ALDH2 polymorphisms and bone mineral density in an elderly Japanese population

Yao, Jin; Hasegawa, Yukiharu; Kawasaki, Masashi; Masui, Tetsuo; Kanoh, Toshiyuki; Ishiguro, Naoki; Hamajima, Nobuyuki

doi:10.1007/s00198-006-0077-2

Cited by 47 publications

(33 citation statements)

References 43 publications

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“…Contrary to the results presented here, it has been reported that GSTM1 and GSTT1 gene deletion genotypes do not significantly affect susceptibility to osteoporosis in Japanese osteoporotic patients assessed using ultrasound bone tissue measurement [24]. According to published data, the genetic diversity in the Japanese population shows slightly higher GSTM1*0 genotype (55.8%) and significantly higher GSTT1*0 genotype (40.0%) frequencies than in the Slovenian population (49.0% and 21.3%, respectively).…”

Section: Discussioncontrasting

confidence: 99%

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Opposite Effects ofGSTM1– andGSTT1– Gene Deletion Variants on Bone Mineral Density

et al. 2011

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Abstract.Oxidative stress is associated with osteoporosis. The glutathione S-transferases form the major detoxifying group of enzymes responsible for eliminating products of oxidative stress. We have therefore proposed GSTM1 and GSTT1 genes as candidates for studying the genetics of osteoporosis. The aim of the present study was to examine possible association of GSTM1 and GSTT1 gene deletion polymorphisms, alone or in combination, with bone mineral density at femoral neck (BMD fn), lumbar spine (BMD ls) and total hip (BMD th) in Slovenian elderly women and men. GSTM1 and GSTT1 gene deletion polymorphisms in 712 elderly people were analyzed using the triplex PCR method for the presence of GSTM1 and GSTT1 gene segments. BMD fn, BMD ls and BMD th were measured by the dual-energy X-ray absorptiometry (DEXA) method. Results were analyzed using univariate statistic model adjusted for sex, body mass index (BMI) and age. Our results showed the significant differences in BMD th, BMD ls and BMD fn values (p = 0.031, 0.017 and 0.023, respectively) in subgroups of GSTT1 gene deletion polymorphism. For GSTM1 gene deletion polymorphism borderline significant association was found with BMD ls (p = 0.100). Furthermore, subjects with homozygous deletion of GSTT1 gene showed higher BMD values on all measured skeletal sites and, in contrast, subjects with homozygous deletion of GSTM1 gene showed lower BMD values. Moreover, a gene-gene interaction study showed significant association of GSTM1-null and GSTT1-null polymorphisms with BMD ls values (p = 0.044). Carriers with a combination of the presence of GSTT1 gene and the homozygous absence of GSTM1 gene fragment were associated with the lower BMD values at all skeletal sites. The significant association of combination of GSTT1 gene presence and homozygous absence of GSTM1 gene with BMD was demonstrated, suggesting that it could be used, if validated in other studies, as genetic marker for low BMD.

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Section: Discussioncontrasting

confidence: 99%

“…While there are data on their potentiation of risk of cytogenetic damage in many diseases, only one osteoporosis-association study on deletion polymorphisms of GSTT1 and GSTM1 genes has been reported; it showed no significant association with bone density values in an elderly Japanese population [24].…”

Section: Introductionmentioning

confidence: 97%

Opposite Effects ofGSTM1– andGSTT1– Gene Deletion Variants on Bone Mineral Density

et al. 2011

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“…In humans, however, the suppression of ALDH2 activity by ALDH2*2 causes various disorders, presumably because of increased oxidative stress. For instance, ALDH2 deficiency was found to contribute to the risk of complication with diabetes mellitus, hypertension, myocardial infarction, osteoporosis, and cancer (Suzuki et al, 1996;Amamoto et al, 2002;Takagi et al, 2002;Yokoyama and Omori, 2003;Yamaguchi et al, 2006). Therefore, we expected the development of model animals closer to humans by introducing the ALDH2*2 gene.…”

Section: Discussionmentioning

confidence: 99%

Age-Dependent Neurodegeneration Accompanying Memory Loss in Transgenic Mice Defective in Mitochondrial Aldehyde Dehydrogenase 2 Activity

Ohsawa

Nishimaki²,

Murakami³

et al. 2008

Journal of Neuroscience

102

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Oxidative stress may underlie age-dependent memory loss and cognitive decline. Toxic aldehydes, including 4-hydroxy-2-nonenal (HNE), an end product of lipid peroxides, are known to accumulate in the brain in neurodegenerative disease. We have previously shown that mitochondrial aldehyde dehydrogenase 2 (ALDH2) detoxifies HNE by oxidizing its aldehyde group. To investigate the role of such toxic aldehydes, we produced transgenic mice, which expressed a dominant-negative form of ALDH2 in the brain. The mice had decreased ability to detoxify HNE in their cortical neurons and accelerated accumulation of HNE in the brain. Consequently, their lifespan was shortened and age-dependent neurodegeneration and hyperphosphorylation of tau were observed. Object recognition and Morris water maze tests revealed that the onset of cognitive impairment correlated with the degeneration, which was further accelerated by APOE (apolipoprotein E) knock-out; therefore, the accumulation of toxic aldehydes is by itself critical in the progression of neurodegenerative disease, which could be suppressed by ALDH2.

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“…ALDH2*2 and osteoporosis: Osteoporosis is characterized by a decrease in bone mineral density, bone mass, and bone strength, which ultimately leads to an increased risk of fracture [59]. In a genetic screen of known osteoporosis related genes in 403 elderly Japanese, ALDH2*2 was the only mutation strongly associated with the risk of osteoporosis [60]. This association was especially prevalent in ALDH2*2/2 homozygotes and in women.…”

Section: Diseases Associated With the Inheritance Of Aldh2*2mentioning

confidence: 99%

Emerging Associations of the ALDH2*2 Polymorphism with Disease Susceptibility

Gueldner¹,

Sayes²,

Abel³

et al. 2016

J Drug Metab Toxicol

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Ethanol is metabolized by Alcohol Dehydrogenase (ADH) to acetaldehyde and then irreversibly oxidized by Aldehyde Dehydrogenase (ALDH) to nontoxic acetate. In individuals expressing the ALDH2*2 variant enzyme, the rate of conversion from acetaldehyde to acetate is reduced and leads to flushing, nausea, and tachycardia due to increased blood levels of acetaldehyde. The ALDH2*2 variant has a lowered NAD + coenzyme binding affinity, which results in a lowered clearance capacity toward acetaldehyde. This polymorphism is caused by the substitution of glutamate for lysine at position 487 within the catalytic active site of ALDH2, resulting in effects on subunit and quaternary complex activity. ALDH2*2 alleles are dominant over ALDH2*1 and therefore are expected to contribute to the formation of inactive heterotetramers decreased enzymatic activity in both homozygous and heterozygous individuals. Consequently, a higher susceptibility to various diseases such as Alzheimer's, osteoporosis, and acute coronary syndrome has been associated with ALDH2*2 carriers. Additionally, the polymorphism seems to affect the efficacy of Glyceryl Trinitrate (GTN), a drug intended to treat coronary heart disease, in carriers of ALDH2*2 alleles. However, the polymorphism is believed to afford a protective effect against alcoholism as the side effects of acetaldehyde build-up are undesirable. Disulfiram, a drug historically used to treat alcohol dependency, induces the same undesirable physiological effects as the variant enzyme in non-carriers by inhibiting the normal functioning of ALDH2 enzyme.

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ALDH2 polymorphisms and bone mineral density in an elderly Japanese population

Abstract: The present results suggest that active prophylactic interventions such as dietary, exercise, and pharmacological therapies should be offered to non-carriers of the Glu allele (Lys/Lys).

Cited by 47 publications

References 43 publications

Opposite Effects ofGSTM1– andGSTT1– Gene Deletion Variants on Bone Mineral Density

Opposite Effects ofGSTM1– andGSTT1– Gene Deletion Variants on Bone Mineral Density

Age-Dependent Neurodegeneration Accompanying Memory Loss in Transgenic Mice Defective in Mitochondrial Aldehyde Dehydrogenase 2 Activity

Emerging Associations of the ALDH2*2 Polymorphism with Disease Susceptibility

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