Genome-Wide Association Study to Identify the Genetic Determinants of Otitis Media Susceptibility in Childhood

Rye, Marie S.; Warrington, Nicole M.; Scaman, Elizabeth S. H.; Vijayasekaran, Shyan; Coates, Harvey; Anderson, Denise; Pennell, Craig E.; Blackwell, Jenefer M.; Jamieson, Sarra E.

doi:10.1371/journal.pone.0048215

Cited by 62 publications

(65 citation statements)

References 46 publications

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“…DNA was extracted from blood samples taken from mothers and adolescents at the 14-or 17-year cohort follow-ups as described elsewhere [25]. Briefly, DNA was extracted from 4 mL ethylenediaminetetraacetic acid (EDTA) anticoagulated blood using Qiagen PureGene chemistry (Qiagen, Hilden, Germany).…”

Section: Dna Extraction and Snp Genotypingmentioning

confidence: 99%

Preeclampsia and cardiovascular disease share genetic risk factors on chromosome 2q22

Løset

Johnson

Melton

et al. 2014

Pregnancy Hypertension: An International Journal of Women's Car

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Objective: Four putative single nucleotide polymorphism (SNP) risk variants at the preeclampsia susceptibility locus on chromosome 2q22; rs2322659 (LCT), rs35821928 (LRP1B), rs115015150 (RND3) and rs17783344 (GCA), were recently shown to associate with known cardiovascular risk factors in a Mexican American cohort. This study aimed to further evaluate the pleiotropic effects of these preeclampsia risk variants in an independent Australian population-based cohort. Methods:The four SNPs were genotyped in the Western Australian Pregnancy Cohort (Raine) Study that included DNA, clinical and biochemical data from 1,246 mothers and 1,404 of their now adolescent offspring. Genotype association analyses were undertaken using the SOLAR software.Results: Nominal associations (P < 0.05) with cardiovascular risk factors were detected for all four SNPs. The LCT SNP was associated with decreased maternal height (P = 0.005) and decreased blood glucose levels in adolescents (P = 0.022). The LRP1B SNP was associated with increased maternal height (P = 0.026) and decreased maternal weight (P = 0.044). The RND3 SNP was associated with decreased triglycerides in adolescents (P = 0.001). The GCA SNP was associated with lower risk in adolescents to be born of a preeclamptic pregnancy (P = 0.003) and having a mother with prior preeclamptic pregnancy (P = 0.033). Conclusions:Our collective findings support the hypothesis that genetic mechanisms for preeclampsia and CVD are, at least in part, shared, but need to be interpreted with some caution as a Bonferroni correction for multiple testing adjusted the statistical significance threshold (adjusted P < 0.001).

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Section: Dna Extraction and Snp Genotypingmentioning

confidence: 99%

Preeclampsia and cardiovascular disease share genetic risk factors on chromosome 2q22

Løset

Johnson

Melton

et al. 2014

Pregnancy Hypertension: An International Journal of Women's Car

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“…115 Analyses included all subjects with available GWAS data from the Raine cohort. OM status was determined using clinical examination and parental report from the first three years of life.…”

Section: Raine Cohort Genome-wide Association Study Of Acute And/or Cmentioning

confidence: 99%

“…115 The most significant associations (P<10 -5 ) from the discovery GWAS were analyzed using the Ingenuity Pathway Analysis and were investigated for replication in WAFSOM. Genes which interact with the TGFβ pathway were focused on due to previous association of Fbxo11 95 in WAFSOM.…”

Section: Family Study Of Otitis Media (Wafsom)mentioning

confidence: 99%

“…Late in the progression of this research, a GWAS of acute and chronic OM was published from a group at the University of Western Australia. 115 In contrast to our GWAS of COME/ROM, this first GWAS of OM included cases with various severities of OM from a general population. With agnostic approaches such as ENU mutatgenesis screens in mice 178 and the first GWAS of acute and chronic OM, additional pathways have been found to be involved in OM risk, including the TGFβ pathway 72,115,179 and HIF-VEGF pathway 13 .…”

Section: Chapter Introductionmentioning

confidence: 99%

“…Recently, the first GWAS for acute and chronic OM in the first three years of life discovered novel associations with OM, including CAPN14, GALNT14, and the BPIFA gene cluster, though the study lacked replication in an independent population of COME/ROM. 115 In an effort to detect common variants contributing to COME/ROM susceptibility, we have conducted the first genome-wide association study (GWAS) of COME/ROM.…”

Section: Introductionmentioning

confidence: 99%

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Chronic Otitis Media: Microbial Environment During Viral Infection and Genetics of Host Susceptibility

Allen

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Otitis media (OM), inflammation of the middle ear, is an upper respiratory tract infection (URTI) caused by viral and bacterial infections. OM is the most common pediatric disease and the leading cause of pediatric health care visits, antibiotic usage and surgery. A subset of OM affected children develops chronic otitis media with effusion (COME) and/or recurrent otitis media (ROM), with significant consequences on hearing and development. The aim of this research was to find novel risk factors that increase OM susceptibility by looking at both bacterial communities during URTI and host genetics. To discover novel OM host risk factors, a multi-stage approach was used. First, a genome-wide association study (GWAS) of COME/ROM was conducted using a familyii based population. The most significantly associated SNP, rs1110060, is located on chromosome 15 in an intron of kinesin family member 7 (KIF7). Association at SNP rs10497394, an intergenic SNP on chromosome 2, was replicated in an independent family-based population of OM. Fine-mapping of associated regions of chromosomes 2 and 15 was carried out using targeted resequencing and subsequent genotyping. Six SNPs were significantly associated (P<2.6x10 -4 ), two in the chromosome 2 region and four in the chromosome 15 region. Explorations of the functional potential of these two loci were carried out. Investigation of chromatin marks revealed an enhancer region on chromosome 2 in the human middle ear epithelial cell line, HMEEC-1. The -G‖ risk allele of the most significantly-associated chromosome 15 SNP, rs1110060, was found to impact expression of IQGAP1 in adenoids (P=0.026). Also, both lipopolysaccharide (LPS) and TGFβ treatment were found to regulate expression of KIF7 in HMEEC-1.The data presented in this dissertation show the complex nature of the microbiome of the nasopharynx during URTI, and we have identified novel regions and genes involved in susceptibility to OM. Moreover, functional assays support the participation of previously unsuspected mechanisms in OM pathogenesis. In summary, this research has provided insights into OM susceptibility from both host and bacterial perspectives.iii Acknowledgements

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Toward Individualization in Medical Education

Barone

Dudas

2016

JAMA Pediatr

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Genome-Wide Association Study to Identify the Genetic Determinants of Otitis Media Susceptibility in Childhood

Cited by 62 publications

References 46 publications

Preeclampsia and cardiovascular disease share genetic risk factors on chromosome 2q22

Preeclampsia and cardiovascular disease share genetic risk factors on chromosome 2q22

Chronic Otitis Media: Microbial Environment During Viral Infection and Genetics of Host Susceptibility

Toward Individualization in Medical Education

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