Linkage analysis of the 5q31–33 candidate region for asthma in 240 UK families

Holloway, John W.; Lonjou, Christine; Beghè, Bianca; Peng, Qianqian; Gaunt, Tom R.; Gomes, Isabela Bronchtein; Hall, IP; Jc, Dewar; Wilkinson, Jane; Ns, Thomas; Holgate, S. T.; Morton, N.E.

doi:10.1038/sj.gene.6363723

Cited by 25 publications

(19 citation statements)

References 30 publications

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“…Our initial report of linkage of BHR to chromosome 5q31-q33 in Dutch families with asthma (6) has been confirmed in six other populations for asthma-associated phenotypes (7)(8)(9)(10)(11)(12). This finding has been extended by showing that chromosome 5q31-q33 interacts with ETS exposure in utero and/or early childhood in the development of BHR and asthma (13,14).…”

mentioning

confidence: 48%

Identification of PCDH1 as a Novel Susceptibility Gene for Bronchial Hyperresponsiveness

Koppelman¹,

Meyers²,

Howard³

et al. 2009

Am J Respir Crit Care Med

127

140

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Rationale: Asthma is a chronic inflammatory airway disease that affects more than 300 million individuals worldwide. Asthma is caused by interaction of genetic and environmental factors. Bronchial hyperresponsiveness (BHR) is a hallmark of asthma and results from increased sensitivity of the airways to physical or chemical stimulants. BHR and asthma are linked to chromosome 5q31-q33. Objectives: To identify a gene for BHR on chromosome 5q31-q33. Methods: In 200 Dutch families with asthma, linkage analysis and fine mapping were performed, and the Protocadherin 1 gene (PCDH1) was identified. PCDH1 was resequenced in 96 subjects from ethnically diverse populations to identify novel sequence variants. Subsequent replication studies were undertaken in seven populations from The Netherlands, the United Kingdom, and the United States, including two general population samples, two family samples, and three case-control samples. PCDH1 mRNA and protein expression was investigated using polymerase chain reaction, Western blotting, and immunohistochemistry. Measurements and Main Results: In seven out of eight populations (n 5 6,168) from The Netherlands, United Kingdom, and United States, PCHD1 gene variants were significantly associated with BHR (P values, 0.005-0.05) This association was present in both families with asthma and general populations. PCDH1 mRNA and protein were expressed in airway epithelial cells and in macrophages. Conclusions: PCDH1 is a novel gene for BHR in adults and children. The identification of PCDH1 as a BHR susceptibility gene may suggest that a structural defect in the integrity of the airway epithelium, the first line of defense against inhaled substances, contributes to the development of BHR.

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mentioning

confidence: 48%

Identification of PCDH1 as a Novel Susceptibility Gene for Bronchial Hyperresponsiveness

Koppelman¹,

Meyers²,

Howard³

et al. 2009

Am J Respir Crit Care Med

127

140

View full text Add to dashboard Cite

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“…53 54 The protective association of the homozygous TC haplotype with asthma, hayfever, and atopy would be consistent with the evidence from genome-wide scans that genes within the 5q31-33 region are not only important in IBD but also in asthma and atopy. [55][56][57][58] Indeed, candidate genes within the 5q31-33 region, including IL12B gene 59 and IL13, 60 have been associated with asthma and atopy.…”

Section: Discussionmentioning

confidence: 99%

Analysis of the influence of OCTN1/2 variants within the IBD5 locus on disease susceptibility and growth indices in early onset inflammatory bowel disease

Russell

2005

Gut

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Background and aims: The OCTN1 (SLC22A4 1672CRT) and OCTN2 (SLC22A5 2207GRC) variants within the IBD5 locus have been associated with susceptibility to adult onset Crohn's disease (CD), but their contribution in children has not been examined. Methods: These OCTN1/2 variants and IBD5 marker single nucleotide polymorphisms (SNPs) (IGR2096a_1, IGR2198a_1, and IGR2230a_1) were examined in 299 Scottish children (200 with CD, 74 with ulcerative colitis (UC), and 25 with indeterminate colitis (IC)), together with 502 parents (for transmission disequilibrium testing) and 256 controls. Results: All SNPs were in strong linkage disequilibrium (D9 .0.94). TDT analysis showed association of the OCTN1 variant with inflammatory bowel disease (IBD) (p = 0.01) and CD (p = 0.04). Allele frequencies of the OCTN1/2 variants were significantly higher in IBD/CD cases (p,0.04). The homozygous mutant OCTN1/2 haplotype was increased in IBD (24.3% v 16.1%, p = 0.02) and UC (28.2% v 16.1%, p = 0.02) compared with controls. The OCTN1/2 variants were not independent of the background IBD5 risk haplotype in conferring disease susceptibility. Unifactorial analysis in CD patients showed that carriage of the TC haplotype was associated with lower weight, height, and BMI centile (,9 th centile) at diagnosis (weight: 87.9% v 67.3% (p = 0.002), odds ratio (OR) = 3.52 (95% confidence interval, 1.51 to 8.22); height: 84.1% v 68.4% (p,0.05), OR = 2.44 (1.00 to 5.99); BMI: 79.6% v 61.1% (p = 0.02), OR = 2.49 (1.14 to 5.44)), and lower weight centile at follow up (87.5% v 64.6% (p = 0.03), OR = 3.83 (1.03 to 14.24)). Multifactorial binary logistic regression analysis confirmed association of the TC haplotype with lower weight centile at diagnosis (p = 0.02, OR = 3.41 (1.20 to 9.66)). Conclusions: These data implicate variants within the IBD5 haplotype, as determinants of disease susceptibility and growth indices in early onset IBD. The OCTN1/2 variants remain potential positional candidate genes, but require further analysis.

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“…The ␤ 2 -adrenergic receptor has been linked to asthma and its related phenotypes in several studies of different populations, including families from China, Australia, England, Japan, and the United States. [58][59][60][61][62][63] A study of children from the Netherlands demonstrated that elevated serum IgE levels were coinherited with BHR and these traits were linked to an area on chromosome 5q. 64 Marker D11S97 on chromosome 11q13 was first linked to atopy in 1989, 65 and this association subsequently was demonstrated multiple times.…”

Section: Genetic Basis For Asthmamentioning

confidence: 99%

Gene-Environment Interactions and Airway Disease in Children

Schwartz

2009

Pediatrics

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Asthma is the most common chronic disease of childhood in the United States, affecting nearly 6.5 million children. The prevalence and severity of childhood asthma have continued to increase over the past 2 decades, despite major advances in the recognition and treatment of this condition. Representing a heterogeneous collection of airway diseases, asthma has multiple pathologic processes resulting from the interactions of genetic susceptibility and environmental exposures. Preventing and treating airway disease in children will require new research approaches to understanding these complex interactions.

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Linkage analysis of the 5q31–33 candidate region for asthma in 240 UK families

Cited by 25 publications

References 30 publications

Identification of PCDH1 as a Novel Susceptibility Gene for Bronchial Hyperresponsiveness

Identification of PCDH1 as a Novel Susceptibility Gene for Bronchial Hyperresponsiveness

Analysis of the influence of OCTN1/2 variants within the IBD5 locus on disease susceptibility and growth indices in early onset inflammatory bowel disease

Gene-Environment Interactions and Airway Disease in Children

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