Limits...
Identification of novel single nucleotide polymorphisms in inflammatory genes as risk factors associated with trachomatous trichiasis.

Atik B, Skwor TA, Kandel RP, Sharma B, Adhikari HK, Steiner L, Erlich H, Dean D - PLoS ONE (2008)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Center for Immunobiology and Vaccine Development, Children's Hospital Oakland Research Institute, Oakland, California, USA.

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.

Show MeSH

Related in: MedlinePlus

Representative linear array results for Strip 1 for samples from six Tharu individuals from a trachoma endemic area of Nepal.Bands represent wild type and SNP probes (see methods). Strip 1 contains 25 SNPs. Strip 2 contains 26 SNPs (not shown). To the left and right of the probes are the names of the alleles; horizontal blur lines represent amplified alleles.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2572999&req=5

pone-0003600-g001: Representative linear array results for Strip 1 for samples from six Tharu individuals from a trachoma endemic area of Nepal.Bands represent wild type and SNP probes (see methods). Strip 1 contains 25 SNPs. Strip 2 contains 26 SNPs (not shown). To the left and right of the probes are the names of the alleles; horizontal blur lines represent amplified alleles.

Mentions: We used an immobilized probe linear array assay developed by Roche Molecular Systems (Alameda, CA) to genotype 51 biallelic SNPs in 36 genes associated with inflammation as previously described by Barcellos et al.[24], although in the referenced study, only 34 genes were used. The selection of SNPs was based on publicly available databases that included Caucasian and Chinese data. Briefly, 25 ng of genomic DNA from each sample was amplified by multiplex PCR using biotinylated primers for all 51-gene polymorphisms. Two probes were designed for each biallelic site to detect and distinguish between variant sequences. The PCR product was denaturated with 10 µl Amplicor base streptavidin-HRP and a colorless soluble substrate, which is converted into a blue precipitate. Bands on the developed arrays were aligned to a guide to identify the respective allele, and the arrays were scanned into a computer (Figure 1). SNP interpretations were made independently by two individuals masked as to all subject data.


Identification of novel single nucleotide polymorphisms in inflammatory genes as risk factors associated with trachomatous trichiasis.

Atik B, Skwor TA, Kandel RP, Sharma B, Adhikari HK, Steiner L, Erlich H, Dean D - PLoS ONE (2008)

Representative linear array results for Strip 1 for samples from six Tharu individuals from a trachoma endemic area of Nepal.Bands represent wild type and SNP probes (see methods). Strip 1 contains 25 SNPs. Strip 2 contains 26 SNPs (not shown). To the left and right of the probes are the names of the alleles; horizontal blur lines represent amplified alleles.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2572999&req=5

pone-0003600-g001: Representative linear array results for Strip 1 for samples from six Tharu individuals from a trachoma endemic area of Nepal.Bands represent wild type and SNP probes (see methods). Strip 1 contains 25 SNPs. Strip 2 contains 26 SNPs (not shown). To the left and right of the probes are the names of the alleles; horizontal blur lines represent amplified alleles.
Mentions: We used an immobilized probe linear array assay developed by Roche Molecular Systems (Alameda, CA) to genotype 51 biallelic SNPs in 36 genes associated with inflammation as previously described by Barcellos et al.[24], although in the referenced study, only 34 genes were used. The selection of SNPs was based on publicly available databases that included Caucasian and Chinese data. Briefly, 25 ng of genomic DNA from each sample was amplified by multiplex PCR using biotinylated primers for all 51-gene polymorphisms. Two probes were designed for each biallelic site to detect and distinguish between variant sequences. The PCR product was denaturated with 10 µl Amplicor base streptavidin-HRP and a colorless soluble substrate, which is converted into a blue precipitate. Bands on the developed arrays were aligned to a guide to identify the respective allele, and the arrays were scanned into a computer (Figure 1). SNP interpretations were made independently by two individuals masked as to all subject data.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Center for Immunobiology and Vaccine Development, Children's Hospital Oakland Research Institute, Oakland, California, USA.

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.

Show MeSH
Related in: MedlinePlus