Polymorphisms of the Tyrosine Hydroxylase Gene in Subjects Susceptible to High-Altitude Pulmonary Edema

Hanaoka, Masayuki; Droma, Yunden; Hotta, Junichi; Matsuzawa, Y.; Kobayashi, Toshio; Kubo, Keishi; Ôta, Masao

doi:10.1378/chest.123.1.54

Cited by 19 publications

(10 citation statements)

References 30 publications

(40 reference statements)

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“…However, SNPs of tyrosine hydroxylase (Hanaoka et al, 2003) and vascular endothelial growth factor (Hanaoka et al, 2009) were not associated with HAPE susceptibility. Therefore, HAPE susceptibility is heterogeneous, and interactions between genetic and environmental factors result in the condition; however, the genetic factors in the majority of HAPE cases are yet to be elucidated.…”

Section: Introductionmentioning

confidence: 83%

Mitochondrial haplogroup D4 confers resistance and haplogroup B is a genetic risk factor for high-altitude pulmonary edema among Han Chinese

Luo¹,

Gao²,

Li³

et al. 2012

Genet. Mol. Res.

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ABSTRACT. High-altitude pulmonary edema (HAPE) is a lifethreatening condition caused by acute exposure to high altitude. Accumulating evidence suggests that genetic factors play an important role in the etiology of HAPE. However, conclusions from association studies have been hindered by limited sample size due to the rareness of this disease. It is known that mitochondria are critical for hypoxic adaptation, and mitochondrial malfunction can be an important factor in HAPE development. Therefore, we tested the hypothesis that ©FUNPEC-RP www.funpecrp.com.br Genetics and Molecular Research 11 (4): 3658-3667 (2012) Mitochondrial haplogroup and HAPE susceptibility 3659 mitochondrial DNA haplotypes and polymorphisms affect HAPE susceptibility. We recruited 204 HAPE patients and 174 healthy controls in Tibet (3658 m above sea level), all Han Chinese, constituting the largest sample size of all HAPE vulnerability studies. Among mtDNA haplogroups, we found that haplogroup D4 is associated with resistance to HAPE, while haplogroup B is a genetic risk factor for this condition. Haplogroup D4 (tagged by 3010A) may enhance the stability of 16S rRNA, resulting in reduced oxidative stress and protection against HAPE. Within haplogroup B, subhaplogroup B4c (tagged by 15436A and 1119C) was associated with increased risk for HAPE, while subhaplogroup B4b may protect against HAPE. We indicate that there are differences in HAPE susceptibility among mtDNA haplogroups. We conclude that mitochondria are involved in adverse reactions to acute hypoxic exposure; our finding of differences in susceptibility as a function of mitochondrial DNA haplotype may shed light on the pathogenesis of other disorders associated with hypoxia, such as chronic obstructive pulmonary disease.

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Section: Introductionmentioning

confidence: 83%

Mitochondrial haplogroup D4 confers resistance and haplogroup B is a genetic risk factor for high-altitude pulmonary edema among Han Chinese

Luo¹,

Gao²,

Li³

et al. 2012

Genet. Mol. Res.

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“…Furthermore, most HAPE-susceptible individuals have a low hypoxic ventilatory response (HVR) (42,47,72), which leads to a low alveolar PO 2 and thus a greater stimulus to HPV at any given altitude. The hypothesis that polymorphisms of the tyrosine hydroxylase gene leading to decreased peripheral chemoreceptor dopamine synthesis might be associated with blunted HVR and susceptibility to HAPE could not be confirmed in Japanese mountaineers (45). Evidence in support of reduced peripheral chemosensitivity to hypoxia contributing to greater HPV comes from studies where carotid body resection and/or denervation of the lung increases Fig.…”

Section: Characteristics Of Susceptible Individualsmentioning

confidence: 99%

Physiological aspects of high-altitude pulmonary edema

Bärtsch

Mairbäurl²,

Maggiorini³

et al. 2005

Journal of Applied Physiology

295

216

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High-altitude pulmonary edema (HAPE) develops in rapidly ascending nonacclimatized healthy individuals at altitudes above 3,000 m. An excessive rise in pulmonary artery pressure (PAP) preceding edema formation is the crucial pathophysiological factor because drugs that lower PAP prevent HAPE. Measurements of nitric oxide (NO) in exhaled air, of nitrites and nitrates in bronchoalveolar lavage (BAL) fluid, and forearm NO-dependent endothelial function all point to a reduced NO availability in hypoxia as a major cause of the excessive hypoxic PAP rise in HAPE-susceptible individuals. Studies using right heart catheterization or BAL in incipient HAPE have demonstrated that edema is caused by an increased microvascular hydrostatic pressure in the presence of normal left atrial pressure, resulting in leakage of large-molecular-weight proteins and erythrocytes across the alveolarcapillary barrier in the absence of any evidence of inflammation. These studies confirm in humans that high capillary pressure induces a high-permeability-type lung edema in the absence of inflammation, a concept first introduced under the term "stress failure." Recent studies using microspheres in swine and magnetic resonance imaging in humans strongly support the concept and primacy of nonuniform hypoxic arteriolar vasoconstriction to explain how hypoxic pulmonary vasoconstriction occurring predominantly at the arteriolar level can cause leakage. This compelling but as yet unproven mechanism predicts that edema occurs in areas of high blood flow due to lesser vasoconstriction. The combination of high flow at higher pressure results in pressures, which exceed the structural and dynamic capacity of the alveolar capillary barrier to maintain normal alveolar fluid balance. pulmonary artery pressure; hypoxic pulmonary vasoconstriction; nitric oxide; inflammation; alveolar fluid clearance; pathophysiology; review CLINICAL PICTUREHigh-altitude pulmonary edema (HAPE) is noncardiogenic pulmonary edema that usually occurs at altitudes above 3,000 m in rapidly ascending nonacclimatized individuals within the first 2-5 days after arrival. It may also occur in high-altitude dwellers who return from sojourns at low altitude. The first medical description of HAPE was published in Peru and recognized the latter form, also called reentry HAPE, as a pulmonary edema associated with electrographic signs of right ventricular overload (67). The first cases of HAPE in unacclimatized lowlanders climbing to high altitude were reported from the Rocky Mountains (53). The two forms very probably share the same pathophysiology.The reader is referred to other reviews (9,41,96,97) for an extensive presentation of the clinical picture. In this review, we point out some particular characteristics that might elucidate the underlying pathophysiology and are revealed by classical and newly evolving pathophysiological concepts.The prevalence of HAPE depends on the degree of susceptibility, the rate of ascent, and the final altitude. At an altitude of 4,500 m, the prevalence may ...

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“…Few studies have explored the association of polymorphisms of the HIF1a gene with tolerance to high altitude, such as in groups of different ethnic origin [31]. Another single study did not find any association between susceptibility to HAPE and blunted HVR and polymorphisms of the tyrosine hydroxylase (TH) gene, even though TH is a ratelimiting enzyme in the carotid body response to hypoxia [15].…”

Section: Discussionmentioning

confidence: 99%

A role for succinate dehydrogenase genes in low chemoresponsiveness to hypoxia?

et al. 2009

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The detection of hypoxia by the carotid bodies elicits a ventilatory response of utmost importance for tolerance to high altitude. Germline mutations in three genes encoding subunit B, C and D of succinate dehydrogenase (SDHB, SDHC and SDHD) have been associated with paragangliomas of the carotid body. We hypothesized that SDH dysfunction within the carotid body could result in low chemoresponsiveness and intolerance to high altitude. The frequency of polymorphisms of SDHs, hypoxia-inducible factor type 1 (HIF1alpha) and angiotensin converting enzyme (ACE) genes was compared between 40 subjects with intolerance to high altitude and a low hypoxic ventilatory response at exercise (HVRe < or = 0.5 ml min(-1) kg(-1); HVR- group) and 41 subjects without intolerance to high altitude and a high HVRe (> or = 0.80 ml min(-1) kg(-1); HVR+). We found no significant association between low or high HVRe and (1) the allele frequencies for nine single nucleotide polymorphisms (SNPs) in the SDHD and SDHB genes, (2) the ACE insertion/deletion polymorphism and (3) four SNPs in the HIF1alpha gene. However, a marginal significant association was found between the synonymous polymorphism c.18A>C of the SDHB gene and chemoresponsiveness: 8/40 (20%) in the HVR- group and 3/41 (7%) in the HVR+ group (p = 0.12). A principal component analysis showed that no subject carrying the 18C allele had both high ventilatory and cardiac response to hypoxia. In conclusion, no clear association was found between gene variants involved in oxygen sensing and chemoresponsiveness, although some mutations in the SDHB and SDHD genes deserve further investigations in a larger population.

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Polymorphisms of the Tyrosine Hydroxylase Gene in Subjects Susceptible to High-Altitude Pulmonary Edema

Cited by 19 publications

References 30 publications

Mitochondrial haplogroup D4 confers resistance and haplogroup B is a genetic risk factor for high-altitude pulmonary edema among Han Chinese

Mitochondrial haplogroup D4 confers resistance and haplogroup B is a genetic risk factor for high-altitude pulmonary edema among Han Chinese

Physiological aspects of high-altitude pulmonary edema

A role for succinate dehydrogenase genes in low chemoresponsiveness to hypoxia?

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