Identification of a chronic obstructive pulmonary disease genetic determinant that regulates HHIP

Zhou, Xiaobo; Baron, Rebecca M.; Hardin, Megan; Cho, Michael H.; Zieliński, J; Hawryłkiewicz, I; Śliwiński, Paweł; Hersh, Craig P.; Mancini, John D.; Lu, Ke; Thibault, Derek; Donahue, Amy; Klanderman, Barbara J.; Rosner, Bernard; Raby, Benjamin A.; Lu, Quan; Geldart, Adriana Miele; Layne, Matthew D.; Perrella, Mark A.; Weiss, Scott T.; Choi, Augustine M.K.; Silverman, Edwin K.

doi:10.1093/hmg/ddr569

Cited by 148 publications

(153 citation statements)

References 49 publications

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“…Motivated by human GWAS studies showing that HHIP is associated with both COPD affection status in case-control studies and FEV 1 levels in general population samples (12,13), we demonstrate that HHIP protects aging-related airspace enlargement and increases in lung compliance in mice. Reduction in HHIP expression in COPD lungs (16), as well as in lungs of aging rodents (23), increases susceptibility to develop emphysema during aging. Furthermore, reduced antioxidant capacity and increased oxidant levels in Hhip +/− mice preceded emphysema development.…”

Section: Hhip Interacts With Gstp1 and Enhances Glutathione-conjugatingmentioning

confidence: 99%

“…Therefore, increased cell death and senescence detected in lungs from Hhip +/− mice may result from a combination of autonomous and paracrine effects in multiple cell types. Although more work is needed to characterize autonomous and paracrine effects of HHIP in lungs during aging, it is noteworthy that the increased oxidant burden and increased lymphoid aggregates accompanied by lung function abnormalities in adult Hhip +/− mice recapitulate those seen in human COPD patients carrying risk alleles in the HHIP GWAS locus (16,22).…”

Section: Hhip Interacts With Gstp1 and Enhances Glutathione-conjugatingmentioning

confidence: 99%

“…Deletion of the Hhip gene in mice is neonatally lethal because of defective branching in the lung (14,15). The reduced expression of HHIP in COPD lungs, and reduced enhancer activity associated with COPD risk alleles at the HHIP locus (16), suggested a protective role of HHIP in COPD pathogenesis.…”

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confidence: 99%

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Hhip haploinsufficiency sensitizes mice to age-related emphysema

Lao

Jiang

Yun

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Genetic variants in Hedgehog interacting protein (HHIP) have consistently been associated with the susceptibility to develop chronic obstructive pulmonary disease and pulmonary function levels, including the forced expiratory volume in 1 s (FEV1), in general population samples by genome-wide association studies. However, in vivo evidence connecting Hhip to age-related FEV1 decline and emphysema development is lacking. Herein, using Hhip heterozygous mice (Hhip+/−), we observed increased lung compliance and spontaneous emphysema in Hhip+/− mice starting at 10 mo of age. This increase was preceded by increases in oxidative stress levels in the lungs of Hhip+/− vs. Hhip+/+ mice. To our knowledge, these results provide the first line of evidence that HHIP is involved in maintaining normal lung function and alveolar structures. Interestingly, antioxidant N-acetyl cysteine treatment in mice starting at age of 5 mo improved lung function and prevented emphysema development in Hhip+/− mice, suggesting that N-acetyl cysteine treatment limits the progression of age-related emphysema in Hhip+/− mice. Therefore, reduced lung function and age-related spontaneous emphysema development in Hhip+/− mice may be caused by increased oxidative stress levels in murine lungs as a result of haploinsufficiency of Hhip.

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Section: Hhip Interacts With Gstp1 and Enhances Glutathione-conjugatingmentioning

confidence: 99%

Section: Hhip Interacts With Gstp1 and Enhances Glutathione-conjugatingmentioning

confidence: 99%

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Hhip haploinsufficiency sensitizes mice to age-related emphysema

Lao

Jiang

Yun

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…42 Zhou and colleagues demonstrated a potential role for the HHIP locus in COPD pathogenesis through a series of functional analyses, integrating genetic and molecular biology techniques. 43 They first demonstrated a significant association between the previously identified upstream variant and severe COPD in a cohort of Caucasian smokers from Poland. They then demonstrated reduced HHIP expression in the lung tissue of individuals with COPD compared to smoking controls.…”

Section: Hhipmentioning

confidence: 99%

Chronic Obstructive Pulmonary Disease Genetics: A Review of the Past and a Look Into the Future

Hardin

Silverman

2014

J COPD F

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Abbreviations: single nucleotide polymorphism, SNP; genome-wide association studies, GWAS; forced expiratory volume in 1 second, FEV1; early-onset COPD, EOCOPD; National Emphysema Treatment Trial, NETT; Normative Aging Study, NAS; International COPD Genetics Network, ICGN; linkage disequilibrium, LD; Evaluation of COPD Longitudinally to Identify Surrogate Endpoints, ECLIPSE; cigarettes per day, CPD; forced volume capacity, FVC; Cohorts for Heart and Aging Research in Genetic Epidemiology Consortium, CHARGE; messenger RNA, mRNA; body mass index, BMI; C-reactive protein, CRP; tumor necrosis factor-alpha, TNF-alpha; Clara cell secretory protein, CC16; surfactant protein D, SP-D; Funding: K12 HL120004, The Sheila J. Goodnight, MD, FCCP, Clinical Research Grant in Women's Lung Health, R01HL089856; P01HL105339; R01HL075478 Date of Acceptance: February 28, 2014 Citation: Hardin M, Silverman EK. Chronic obstructive pulmonary disease genetics: a review of the past and a look into the future.

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“…In a previous analysis, we demonstrated that HHIP singlenucleotide polymorphisms (SNPs) were also associated with COPD in a cohort of Polish subjects with severe COPD (12). Given this finding, we examined the relationship between previously reported COPD and lung function GWAS SNPs in this novel population comprised of cases with severe to very severe COPD.…”

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confidence: 93%

CHRNA3/5, IREB2, and ADCY2 Are Associated with Severe Chronic Obstructive Pulmonary Disease in Poland

Hardin

Zieliński

Wan

et al. 2012

Am J Respir Cell Mol Biol

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We examined the association between single-nucleotide polymorphisms (SNPs) previously associated with chronic obstructive pulmonary disease (COPD) and/or lung function with COPD and COPD-related phenotypes in a novel cohort of patients with severe to very severe COPD. We examined 315 cases of COPD and 330 Caucasian control smokers from Poland. We included three SNPs previously associated with COPD: rs7671167 (FAM13A), rs13180 (IREB2), and rs8034191 (CHRNA 3/5), and four SNPs associated with lung function in a genome-wide association study of general population samples: rs2070600 (AGER), rs11134242 (ADCY2), rs4316710 (THSD4), and rs17096090 (INTS12). We tested for associations with severe COPD and COPD-related phenotypes, including lung function, smoking behavior, and body mass index. Subjects with COPD were older (average age 62 versus 58 years, P , 0.01), with more pack-years of smoking (45 versus 33 pack-years, P , 0.01). CHRNA3/5 (odds ratio [OR], 1.89; 95% confidence interval [CI], 1.5-2.4; P ¼ 7.4 3 10 27 ), IREB2 (OR, 0.69; 95% CI, 0.5-0.9; P ¼ 3.4 3 10 23 ), and ADCY2 (OR, 1.35; 95% CI, 1.1-1.7; P ¼ 0.01) demonstrated significant associations with COPD. FAM13A (OR, 0.8; 95% CI, 0.7-1.0; P ¼ 0.11) approached statistical significance. FAM13A and ADCY2 also demonstrated a significant association with lung function. Thus, in severe to very severe COPD, we demonstrate a replication of association between two SNPs previously associated with COPD (CHRNA3/5 and IREB2), as well as an association with COPD of one locus initially associated with lung function (ADCY2).Keywords: chronic obstructive pulmonary disease; genetic association analysis; lung function; smoking; nicotine addiction Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the United States, and its prevalence continues to grow (1). Although cigarette smoking is the most significant risk factor for COPD, cigarette smoking differentially affects lung function decline, and not all smokers will develop COPD (2). The individual response to cigarette smoke and other environmental factors is affected in part by genetic factors, and the development of COPD is the culmination of the environment acting in concert with a complex array of genetic traits (3).Although the development of COPD is mediated by multiple genetic factors, to date few susceptibility genes other than a 1 -antitrypsin (SERPINA1) have been convincingly identified.Early candidate gene studies yielded inconsistent results (4). These studies were limited by small sample sizes and a lack of uniformity in COPD phenotypes, including the degree of airflow obstruction and intensity of smoking exposure in subjects examined. However, several recent genome-wide association studies (GWAS) have identified genomic regions that demonstrate a highly significant and reproducible association with COPD in large studies including subjects with a range of impaired lung function and smoking history. These GWAS regions are located in FAM13A on chromosome 4q22 (5), on chromosome 4q31...

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Identification of a chronic obstructive pulmonary disease genetic determinant that regulates HHIP

Cited by 148 publications

References 49 publications

Hhip haploinsufficiency sensitizes mice to age-related emphysema

Hhip haploinsufficiency sensitizes mice to age-related emphysema

Chronic Obstructive Pulmonary Disease Genetics: A Review of the Past and a Look Into the Future

CHRNA3/5, IREB2, and ADCY2 Are Associated with Severe Chronic Obstructive Pulmonary Disease in Poland

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