title: Identification of novel single nucleotide polymorphisms in inflammatory genes as risk factors associated with trachomatous trichiasis.
abstract: BACKGROUND
  Trachoma is the leading preventable cause of global blindness. A balanced Th1/Th2/Th3 immune response is critical for resolving Chlamydia trachomatis infection, the primary cause of trachoma. Despite control programs that include mass antibiotic treatment, reinfection and recurrence of trachoma are common after treatment cessation. Furthermore, a subset of infected individuals develop inflammation and are at greater risk for developing the severe sequela of trachoma known as trachomatous trichiasis (TT). While there are a number of environmental and behavioral risk factors for trachoma, genetic factors that influence inflammation and TT risk remain ill defined.
  
  
  RESULTS
  We identified single nucleotide polymorphisms (SNP) in 36 candidate inflammatory genes and interactions among these SNPs that likely play a role in the overall risk for TT. We conducted a case control study of 538 individuals of Tharu ethnicity residing in an endemic region of Nepal. Trachoma was graded according to World Health Organization guidelines. A linear array was used to genotype 51 biallelic SNPs in the 36 genes. Analyses were performed using logic regression modeling, which controls for multiple comparisons. We present, to our knowledge, the first significant association of TNFA (-308GA), LTA (252A), VCAM1 (-1594TC), and IL9 (T113M) polymorphisms, synergistic SNPs and risk of TT. TT risk decreased 5 times [odds ratio = 0.2 (95% confidence interval 0.11.-0.33), p = 0.001] with the combination of TNFA (-308A), LTA (252A), VCAM1 (-1594C), SCYA 11 (23T) minor allele, and the combination of TNFA (-308A), IL9 (113M), IL1B (5'UTR-T), and VCAM1 (-1594C). However, TT risk increased 13.5 times [odds ratio = 13.5 (95% confidence interval 3.3-22), p = 0.001] with the combination of TNFA (-308G), VDR (intron G), IL4R (50V), and ICAM1 (56M) minor allele.
  
  
  CONCLUSIONS
  Evaluating genetic risk factors for trachoma will advance our understanding of disease pathogenesis, and should be considered in the context of designing global control programs.
authors.affiliation: Center for Immunobiology and Vaccine Development, Children's Hospital Oakland Research Institute, Oakland, California, USA.
authors.forename: Berna
authors.initials: B
authors.lastname: Atik
authors.forename: Troy A
authors.initials: TA
authors.lastname: Skwor
authors.forename: Ram Prasad
authors.initials: RP
authors.lastname: Kandel
authors.forename: Bassant
authors.initials: B
authors.lastname: Sharma
authors.forename: Him Kant
authors.initials: HK
authors.lastname: Adhikari
authors.forename: Lori
authors.initials: L
authors.lastname: Steiner
authors.forename: Henry
authors.initials: H
authors.lastname: Erlich
authors.forename: Deborah
authors.initials: D
authors.lastname: Dean
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D002690:Chlamydia Infections / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics / Q000382:microbiology; D002692:Chlamydia trachomatis / Q000235:genetics / Q000302:isolation & purification; D016207:Cytokines / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007249:Inflammation / Q000150:complications / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009390:Nepal; D020641:Polymorphism, Single Nucleotide; D015995:Prevalence; D040081:Protein Array Analysis; D012307:Risk Factors; D014141:Trachoma / Q000150:complications / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators