Polymorphism of the Serotonin Transporter Gene and Pulmonary Hypertension in Chronic Obstructive Pulmonary Disease

Eddahibi, Saadia; Chaouat, Ari; Morrell, Nicholas W.; Fadel, Élie; Fuhrman, C.; Bugnet, Anne-Sophie; Dartevelle, Philippe; Housset, B.; Hamon, Michel; Weitzenblum, E; Adnot, Serge

doi:10.1161/01.cir.0000091409.53101.e8

Cited by 211 publications

(129 citation statements)

References 18 publications

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“…Individuals with spontaneous primary pulmonary hypertension more frequently have the 5HTTLPR LL genotype. Unlike primarily hypertensive patients, hypoxic patients with COPD do not differ from controls in 5HT-TLPR genotype frequencies; however, the LL variant of 5 HTTLPR in COPD patients, who have higher SERT expression in pulmonary artery cells, was associated with significantly more severe pulmonary hypertension compared to LS or SS patients (Eddahibi et al 2003), what is in accordance with findings in rodent models (Eddahibi et al 2000).…”

Section: Serotonin Transportersupporting

confidence: 82%

The role of gene polymorphisms in the pathogenesis of chronic obstructive pulmonary disease

et al. 2008

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Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide. Irreversible airflow limitation, both progressive and associated with an inflammatory response of the lungs to noxious particles or gases, is a hallmark of the disease. Cigarette smoking is the most important environmental risk factor for COPD, nevertheless, only approximately 20-30% of smokers develop symptomatic disease. Epidemiological studies, case-control studies in relatives of patients with COPD, and twin studies suggest that COPD is a genetically complex disease with environmental factors and many involved genes interacting together. Two major strategies have been employed to identify the genes and the polymorphisms that likely contribute to the development of complex diseases: association studies and linkage analyses. Biologically plausible pathogenetic mechanisms are prerequisites to focus the search for genes of known function in association studies. Protease-antiprotease imbalance, generation of oxidative stress, and chronic inflammation are recognized as the principal mechanisms leading to irreversible airflow obstruction and parenchymal destruction in the lung. Therefore, genes which have been implicated in the pathogenesis of COPD are involved in antiproteolysis, antioxidant barrier and metabolism of xenobiotic substances, inflammatory response to cigarette smoke, airway hyperresponsiveness, and pulmonary vascular remodelling. Significant associations with COPD-related phenotypes have been reported for polymorphisms in genes coding for matrix metalloproteinases, microsomal epoxide hydrolase, glutathione-S-transferases, heme oxygenase, tumor necrosis factor, interleukines 1, 8, and 13, vitamin D-binding protein and β-2-adrenergic receptor (ADRB2), whereas adequately powered replication studies failed to confirm most of the previously observed associations. Genome-wide linkage analyses provide us with a novel tool to identify the general locations of COPD susceptibility genes, and should be followed by association analyses of positional candidate genes from COPD pathophysiology, positional candidate genes selected from gene expression studies, or dense single nucleotide polymorphism panels across regions of linkage. Haplotype analyses of genes with multiple polymorphic sites in linkage disequilibrium, such as the ADRB2 gene, provide another promising field that has yet to be explored in patients with COPD. In the present article we review the current knowledge about gene polymorphisms that have been recently linked to the risk of developing COPD and/or may account for variations in the disease course.

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Section: Serotonin Transportersupporting

confidence: 82%

The role of gene polymorphisms in the pathogenesis of chronic obstructive pulmonary disease

et al. 2008

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“…N Group 3, PH due to lung diseases and/or hypoxia: one study has shown that serotonin gene polymorphism appears to determine the severity of PH in hypoxaemic patients with chronic obstructive pulmonary disease (COPD) [34]. Based on published series, the incidence of significant PH in COPD patients with at least one previous hospitalisation for exacerbation of respiratory failure is 20%.…”

Section: Genetics Epidemiology and Risk Factors Of Pulmonary Hypertementioning

confidence: 99%

“…Recommendations for a PH referral centre are summarised in table 34. ESC/ERS GUIDELINES N. GALIÈ ET AL.…”

Section: Definition Of a Pulmonary Arterial Hypertension Referral Centrementioning

confidence: 99%

Guidelines for the diagnosis and treatment of pulmonary hypertension

Galiè¹,

Hoeper²,

Humbert³

et al. 2012

Revista Portuguesa de Cardiologia (English Edition)

419

738

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“…In one report, the L allele was found to be more prevalent in patients with IPAH than in control subjects (7,15). In a study of patients with chronic obstructive pulmonary disease, 56% of patients had the LL genotype, which was associated with increased SERT transcription and more severe pulmonary hypertension (PH) (16). The role of SERT polymorphisms in the penetrance and severity of PAH is unknown.…”

mentioning

confidence: 99%

Serotonin Transporter Polymorphisms in Familial and Idiopathic Pulmonary Arterial Hypertension

Willers

Newman

Loyd

et al. 2006

Am J Respir Crit Care Med

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Rationale: Serotonin is a pulmonary vasoconstrictor and smooth muscle cell mitogen. The serotonin transporter (SERT) is abundant in pulmonary vascular smooth muscle. Compared with the short (S) allele, the long (L) SERT promoter allele is associated with increased SERT transcription and more severe pulmonary hypertension in a cohort of patients with chronic obstructive pulmonary disease, and was more prevalent in a cohort with idiopathic pulmonary arterial hypertension (IPAH), compared with control subjects. Objective: We hypothesized that the SERT L allele would associate with an earlier age at diagnosis and/or shorter survival interval in pulmonary arterial hypertension (PAH) than the S allele. Methods: SERT promoters from 166 familial PAH (FPAH), 83 IPAH, and 125 control subjects were sequenced. One hundred twentyseven of the patients with FPAH had a known mutation in bone morphogenetic protein receptor 2 (BMPR2). Results: The mean age at diagnosis was 35.8 yr in patients with FPAH and 41.1 yr in patients with IPAH (p ϭ 0.02). There were no significant differences in distribution of the LL, LS, or SS genotypes in IPAH, FPAH, or unaffected BMPR2 mutation carriers. In FPAH, the LL genotype was associated with an earlier age at diagnosis (p Ͻ 0.02). Conclusions:In patients with IPAH, these SERT genotypes do not correlate with age at diagnosis or survival interval. In patients with FPAH, the LL genotype correlates with an earlier age at diagnosis than SL or SS, although survival among the groups was similar. The correlation of the SERT promoter polymorphism with age at diagnosis in FPAH suggests a possible relationship between the SERT and BMPR2.Keywords: familial pulmonary arterial hypertension; 5-HT; 5-HTT; idiopathic pulmonary arterial hypertension; primary pulmonary hypertension; serotonin transporter Much of what is known about the genetic basis of pulmonary arterial hypertension (PAH) is related to mutations in bone morphogenetic protein receptor 2 (BMPR2), which have been identified in over 75% of patients with familial PAH (FPAH) (1-3), but are likely to be responsible for over 90% of FPAH. This discovery has provided a genetic explanation for PAH as

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Polymorphism of the Serotonin Transporter Gene and Pulmonary Hypertension in Chronic Obstructive Pulmonary Disease

Cited by 211 publications

References 18 publications

The role of gene polymorphisms in the pathogenesis of chronic obstructive pulmonary disease

The role of gene polymorphisms in the pathogenesis of chronic obstructive pulmonary disease

Guidelines for the diagnosis and treatment of pulmonary hypertension

Serotonin Transporter Polymorphisms in Familial and Idiopathic Pulmonary Arterial Hypertension

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