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      Identification of Novel Single Nucleotide Polymorphisms in Inflammatory Genes as Risk Factors Associated with Trachomatous Trichiasis

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          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.

          Methodology/Findings

          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.

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          Most cited references67

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          Global data on visual impairment in the year 2002.

          This paper presents estimates of the prevalence of visual impairment and its causes in 2002, based on the best available evidence derived from recent studies. Estimates were determined from data on low vision and blindness as defined in the International statistical classification of diseases, injuries and causes of death, 10th revision. The number of people with visual impairment worldwide in 2002 was in excess of 161 million, of whom about 37 million were blind. The burden of visual impairment is not distributed uniformly throughout the world: the least developed regions carry the largest share. Visual impairment is also unequally distributed across age groups, being largely confined to adults 50 years of age and older. A distribution imbalance is also found with regard to gender throughout the world: females have a significantly higher risk of having visual impairment than males. Notwithstanding the progress in surgical intervention that has been made in many countries over the last few decades, cataract remains the leading cause of visual impairment in all regions of the world, except in the most developed countries. Other major causes of visual impairment are, in order of importance, glaucoma, age-related macular degeneration, diabetic retinopathy and trachoma.
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            Risk alleles for multiple sclerosis identified by a genomewide study.

            Multiple sclerosis has a clinically significant heritable component. We conducted a genomewide association study to identify alleles associated with the risk of multiple sclerosis. We used DNA microarray technology to identify common DNA sequence variants in 931 family trios (consisting of an affected child and both parents) and tested them for association. For replication, we genotyped another 609 family trios, 2322 case subjects, and 789 control subjects and used genotyping data from two external control data sets. A joint analysis of data from 12,360 subjects was performed to estimate the overall significance and effect size of associations between alleles and the risk of multiple sclerosis. A transmission disequilibrium test of 334,923 single-nucleotide polymorphisms (SNPs) in 931 family trios revealed 49 SNPs having an association with multiple sclerosis (P<1x10(-4)); of these SNPs, 38 were selected for the second-stage analysis. A comparison between the 931 case subjects from the family trios and 2431 control subjects identified an additional nonoverlapping 32 SNPs (P<0.001). An additional 40 SNPs with less stringent P values (<0.01) were also selected, for a total of 110 SNPs for the second-stage analysis. Of these SNPs, two within the interleukin-2 receptor alpha gene (IL2RA) were strongly associated with multiple sclerosis (P=2.96x10(-8)), as were a nonsynonymous SNP in the interleukin-7 receptor alpha gene (IL7RA) (P=2.94x10(-7)) and multiple SNPs in the HLA-DRA locus (P=8.94x10(-81)). Alleles of IL2RA and IL7RA and those in the HLA locus are identified as heritable risk factors for multiple sclerosis. Copyright 2007 Massachusetts Medical Society.
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              A simple system for the assessment of trachoma and its complications.

              A simple grading system for trachoma, based on the presence or absence of five selected "key" signs, has been developed. The method was tested in the field and showed good observer agreement, the most critical point being the identification of severe cases of the disease. It is expected that the system will facilitate the assessment of trachoma and its complications by non-specialist health personnel working at the community level.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2008
                31 October 2008
                : 3
                : 10
                : e3600
                Affiliations
                [1 ]Center for Immunobiology and Vaccine Development, Children's Hospital Oakland Research Institute, Oakland, California, United States of America
                [2 ]Lumbini Rana-Ambika Eye Hospital, Bhairahawa, Nepal
                [3 ]Roche Molecular Systems, Pleasanton, California, United States of America
                [4 ]HLA Laboratory, Children's Hospital Oakland Research Institute, Oakland, California, United States of America
                [5 ]Department of Medicine, University of California at San Francisco School of Medicine, San Francisco, California, United States of America
                [6 ]Joint Graduate Group in Bioengineering, University of California at San Francisco, San Francisco, California, United States of America
                [7 ]University of California Berkeley, Berkeley, California, United States of America
                Ohio State University Medical Center, United States of America
                Author notes

                Conceived and designed the experiments: DD. Analyzed the data: BA TAS DD. Contributed reagents/materials/analysis tools: RPK BS HKA LS HE DD. Wrote the paper: BA TAS DD. Acquisition of data: DD RPK BS HKA. Obtained funding: DD. Supervised study: DD. Critical revision of the manuscript: HE.

                Article
                08-PONE-RA-06041R1
                10.1371/journal.pone.0003600
                2572999
                18974840
                f9714b6b-df7d-47f9-9a1b-04ba5aa8ffd9
                Atik et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 20 August 2008
                : 8 October 2008
                Page count
                Pages: 11
                Categories
                Research Article
                Genetics and Genomics/Genetics of Disease
                Genetics and Genomics/Medical Genetics
                Infectious Diseases/Bacterial Infections
                Infectious Diseases/Neglected Tropical Diseases

                Uncategorized
                Uncategorized

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