongly associated with RF-positive polyarticular JIA (P = 5.51 × 10 ). Nineteen of 44 RA risk loci and 6 of 27 oligoarticular/RF-negative polyarticular JIA risk loci were associated with RF-positive polyarticular JIA (P < 0.05). The RA wGRS predicted RF-positive polyarticular JIA (area under the curve [AUC] 0.71) better than did the oligoarticular/RF-negative polyarticular JIA wGRS (AUC 0.59). The genetic profile of patients with RF-positive polyarticular JIA was more similar to that of RA patients with age at onset 16-29 years than to that of RA patients with age at onset ≥70 years.

Conclusion: RF-positive polyarticular JIA is genetically more similar to adult RA than to the most common JIA categories and thus appears to be a childhood-onset presentation of autoantibody-positive RA. These findings suggest common disease mechanisms, which could lead to novel therapeutic targets and shared treatment strategies.
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http://dx.doi.org/10.1002/art.40443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5984672PMC
June 2018

Association of Natural Killer Cell Ligand Polymorphism HLA-C Asn80Lys With the Development of Anti-SSA/Ro-Associated Congenital Heart Block.

Arthritis Rheumatol 2017 11 17;69(11):2170-2174. Epub 2017 Oct 17.

New York University Langone Medical Center, New York, New York.

Objective: Fetal exposure to maternal anti-SSA/Ro antibodies is necessary but not sufficient for the development of autoimmune congenital heart block (CHB), suggesting that other factors, such as fetal genetic predisposition, are important. Given the previously described association between major histocompatibility complex alleles and CHB risk, we undertook the present study to test the hypothesis that a variant form of HLA-C Asn80Lys, which binds with high affinity to an inhibitory killer cell immunoglobulin-like receptor (KIR) and thus renders natural killer (NK) cells incapable of restricting inflammation, contributes to the development of CHB.

Methods: Members of 192 pedigrees in the US and Europe (194 cases of CHB, 91 unaffected siblings, 152 fathers, 167 mothers) and 1,073 out-of-study controls were genotyped on the Immunochip single-nucleotide polymorphism microarray. Imputation was used to identify associations at HLA-C Asn80Lys (Asn, C1; Lys, C2) and KIR. Tests for association were performed using logistic regression. McNemar's test and the pedigree disequilibrium test (PDT) were used for matched analyses between affected and unaffected children.

Results: Compared with out-of-study controls of the same sex, the C2 allele was less frequent in the mothers (odds ratio [OR] 0.63, P = 0.0014) and more frequent in the fathers (OR 1.40, P = 0.0123), yielding a significant sex-by-C2 interaction (P = 0.0002). The C2 allele was more frequent in affected siblings than in unaffected siblings (OR 3.67, P = 0.0025), which was consistent with the PDT results (P = 0.016); these results were observed in both sexes and across the US and European cohorts. There was no difference in the frequency of the inhibitory KIR genotype (KIR AA) between affected and unaffected children (P = 0.55).

Conclusion: These data establish C2 as a novel genetic risk factor associated with CHB. This observation supports a model in which fetuses with C2 ligand expression and maternal anti-SSA/Ro positivity may have impaired NK cell surveillance, resulting in unchecked cardiac inflammation and scarring.
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http://dx.doi.org/10.1002/art.40228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5679096PMC
November 2017

Uncovering the DNA methylation landscape in key regulatory regions within the FADS cluster.

PLoS One 2017 28;12(9):e0180903. Epub 2017 Sep 28.

Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston-Salem, NC, United States of America.

Genetic variants near and within the fatty acid desaturase (FADS) cluster are associated with polyunsaturated fatty acid (PUFA) biosynthesis, levels of several disease biomarkers and risk of human disease. However, determining the functional mechanisms by which these genetic variants impact PUFA levels remains a challenge. Utilizing an Illumina 450K array, we previously reported strong allele-specific methylation (ASM) associations (p = 2.69×10-29) between a single nucleotide polymorphism (SNP) rs174537 and DNA methylation of CpG sites located in the putative enhancer region between FADS1 and FADS2, in human liver tissue. However, this array only featured 20 CpG sites within this 12kb region. To better understand the methylation landscape within this region, we conducted bisulfite sequencing of the region between FADS1 and FADS2. Liver tissues from 50 male subjects (27 European Americans, 23 African Americans) were obtained from the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study, and used to ascertain the genotype at rs174537 and methylation status across the region of interest. Associations between rs174537 genotype and methylation status of 136 CpG sites were determined. Age-adjusted linear regressions were used to assess ASM associations with rs174537 genotype. The majority of CpG sites (117 out of 136, 86%) exhibited high levels of methylation with the greatest variability observed at three key regulatory regions-the promoter regions for FADS1 and FADS2 and a putative enhancer site between the two genes. Eight CpG sites within the putative enhancer region displayed significant (FDR p <0.05) ASM associations with rs174537. These data support the concept that both genetic and epigenetic factors regulate PUFA biosynthesis, and raise fundamental questions as to how genetic variants such as rs174537 impact DNA methylation in distant regulatory regions, and ultimately the capacity of tissues to synthesize PUFAs.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0180903PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5619705PMC
October 2017

Transancestral mapping and genetic load in systemic lupus erythematosus.

Authors:
Carl D Langefeld Hannah C Ainsworth Deborah S Cunninghame Graham Jennifer A Kelly Mary E Comeau Miranda C Marion Timothy D Howard Paula S Ramos Jennifer A Croker David L Morris Johanna K Sandling Jonas Carlsson Almlöf Eduardo M Acevedo-Vásquez Graciela S Alarcón Alejandra M Babini Vicente Baca Anders A Bengtsson Guillermo A Berbotto Marc Bijl Elizabeth E Brown Hermine I Brunner Mario H Cardiel Luis Catoggio Ricard Cervera Jorge M Cucho-Venegas Solbritt Rantapää Dahlqvist Sandra D'Alfonso Berta Martins Da Silva Iñigo de la Rúa Figueroa Andrea Doria Jeffrey C Edberg Emőke Endreffy Jorge A Esquivel-Valerio Paul R Fortin Barry I Freedman Johan Frostegård Mercedes A García Ignacio García de la Torre Gary S Gilkeson Dafna D Gladman Iva Gunnarsson Joel M Guthridge Jennifer L Huggins Judith A James Cees G M Kallenberg Diane L Kamen David R Karp Kenneth M Kaufman Leah C Kottyan László Kovács Helle Laustrup Bernard R Lauwerys Quan-Zhen Li Marco A Maradiaga-Ceceña Javier Martín Joseph M McCune David R McWilliams Joan T Merrill Pedro Miranda José F Moctezuma Swapan K Nath Timothy B Niewold Lorena Orozco Norberto Ortego-Centeno Michelle Petri Christian A Pineau Bernardo A Pons-Estel Janet Pope Prithvi Raj Rosalind Ramsey-Goldman John D Reveille Laurie P Russell José M Sabio Carlos A Aguilar-Salinas Hugo R Scherbarth Raffaella Scorza Michael F Seldin Christopher Sjöwall Elisabet Svenungsson Susan D Thompson Sergio M A Toloza Lennart Truedsson Teresa Tusié-Luna Carlos Vasconcelos Luis M Vilá Daniel J Wallace Michael H Weisman Joan E Wither Tushar Bhangale Jorge R Oksenberg John D Rioux Peter K Gregersen Ann-Christine Syvänen Lars Rönnblom Lindsey A Criswell Chaim O Jacob Kathy L Sivils Betty P Tsao Laura E Schanberg Timothy W Behrens Earl D Silverman Marta E Alarcón-Riquelme Robert P Kimberly John B Harley Edward K Wakeland Robert R Graham Patrick M Gaffney Timothy J Vyse

Nat Commun 2017 07 17;8:16021. Epub 2017 Jul 17.

Divisions of Genetics and Molecular Medicine and Immunology, Infection and Inflammatory Diseases, King's College London, Guy's Hospital, London SE1 9RT, UK.

Systemic lupus erythematosus (SLE) is an autoimmune disease with marked gender and ethnic disparities. We report a large transancestral association study of SLE using Immunochip genotype data from 27,574 individuals of European (EA), African (AA) and Hispanic Amerindian (HA) ancestry. We identify 58 distinct non-HLA regions in EA, 9 in AA and 16 in HA (∼50% of these regions have multiple independent associations); these include 24 novel SLE regions (P<5 × 10), refined association signals in established regions, extended associations to additional ancestries, and a disentangled complex HLA multigenic effect. The risk allele count (genetic load) exhibits an accelerating pattern of SLE risk, leading us to posit a cumulative hit hypothesis for autoimmune disease. Comparing results across the three ancestries identifies both ancestry-dependent and ancestry-independent contributions to SLE risk. Our results are consistent with the unique and complex histories of the populations sampled, and collectively help clarify the genetic architecture and ethnic disparities in SLE.
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http://dx.doi.org/10.1038/ncomms16021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5520018PMC
July 2017

Genetic epidemiology in kidney disease.

Nephrol Dial Transplant 2017 04;32(suppl_2):ii159-ii169

Center for Public Health Genomics, Wake Forest School of Medicine, Winston-Salem, NC, USA.

Familial aggregation of chronic kidney disease and its component phenotypes-reduced glomerular filtration rate, proteinuria and renal histologic changes-has long been recognized. Rates of severe kidney disease are also known to differ markedly between populations based on ancestry. These epidemiologic observations support the existence of nephropathy susceptibility genes. Several molecular genetic technologies are now available to identify causative loci. The present article summarizes available strategies useful for identifying nephropathy susceptibility genes, including candidate gene association, family-based linkage, genome-wide association and admixture mapping (mapping by admixture linkage disequilibrium) approaches. Examples of loci detected using these techniques are provided. Epigenetic studies and future directions are also discussed. The identification of nephropathy susceptibility genes, coupled with modifiable environmental triggers impacting their function, is likely to improve risk prediction and transform care. Development of novel therapies to prevent progression of kidney disease will follow.
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http://dx.doi.org/10.1093/ndt/gfw270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5837632PMC
April 2017

Genome-wide imputation study identifies novel HLA locus for pulmonary fibrosis and potential role for auto-immunity in fibrotic idiopathic interstitial pneumonia.

BMC Genet 2016 06 7;17(1):74. Epub 2016 Jun 7.

Center for Genes, Environment and Health, National Jewish Health, Denver, CO, USA.

Background: Fibrotic idiopathic interstitial pneumonias (fIIP) are a group of fatal lung diseases with largely unknown etiology and without definitive treatment other than lung transplant to prolong life. There is strong evidence for the importance of both rare and common genetic risk alleles in familial and sporadic disease. We have previously used genome-wide single nucleotide polymorphism data to identify 10 risk loci for fIIP. Here we extend that work to imputed genome-wide genotypes and conduct new RNA sequencing studies of lung tissue to identify and characterize new fIIP risk loci.

Results: We performed genome-wide genotype imputation association analyses in 1616 non-Hispanic white (NHW) cases and 4683 NHW controls followed by validation and replication (878 cases, 2017 controls) genotyping and targeted gene expression in lung tissue. Following meta-analysis of the discovery and replication populations, we identified a novel fIIP locus in the HLA region of chromosome 6 (rs7887 P meta  = 3.7 × 10(-09)). Imputation of classic HLA alleles identified two in high linkage disequilibrium that are associated with fIIP (DRB1*15:01 P = 1.3 × 10(-7) and DQB1*06:02 P = 6.1 × 10(-8)). Targeted RNA-sequencing of the HLA locus identified 21 genes differentially expressed between fibrotic and control lung tissue (Q < 0.001), many of which are involved in immune and inflammatory response regulation. In addition, the putative risk alleles, DRB1*15:01 and DQB1*06:02, are associated with expression of the DQB1 gene among fIIP cases (Q < 1 × 10(-16)).

Conclusions: We have identified a genome-wide significant association between the HLA region and fIIP. Two HLA alleles are associated with fIIP and affect expression of HLA genes in lung tissue, indicating that the potential genetic risk due to HLA alleles may involve gene regulation in addition to altered protein structure. These studies reveal the importance of the HLA region for risk of fIIP and a basis for the potential etiologic role of auto-immunity in fIIP.
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http://dx.doi.org/10.1186/s12863-016-0377-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4895966PMC
June 2016

Genome-Wide Association Study in an Amerindian Ancestry Population Reveals Novel Systemic Lupus Erythematosus Risk Loci and the Role of European Admixture.

Arthritis Rheumatol 2016 Apr;68(4):932-43

University of Southern California School of Medicine, Los Angeles.

Objective: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with a strong genetic component. We undertook the present work to perform the first genome-wide association study on individuals from the Americas who are enriched for Native American heritage.

Methods: We analyzed 3,710 individuals from the US and 4 countries of Latin America who were diagnosed as having SLE, and healthy controls. Samples were genotyped with HumanOmni1 BeadChip. Data on out-of-study controls genotyped with HumanOmni2.5 were also included. Statistical analyses were performed using SNPtest and SNPGWA. Data were adjusted for genomic control and false discovery rate. Imputation was performed using Impute2 and, for classic HLA alleles, HiBag. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated.

Results: The IRF5-TNPO3 region showed the strongest association and largest OR for SLE (rs10488631: genomic control-adjusted P [Pgcadj ] = 2.61 × 10(-29), OR 2.12 [95% CI 1.88-2.39]), followed by HLA class II on the DQA2-DQB1 loci (rs9275572: Pgcadj  = 1.11 × 10(-16), OR 1.62 [95% CI 1.46-1.80] and rs9271366: Pgcadj  = 6.46 × 10(-12), OR 2.06 [95% CI 1.71-2.50]). Other known SLE loci found to be associated in this population were ITGAM, STAT4, TNIP1, NCF2, and IRAK1. We identified a novel locus on 10q24.33 (rs4917385: Pgcadj  = 1.39 × 10(-8)) with an expression quantitative trait locus (eQTL) effect (Peqtl  = 8.0 × 10(-37) at USMG5/miR1307), and several new suggestive loci. SLE risk loci previously identified in Europeans and Asians were corroborated. Local ancestry estimation showed that the HLA allele risk contribution is of European ancestral origin. Imputation of HLA alleles suggested that autochthonous Native American haplotypes provide protection against development of SLE.

Conclusion: Our results demonstrate that studying admixed populations provides new insights in the delineation of the genetic architecture that underlies autoimmune and complex diseases.
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http://dx.doi.org/10.1002/art.39504DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4829354PMC
April 2016

LTC4 synthase polymorphism modifies efficacy of botanical seed oil combination in asthma.

Springerplus 2014 6;3:661. Epub 2014 Nov 6.

Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115 USA.

Unlabelled: Botanical seed oils reduce the generation of leukotrienes in patients with asthma. Our objective was to determine the efficacy of a botanical seed oil combination against airflow obstruction in asthma, and to determine the pharmacogenomic effect of the leukotriene C4 synthase (LTC4S) polymorphism A-444C. We conducted a randomized, double-blind, placebo-controlled, cross-over clinical trial in mild to moderate asthmatics to determine the change in FEV1 after 6 weeks of therapy with borage and echium seed oils versus corn oil placebo. We also examined the effect of the variant LTC4S -444C allele on the change in lung function. We did not identify a difference in FEV1 in the study cohort as a whole (n = 28), nor in the group of A homozygotes. In the C allele carriers (n = 9), FEV1 improved by 3% after treatment with borage and echium seed oils and declined by 4% after placebo corn oil (p = 0.02). All 9 C allele carriers demonstrated an improvement in their FEV1 on active treatment compared to placebo as compared to only 7 out of 19 A allele homozygotes (p = 0.007). We observed transient differences in ex vivo leukotriene generation from circulating basophils and granulocytes. We did not observe significant differences in urinary LTE4 levels. We conclude that compared to corn oil, a combination of borage and echium seed oils improves airflow obstruction in mild to moderate asthmatics who carry the variant allele in the LTC4S gene (A-444C). Botanical oil supplementation may have therapeutic potential in asthma if used in a personalized manner.

Trial Registration: This trial was registered at http://www.clinicaltrials.gov as NCT00806442.
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http://dx.doi.org/10.1186/2193-1801-3-661DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4236308PMC
December 2014

DNA methylation in an enhancer region of the FADS cluster is associated with FADS activity in human liver.

PLoS One 2014 19;9(5):e97510. Epub 2014 May 19.

Department of Physiology/Pharmacology, Wake Forest Health Sciences, Winston-Salem, North Carolina, United States of America; Wake Forest Center for Botanical Lipids and Inflammatory Disease Prevention, Wake Forest University Health Sciences, Winston-Salem, North Carolina, United States of America.

Levels of omega-6 (n-6) and omega-3 (n-3), long chain polyunsaturated fatty acids (LcPUFAs) such as arachidonic acid (AA; 20:4, n-6), eicosapentaenoic acid (EPA; 20:5, n-3) and docosahexaenoic acid (DHA; 22:6, n-3) impact a wide range of biological activities, including immune signaling, inflammation, and brain development and function. Two desaturase steps (Δ6, encoded by FADS2 and Δ5, encoded by FADS1) are rate limiting in the conversion of dietary essential 18 carbon PUFAs (18C-PUFAs) such as LA (18:2, n-6) to AA and α-linolenic acid (ALA, 18:3, n-3) to EPA and DHA. GWAS and candidate gene studies have consistently identified genetic variants within FADS1 and FADS2 as determinants of desaturase efficiencies and levels of LcPUFAs in circulating, cellular and breast milk lipids. Importantly, these same variants are documented determinants of important cardiovascular disease risk factors (total, LDL, and HDL cholesterol, triglycerides, CRP and proinflammatory eicosanoids). FADS1 and FADS2 lie head-to-head (5' to 5') in a cluster configuration on chromosome 11 (11q12.2). There is considerable linkage disequilibrium (LD) in this region, where multiple SNPs display association with LcPUFA levels. For instance, rs174537, located ∼ 15 kb downstream of FADS1, is associated with both FADS1 desaturase activity and with circulating AA levels (p-value for AA levels = 5.95 × 10(-46)) in humans. To determine if DNA methylation variation impacts FADS activities, we performed genome-wide allele-specific methylation (ASM) with rs174537 in 144 human liver samples. This approach identified highly significant ASM with CpG sites between FADS1 and FADS2 in a putative enhancer signature region, leading to the hypothesis that the phenotypic associations of rs174537 are likely due to methylation differences. In support of this hypothesis, methylation levels of the most significant probe were strongly associated with FADS1 and, to a lesser degree, FADS2 activities.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0097510PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4026313PMC
December 2014

Adaptive evolution of the FADS gene cluster within Africa.

PLoS One 2012 19;7(9):e44926. Epub 2012 Sep 19.

Division of General Internal Medicine, Department of Medicine, The Johns Hopkins University, Baltimore, Maryland, United States of America.

Long chain polyunsaturated fatty acids (LC-PUFAs) are essential for brain structure, development, and function, and adequate dietary quantities of LC-PUFAs are thought to have been necessary for both brain expansion and the increase in brain complexity observed during modern human evolution. Previous studies conducted in largely European populations suggest that humans have limited capacity to synthesize brain LC-PUFAs such as docosahexaenoic acid (DHA) from plant-based medium chain (MC) PUFAs due to limited desaturase activity. Population-based differences in LC-PUFA levels and their product-to-substrate ratios can, in part, be explained by polymorphisms in the fatty acid desaturase (FADS) gene cluster, which have been associated with increased conversion of MC-PUFAs to LC-PUFAs. Here, we show evidence that these high efficiency converter alleles in the FADS gene cluster were likely driven to near fixation in African populations by positive selection ∼85 kya. We hypothesize that selection at FADS variants, which increase LC-PUFA synthesis from plant-based MC-PUFAs, played an important role in allowing African populations obligatorily tethered to marine sources for LC-PUFAs in isolated geographic regions, to rapidly expand throughout the African continent 60-80 kya.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0044926PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3446990PMC
March 2013

Differences in arachidonic acid levels and fatty acid desaturase (FADS) gene variants in African Americans and European Americans with diabetes or the metabolic syndrome.

Br J Nutr 2012 Feb 4;107(4):547-55. Epub 2011 Jul 4.

The Center for Botanical Lipids and Inflammatory Disease Prevention, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.

Over the past 50 years, increases in dietary n-6 PUFA, such as linoleic acid, have been hypothesised to cause or exacerbate chronic inflammatory diseases. The present study examines an individual's innate capacity to synthesise n-6 long-chain PUFA (LC-PUFA) with respect to the fatty acid desaturase (FADS) locus in Americans of African and European descent with diabetes or the metabolic syndrome. Compared with European Americans (EAm), African Americans (AfAm) exhibited markedly higher serum levels of arachidonic acid (AA) (EAm 7·9 (sd 2·1), AfAm 9·8 (sd 1·9) % of total fatty acids; P < 2·29 × 10⁻⁹) and the AA:n-6-precursor fatty acid ratio, which estimates FADS1 activity (EAm 5·4 (sd 2·2), AfAm 6·9 (sd 2·2); P = 1·44 × 10⁻⁵). In all, seven SNP mapping to the FADS locus revealed strong association with AA, EPA and dihomo-γ-linolenic acid (DGLA) in the EAm. Importantly, EAm homozygous for the minor allele (T) had significantly lower AA levels (TT 6·3 (sd 1·0); GG 8·5 (sd 2·1); P = 3·0 × 10⁻⁵) and AA:DGLA ratios (TT 3·4 (sd 0·8), GG 6·5 (sd 2·3); P = 2·2 × 10⁻⁷) but higher DGLA levels (TT 1·9 (sd 0·4), GG 1·4 (sd 0·4); P = 3·3 × 10⁻⁷) compared with those homozygous for the major allele (GG). Allele frequency patterns suggest that the GG genotype at rs174537 (associated with higher circulating levels of AA) is much higher in AfAm (0·81) compared with EAm (0·46). Similarly, marked differences in rs174537 genotypic frequencies were observed in HapMap populations. These data suggest that there are probably important differences in the capacity of different populations to synthesise LC-PUFA. These differences may provide a genetic mechanism contributing to health disparities between populations of African and European descent.
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http://dx.doi.org/10.1017/S0007114511003230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3494092PMC
February 2012