Gene–environment interactions in the development of asthma and atopy

References

• Bateman ED, Hurd SS, Barnes PJ et al. Global strategy for asthma management and prevention: GINA executive summary. Eur. Respir. J. 31(1), 143–178 (2008).
   PubMed Web of Science ®Google Scholar
• Proceedings of the ATS Workshop on Refractory Asthma. Current understanding, recommendations, and unanswered questions. Am. J. Respir. Crit. Care Med. 162(6), 2341–2351 (2000).
   PubMedGoogle Scholar
• Ayres JG, Miles JF, Barnes PJ. Brittle asthma. Thorax 53(4), 315–321 (1998).
   PubMed Web of Science ®Google Scholar
• Szefler SJ, Phillips BR, Martinez FD et al. Characterization of within-subject responses to fluticasone and montelukast in childhood asthma. J. Allergy Clin. Immunol. 115(2), 233–242 (2005).
   PubMed Web of Science ®Google Scholar
• Anderson GP. Endotyping asthma: new insights into key pathogenic mechanisms in a complex, heterogeneous disease. Lancet 372(9643), 1107–1119 (2008).
   PubMed Web of Science ®Google Scholar
• Lötvall J, Akdis CA, Bacharier LB et al. Asthma endotypes: a new approach to classification of disease entities within the asthma syndrome. J. Allergy Clin. Immunol. 127(2), 355–360 (2011).
   PubMed Web of Science ®Google Scholar
• Smith JA, Drake R, Simpson A, Woodcock A, Pickles A, Custovic A. Dimensions of respiratory symptoms in preschool children: population-based birth cohort study. Am. J. Respir. Crit. Care Med. 177(12), 1358–1363 (2008).
   PubMedGoogle Scholar
• Martinez FD, Wright AL, Taussig LM, Holberg CJ, Halonen M, Morgan WJ. Asthma and wheezing in the first six years of life. The Group Health Medical Associates. N. Engl. J. Med. 332(3), 133–138 (1995).
   PubMed Web of Science ®Google Scholar
• Lowe LA, Simpson A, Woodcock A, Morris J, Murray CS, Custovic A; NAC Manchester Asthma and Allergy Study Group. Wheeze phenotypes and lung function in preschool children. Am. J. Respir. Crit. Care Med. 171(3), 231–237 (2005).
   PubMed Web of Science ®Google Scholar
• Lowe L, Murray CS, Martin L et al. Reported versus confirmed wheeze and lung function in early life. Arch. Dis. Child. 89(6), 540–543 (2004).
   PubMedGoogle Scholar
• Ober C, Vercelli D. Gene–environment interactions in human disease: nuisance or opportunity? Trends Genet. 27(3), 107–115 (2011).
   PubMed Web of Science ®Google Scholar
• Jenkins MA, Hopper JL, Giles GG. Regressive logistic modeling of familial aggregation for asthma in 7,394 population-based nuclear families. Genet. Epidemiol. 14(3), 317–332 (1997).
   PubMed Web of Science ®Google Scholar
• Duffy DL, Martin NG, Battistutta D, Hopper JL, Mathews JD. Genetics of asthma and hay fever in Australian twins. Am. Rev. Respir. Dis. 142(6 Pt 1), 1351–1358 (1990).
   PubMed Web of Science ®Google Scholar
• Ober C, Hoffjan S. Asthma genetics 2006: the long and winding road to gene discovery. Genes Immun. 7(2), 95–100 (2006).
   PubMed Web of Science ®Google Scholar
• Ober C, Yao TC. The genetics of asthma and allergic disease: a 21st century perspective. Immunol. Rev. 242(1), 10–30 (2011).
   PubMed Web of Science ®Google Scholar
• Daniels SE, Bhattacharrya S, James A et al. A genome-wide search for quantitative trait loci underlying asthma. Nature 383(6597), 247–250 (1996).
   PubMed Web of Science ®Google Scholar
• Van Eerdewegh P, Little RD, Dupuis J et al. Association of the ADAM33 gene with asthma and bronchial hyperresponsiveness. Nature 418(6896), 426–430 (2002).
   PubMed Web of Science ®Google Scholar
• Zhang Y, Leaves NI, Anderson GG et al. Positional cloning of a quantitative trait locus on chromosome 13q14 that influences immunoglobulin E levels and asthma. Nat. Genet. 34(2), 181–186 (2003).
   PubMed Web of Science ®Google Scholar
• Allen M, Heinzmann A, Noguchi E et al. Positional cloning of a novel gene influencing asthma from chromosome 2q14. Nat. Genet. 35(3), 258–263 (2003).
   PubMed Web of Science ®Google Scholar
• Laitinen T, Polvi A, Rydman P et al. Characterization of a common susceptibility locus for asthma-related traits. Science 304(5668), 300–304 (2004).
   PubMed Web of Science ®Google Scholar
• Nicolae D, Cox NJ, Lester LA et al. Fine mapping and positional candidate studies identify HLA-G as an asthma susceptibility gene on chromosome 6p21. Am. J. Hum. Genet. 76(2), 349–357 (2005).
   PubMed Web of Science ®Google Scholar
• Noguchi E, Yokouchi Y, Zhang J et al. Positional identification of an asthma susceptibility gene on human chromosome 5q33. Am. J. Respir. Crit. Care Med. 172(2), 183–188 (2005).
   PubMedGoogle Scholar
• Moffatt MF, Kabesch M, Liang L et al. Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma. Nature 448(7152), 470–473 (2007).
   PubMed Web of Science ®Google Scholar
• Moffatt MF, Gut IG, Demenais F et al.; GABRIEL Consortium. A large-scale, consortium-based genomewide association study of asthma. N. Engl. J. Med. 363(13), 1211–1221 (2010).
   PubMed Web of Science ®Google Scholar
• Ober C, Tan Z, Sun Y et al. Effect of variation in CHI3L1 on serum YKL-40 level, risk of asthma, and lung function. N. Engl. J. Med. 358(16), 1682–1691 (2008).
   PubMed Web of Science ®Google Scholar
• Sleiman PM, Flory J, Imielinski M et al. Variants of DENND1B associated with asthma in children. N. Engl. J. Med. 362(1), 36–44 (2010).
   PubMed Web of Science ®Google Scholar
• Hirschhorn JN, Lohmueller K, Byrne E, Hirschhorn K. A comprehensive review of genetic association studies. Genet. Med. 4(2), 45–61 (2002).
   PubMed Web of Science ®Google Scholar
• Granada M, Wilk JB, Tuzova M et al. A genome-wide association study of plasma total IgE concentrations in the Framingham Heart Study. J. Allergy Clin. Immunol. 129(3), 840–845.e21 (2012).
   PubMed Web of Science ®Google Scholar
• Soler Artigas M, Loth DW, Wain LV et al.; International Lung Cancer ConsortiumGIANT consortium. Genome-wide association and large-scale follow up identifies 16 new loci influencing lung function. Nat. Genet. 43(11), 1082–1090 (2011).
   PubMed Web of Science ®Google Scholar
• Paternoster L, Standl M, Chen CM et al.; Australian Asthma Genetics Consortium (AAGC); Genetics of Overweight Young Adults (GOYA) Consortium; Early Genetics & Lifecourse Epidemiology (EAGLE) Consortium. Meta-analysis of genome-wide association studies identifies three new risk loci for atopic dermatitis. Nat. Genet. 44(2), 187–192 (2012).
   Google Scholar
• Strachan DP, Wong HJ, Spector TD. Concordance and interrelationship of atopic diseases and markers of allergic sensitization among adult female twins. J. Allergy Clin. Immunol. 108(6), 901–907 (2001).
   PubMed Web of Science ®Google Scholar
• Maier LM, Howson JM, Walker N et al. Association of IL13 with total IgE: evidence against an inverse association of atopy and diabetes. J. Allergy Clin. Immunol. 117(6), 1306–1313 (2006).
   PubMed Web of Science ®Google Scholar
• Hancock DB, Eijgelsheim M, Wilk JB et al. Meta-analyses of genome-wide association studies identify multiple loci associated with pulmonary function. Nat. Genet. 42(1), 45–52 (2010).
   PubMed Web of Science ®Google Scholar
• Repapi E, Sayers I, Wain LV et al.; Wellcome Trust Case Control Consortium; NSHD Respiratory Study Team. Genome-wide association study identifies five loci associated with lung function. Nat. Genet. 42(1), 36–44 (2010).
   PubMed Web of Science ®Google Scholar
• Weiss ST. Lung function and airway diseases. Nat. Genet. 42(1), 14–16 (2010).
   PubMed Web of Science ®Google Scholar
• Addo-Yobo EO, Woodcock A, Allotey A, Baffoe-Bonnie B, Strachan D, Custovic A. Exercise-induced bronchospasm and atopy in Ghana: two surveys ten years apart. PLoS Med. 4(2), e70 (2007).
   PubMedGoogle Scholar
• Asher MI, Montefort S, Björkstén B et al.; ISAAC Phase Three Study Group. Worldwide time trends in the prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and eczema in childhood: ISAAC Phases One and Three repeat multicountry cross-sectional surveys. Lancet 368(9537), 733–743 (2006).
   PubMed Web of Science ®Google Scholar
• Custovic A, Simpson A, Woodcock A. Importance of indoor allergens in the induction of allergy and elicitation of allergic disease. Allergy 53(Suppl. 48), 115–120 (1998).
   PubMedGoogle Scholar
• Schaub B, Lauener R, von Mutius E. The many faces of the hygiene hypothesis. J. Allergy Clin. Immunol. 117(5), 969–977; quiz 978 (2006).
   PubMed Web of Science ®Google Scholar
• Simpson A, Custovic A. Pets and the development of allergic sensitization. Curr. Allergy Asthma Rep. 5(3), 212–220 (2005).
   PubMed Web of Science ®Google Scholar
• Hesselmar B, Aberg N, Aberg B, Eriksson B, Björkstén B. Does early exposure to cat or dog protect against later allergy development? Clin. Exp. Allergy 29(5), 611–617 (1999).
   PubMed Web of Science ®Google Scholar
• Noertjojo K, Dimich-Ward H, Obata H, Manfreda J, Chan-Yeung M. Exposure and sensitization to cat dander: asthma and asthma-like symptoms among adults. J. Allergy Clin. Immunol. 103(1 Pt 1), 60–65 (1999).
   PubMed Web of Science ®Google Scholar
• Rhodes HL, Sporik R, Thomas P, Holgate ST, Cogswell JJ. Early life risk factors for adult asthma: a birth cohort study of subjects at risk. J. Allergy Clin. Immunol. 108(5), 720–725 (2001).
   PubMed Web of Science ®Google Scholar
• Simpson A, Custovic A. Early pet exposure: friend or foe? Curr. Opin. Allergy Clin. Immunol. 3(1), 7–14 (2003).
   PubMed Web of Science ®Google Scholar
• Custovic A, Hallam CL, Simpson BM, Craven M, Simpson A, Woodcock A. Decreased prevalence of sensitization to cats with high exposure to cat allergen. J. Allergy Clin. Immunol. 108(4), 537–539 (2001).
   PubMedGoogle Scholar
• Custovic A, Simpson BM, Simpson A et al.; National Asthma Campaign Manchester Asthma and Allergy Study Group. Current mite, cat, and dog allergen exposure, pet ownership, and sensitization to inhalant allergens in adults. J. Allergy Clin. Immunol. 111(2), 402–407 (2003).
   PubMed Web of Science ®Google Scholar
• Hagerhed-Engman L, Bornehag CG, Sundell J, Aberg N. Daycare attendance and increased risk for respiratory and allergic symptoms in preschool age. Allergy 61(4), 447–453 (2006).
   PubMed Web of Science ®Google Scholar
• Nafstad P, Brunekreef B, Skrondal A, Nystad W. Early respiratory infections, asthma, and allergy: 10-year follow-up of the Oslo Birth Cohort. Pediatrics 116(2), e255–e262 (2005).
   PubMedGoogle Scholar
• Nicolaou NC, Simpson A, Lowe LA, Murray CS, Woodcock A, Custovic A. Daycare attendance, position in sibship, and early childhood wheezing: a population-based birth cohort study. J. Allergy Clin. Immunol. 122(3), 500–506.e5 (2008).
   PubMed Web of Science ®Google Scholar
• Simpson A, Custovic A. Prevention of allergic sensitization by environmental control. Curr. Allergy Asthma Rep. 9(5), 363–369 (2009).
   PubMedGoogle Scholar
• Simpson A, Custovic A. Allergen avoidance in the primary prevention of asthma. Curr. Opin. Allergy Clin. Immunol. 4(1), 45–51 (2004).
   PubMedGoogle Scholar
• Woodcock A, Lowe LA, Murray CS et al.; NAC Manchester Asthma and Allergy Study Group. Early life environmental control: effect on symptoms, sensitization, and lung function at age 3 years. Am. J. Respir. Crit. Care Med. 170(4), 433–439 (2004).
   PubMed Web of Science ®Google Scholar
• Simpson A, Simpson B, Custovic A, Craven M, Woodcock A. Stringent environmental control in pregnancy and early life: the long-term effects on mite, cat and dog allergen. Clin. Exp. Allergy 33(9), 1183–1189 (2003).
   PubMedGoogle Scholar
• Gore C, Custovic A. Can we prevent allergy? Allergy 59(2), 151–161 (2004).
   PubMedGoogle Scholar
• Vercelli D, Martinez FD. The Faustian bargain of genetic association studies: bigger might not be better, or at least it might not be good enough. J. Allergy Clin. Immunol. 117(6), 1303–1305 (2006).
   PubMedGoogle Scholar
• Simpson A, John SL, Jury F et al. Endotoxin exposure, CD14, and allergic disease: an interaction between genes and the environment. Am. J. Respir. Crit. Care Med. 174(4), 386–392 (2006).
   PubMed Web of Science ®Google Scholar
• von Mutius E. Allergies, infections and the hygiene hypothesis – the epidemiological evidence. Immunobiology 212(6), 433–439 (2007).
   PubMed Web of Science ®Google Scholar
• Gore C, Custovic A. Protective parasites and medicinal microbes? The case for the hygiene hypothesis. Prim. Care Respir. J. 13(2), 68–75; discussion 83 (2004).
   PubMedGoogle Scholar
• Braun-Fahrländer C, Riedler J, Herz U et al.; Allergy and Endotoxin Study Team. Environmental exposure to endotoxin and its relation to asthma in school-age children. N. Engl. J. Med. 347(12), 869–877 (2002).
   PubMed Web of Science ®Google Scholar
• Gereda JE, Leung DY, Thatayatikom A et al. Relation between house-dust endotoxin exposure, type 1 T-cell development, and allergen sensitisation in infants at high risk of asthma. Lancet 355(9216), 1680–1683 (2000).
   PubMed Web of Science ®Google Scholar
• Nicolaou N, Yiallouros P, Pipis S, Ioannou P, Simpson A, Custovic A. Domestic allergen and endotoxin exposure and allergic sensitization in Cyprus. Pediatr. Allergy Immunol. 17(1), 17–21 (2006).
   PubMedGoogle Scholar
• Böttcher MF, Björkstén B, Gustafson S, Voor T, Jenmalm MC. Endotoxin levels in Estonian and Swedish house dust and atopy in infancy. Clin. Exp. Allergy 33(3), 295–300 (2003).
   PubMed Web of Science ®Google Scholar
• Baldini M, Lohman IC, Halonen M, Erickson RP, Holt PG, Martinez FD. A Polymorphism* in the 5´ flanking region of the CD14 gene is associated with circulating soluble CD14 levels and with total serum immunoglobulin E. Am. J. Respir. Cell Mol. Biol. 20(5), 976–983 (1999).
   PubMed Web of Science ®Google Scholar
• Simpson A, Martinez FD. The role of lipopolysaccharide in the development of atopy in humans. Clin. Exp. Allergy 40(2), 209–223 (2010).
   PubMed Web of Science ®Google Scholar
• Kabesch M, Hasemann K, Schickinger V et al. A promoter polymorphism in the CD14 gene is associated with elevated levels of soluble CD14 but not with IgE or atopic diseases. Allergy 59(5), 520–525 (2004).
   PubMed Web of Science ®Google Scholar
• Ober C, Tsalenko A, Parry R, Cox NJ. A second-generation genomewide screen for asthma-susceptibility alleles in a founder population. Am. J. Hum. Genet. 67(5), 1154–1162 (2000).
   PubMed Web of Science ®Google Scholar
• Eder W, Klimecki W, Yu L et al.; Allergy and Endotoxin Alex Study Team. Opposite effects of CD 14/-260 on serum IgE levels in children raised in different environments. J. Allergy Clin. Immunol. 116(3), 601–607 (2005).
   PubMed Web of Science ®Google Scholar
• Williams LK, McPhee RA, Ownby DR et al. Gene–environment interactions with CD14 C-260T and their relationship to total serum IgE levels in adults. J. Allergy Clin. Immunol. 118(4), 851–857 (2006).
   PubMed Web of Science ®Google Scholar
• Zambelli-Weiner A, Ehrlich E, Stockton ML et al. Evaluation of the CD14/-260 polymorphism and house dust endotoxin exposure in the Barbados Asthma Genetics Study. J. Allergy Clin. Immunol. 115(6), 1203–1209 (2005).
   PubMed Web of Science ®Google Scholar
• Custovic A, Rothers J, Stern D et al. Effect of daycare attendance on sensitization and atopic wheezing differs by Toll-like receptor 2 genotype in 2 population-based birth cohort studies. J. Allergy Clin. Immunol. 127(2), 390–397.e1 (2011).
   PubMedGoogle Scholar
• Sandilands A, Terron-Kwiatkowski A, Hull PR et al. Comprehensive analysis of the gene encoding filaggrin uncovers prevalent and rare mutations in ichthyosis vulgaris and atopic eczema. Nat. Genet. 39(5), 650–654 (2007).
   PubMed Web of Science ®Google Scholar
• Bisgaard H, Simpson A, Palmer CN et al. Gene–environment interaction in the onset of eczema in infancy: filaggrin loss-of-function mutations enhanced by neonatal cat exposure. PLoS Med. 5(6), e131 (2008).
   PubMed Web of Science ®Google Scholar
• Strachan DP, Cook DG. Health effects of passive smoking. 6. Parental smoking and childhood asthma: longitudinal and case–control studies. Thorax 53(3), 204–212 (1998).
   PubMed Web of Science ®Google Scholar
• Chalmers GW, Macleod KJ, Little SA, Thomson LJ, McSharry CP, Thomson NC. Influence of cigarette smoking on inhaled corticosteroid treatment in mild asthma. Thorax 57(3), 226–230 (2002).
   PubMed Web of Science ®Google Scholar
• Murray CS, Woodcock A, Smillie FI, Cain G, Kissen P, Custovic A; NACMAAS Study Group. Tobacco smoke exposure, wheeze, and atopy. Pediatr. Pulmonol. 37(6), 492–498 (2004).
   PubMed Web of Science ®Google Scholar
• Murray CS, Pipis SD, McArdle EC, Lowe LA, Custovic A, Woodcock A; National Asthma Campaign–Manchester Asthma and Allergy Study Group. Lung function at one month of age as a risk factor for infant respiratory symptoms in a high risk population. Thorax 57(5), 388–392 (2002).
   PubMedGoogle Scholar
• Panasevich S, Lindgren C, Kere J et al. Interaction between early maternal smoking and variants in TNF and GSTP1 in childhood wheezing. Clin. Exp. Allergy 40(3), 458–467 (2010).
   PubMedGoogle Scholar
• Palmer CN, Doney AS, Lee SP et al. Glutathione S-transferase M1 and P1 genotype, passive smoking, and peak expiratory flow in asthma. Pediatrics 118(2), 710–716 (2006).
   PubMed Web of Science ®Google Scholar
• Rogers AJ, Brasch-Andersen C, Ionita-Laza I et al. The interaction of glutathione S-transferase M1-null variants with tobacco smoke exposure and the development of childhood asthma. Clin. Exp. Allergy 39(11), 1721–1729 (2009).
   PubMedGoogle Scholar
• Wu H, Romieu I, Sienra-Monge JJ et al. Parental smoking modifies the relation between genetic variation in tumor necrosis factor-alpha (TNF) and childhood asthma. Environ. Health Perspect. 115(4), 616–622 (2007).
   PubMedGoogle Scholar
• Wang Z, Chen C, Niu T et al. Association of asthma with beta(2)-adrenergic receptor gene polymorphism and cigarette smoking. Am. J. Respir. Crit. Care Med. 163(6), 1404–1409 (2001).
   PubMed Web of Science ®Google Scholar
• Colilla S, Nicolae D, Pluzhnikov A et al.; Collaborative Study for the Genetics of Asthma. Evidence for gene–environment interactions in a linkage study of asthma and smoking exposure. J. Allergy Clin. Immunol. 111(4), 840–846 (2003).
   PubMed Web of Science ®Google Scholar
• Dizier MH, Bouzigon E, Guilloud-Bataille M et al. Evidence for gene × smoking exposure interactions in a genome-wide linkage screen of asthma and bronchial hyper-responsiveness in EGEA families. Eur. J. Hum. Genet. 15(7), 810–815 (2007).
   PubMedGoogle Scholar
• Meyers DA, Postma DS, Stine OC et al. Genome screen for asthma and bronchial hyperresponsiveness: interactions with passive smoke exposure. J. Allergy Clin. Immunol. 115(6), 1169–1175 (2005).
   PubMedGoogle Scholar
• Reijmerink NE, Kerkhof M, Koppelman GH et al. Smoke exposure interacts with ADAM33 polymorphisms in the development of lung function and hyperresponsiveness. Allergy 64(6), 898–904 (2009).
   PubMedGoogle Scholar
• Schedel M, Depner M, Schoen C et al. The role of polymorphisms in ADAM33, a disintegrin and metalloprotease 33, in childhood asthma and lung function in two German populations. Respir. Res. 7, 91 (2006).
   PubMed Web of Science ®Google Scholar
• van Diemen CC, Postma DS, Vonk JM, Bruinenberg M, Schouten JP, Boezen HM. A disintegrin and metalloprotease 33 polymorphisms and lung function decline in the general population. Am. J. Respir. Crit. Care Med. 172(3), 329–333 (2005).
   PubMed Web of Science ®Google Scholar
• Ege MJ, Strachan DP, Cookson WO et al.; GABRIELA Study Group. Gene–environment interaction for childhood asthma and exposure to farming in Central Europe. J. Allergy Clin. Immunol. 127(1), 138–144, 144.e1 (2011).
   PubMed Web of Science ®Google Scholar
• Cardon LR, Palmer LJ. Population stratification and spurious allelic association. Lancet 361(9357), 598–604 (2003).
   PubMed Web of Science ®Google Scholar
• Haldar P, Pavord ID, Shaw DE et al. Cluster analysis and clinical asthma phenotypes. Am. J. Respir. Crit. Care Med. 178(3), 218–224 (2008).
   PubMed Web of Science ®Google Scholar
• Henderson J, Granell R, Heron J et al. Associations of wheezing phenotypes in the first 6 years of life with atopy, lung function and airway responsiveness in mid-childhood. Thorax 63(11), 974–980 (2008).
   PubMed Web of Science ®Google Scholar
• Moore WC, Meyers DA, Wenzel SE et al.; National Heart, Lung, and Blood Institute’s Severe Asthma Research Program. Identification of asthma phenotypes using cluster analysis in the Severe Asthma Research Program. Am. J. Respir. Crit. Care Med. 181(4), 315–323 (2010).
   PubMed Web of Science ®Google Scholar
• Spycher BD, Silverman M, Brooke AM, Minder CE, Kuehni CE. Distinguishing phenotypes of childhood wheeze and cough using latent class analysis. Eur. Respir. J. 31(5), 974–981 (2008).
   PubMed Web of Science ®Google Scholar
• Simpson A, Tan VY, Winn J et al. Beyond atopy: multiple patterns of sensitization in relation to asthma in a birth cohort study. Am. J. Respir. Crit. Care Med. 181(11), 1200–1206 (2010).
   PubMed Web of Science ®Google Scholar
• Custovic A, Arifhodzic N, Robinson A, Woodcock A. Exercise testing revisited. The response to exercise in normal and atopic children. Chest 105(4), 1127–1132 (1994).
   PubMed Web of Science ®Google Scholar
• Simpson A, Curtin JA, Winn J, Bishop CM, Custovic A. Genome wide association studies in allergic disease – re-definition of endotypes helps identify true genetic associations. Presented at: 12th International Congress of Human Genetics/61st Annual Meeting of The American Society of Human Genetics. Montreal, Canada, 14 October 2011.
   Google Scholar
• Custovic A, Simpson A. Environmental allergen exposure, sensitisation and asthma: from whole populations to individuals at risk. Thorax 59(10), 825–827 (2004).
   PubMed Web of Science ®Google Scholar