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Genetic Susceptibility to Obstructive Sleep Apnea in Children

Kalra, Maninder

Abstract Details

2008, PhD, University of Cincinnati, Medicine : Epidemiology (Environmental Health).

Introduction: Obstructive sleep apnea (OSA) affects 2%-5% children and is associated with neurocognitive deficits and cardiovascular and metabolic sequelae. Familial aggregation and heritability of this disorder support a genetic basis for OSA. The overall objective of this research is to identify factors that explain genetic susceptibility to OSA in children. This will enable early diagnosis and therefore intervention, ultimately resulting in reduction in morbidity and the public health concerns associated with OSA in children. The overall research objective will be evaluated with the following two hypotheses. Hypothesis 1: Polymorphisms in candidate genes for central adiposity, craniofacial development, skeletal muscle development, control of breathing and airway collapsibility will be associated with OSA status in children. Hypothesis 2: The genetic risk to OSA is explained by a combination of SNPs which are individually associated with OSA status.

Methods: One hundred and sixty five Caucasian children with OSA, age 2-18 yrs, were recruited as cases. A control group of approximately twice the number of children as in the case group (N=381), with group matching for race and gender, were recruited from subjects enrolled in the Princeton school district study. Comparison of allele frequencies between cases and controls was done by constructing a r x c contingency table- association statistic whose significance was judged by permutation tests. Hardy- Weinberg test of genotype frequencies and Linkage Disequilibrium plot was performed by Helix Tree® version 3.1. Logistic regression analysis was used to explore the effects of multiple genetic variants on disease expression after controlling for BMIz score.

Results: Of the 34 SNPs with genotyping success rate of ≥ 70%, 3 SNPs (rs709156, rs405509 and rs9905842) did not meet Hardy-Weinberg Equilibrium expectation at a P value of 0.001. Comparison of allele frequencies between cases and controls revealed significant differences for 14 of the 31 SNPs included in the analysis (P<0.05). Multivariate logistic regression analysis with OSA (dichotomous) as the dependent variable and BMIz score as covariate revealed a significant association (P<0.001) between OSA and 4 SNPs (rs3121, rs1163254, rs7207113 and rs8110090). The 4 SNPs that were significantly associated with OSA in logistic regression analysis were used to calculate the multilocus genotype risk score. The case group had a significantly higher median genotype risk score as compared to the control group (2.0 vs. 0.0, p< 0.01). Multivariate logistic regression analysis OSA (dichotomous) as dependent variable and BMIz score as covariate revealed a significant association between OSA and total genotype risk score.

Conclusions: We observed an association between polymorphisms involving more than one gene and OSA in children. Further, a combination of SNPs of potential biological relevance in OSA pathogenesis predicted OSA status in children. To our knowledge this is the first report on use of multiple markers in different candidate genes to predict OSA status. These data can be used to identify children at higher risk for OSA, thereby prioritizing them for the overnight polysomnogram.

Ranajit Chakraborty (Committee Chair)
Ranjan Deka (Committee Member)
Grace LeMasters (Committee Member)
Ravindhra Elluru (Committee Member)
59 p.

Recommended Citations

Citations

  • Kalra, M. (2008). Genetic Susceptibility to Obstructive Sleep Apnea in Children [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1226552538

    APA Style (7th edition)

  • Kalra, Maninder. Genetic Susceptibility to Obstructive Sleep Apnea in Children. 2008. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1226552538.

    MLA Style (8th edition)

  • Kalra, Maninder. "Genetic Susceptibility to Obstructive Sleep Apnea in Children." Doctoral dissertation, University of Cincinnati, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1226552538

    Chicago Manual of Style (17th edition)