DNMT3B gene variant influences nicotine dependence

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December 09, 2017 – Newest research has revealed that a DNMT3B gene variant influences nicotine dependence identified in people of European (Caucasian) descent and African-American decent as well.

Smoke and genes

Thus, a DNA variant, located in the DNMT3B gene and commonly found in people of European (Caucasian) and African-American descent, increases the likelihood of developing nicotine dependence, smoking heavily, and developing lung cancer, according to a new study led by RTI International and published in the Journal of Molecular Psychiatry in 2017.

Nearly 1 billion people smoke and 6 million premature deaths occur worldwide each year from cigarette smoking, according to the World Health Organization. Smoking is the leading cause of preventable death and one person dies approximately every 6 seconds from smoking-related causes, according to the World Health Organization (WHO). Nicotine dependence, which reduces the likelihood of quitting smoking, is a heritable trait with firmly established associations with sequence variants in nicotine acetylcholine receptor (nAChR) genes and at other loci.

To search for additional risk loci, in the current study,  a genome-wide association study (GWAS) meta-analysis of nicotine dependence, totaling 38,602 smokers (28,677 Europeans (Caucasian) or Americans of European (Caucasian) descent and 9925 African Americans) across 15 studies was performed. In this largest-ever GWAS meta-analysis for nicotine dependence and the largest-ever cross-ancestry GWAS meta-analysis for any smoking phenotype, the well-known CHRNA5-CHRNA3-CHRNB4 genes, previously known to be involved in nicotine dependence, were confirmed. Further analysis yielded a novel association with the DNMT3 (BDNA (cytosine-5-) methyltransferase 3 beta) gene. The intronic DNMT3B rs910083-C allele (with a frequency of 44–77% within these populations) was associated with increased risk of nicotine dependence at P=3.7 × 10−8 (odds ratio (OR)=1.06 and 95% confidence interval (CI)=1.04–1.07 for severe vs mild dependence).

Effectively, this study is the largest genome-wide association study of nicotine dependence. The researchers involved studied more than 38,600 former and current smokers from the United States, Iceland, Finland, and the Netherlands. The new finding widens the scope of how genetic factors are known to influence nicotine dependence. The allelic variant of the DNMT3 gene that has been identified here is common in the populations analysed (i.e. 44% of Europeans (Caucasian) or European (Caucasian) Americans and 77% of African Americans are carriers), and it exerts important effects on gene regulation in human brain, specifically in the cerebellum, which has long been overlooked in the study of addiction. On the other hand, we should not over-interpret its contribution to nicotine dependence in that the study found an Odds ratio of 1.06 only. Usually, the Odds ratio value signifies the contribution of a molecular factor (i.e., the genetic variation in DNMT3B in this case) to the appearance in a population of a clinical phenotype (i.e., nicotine dependence in this case). The the higher the Odds ratio value is, the tighter (and in some cases absolutely dominant and decisively) is the molecular status associated with the clinical phenotype. Here, this association is weak; nevertheless, the DNMT3B rs910083-C Allele is certainly a contribution factor to nicotine dependency in carriers of this allele.

It would also be of outmost interest, if this allele occurs in other ethnicities worldwide as well, and what would be its abundance and contribution to nicotine dependence in those ethnicities.

You may also want to consult an earlier post in Thasso Post on the smoking subject, entitled “Where there is a cigarette, there is smoke. How much, that may be in your  genes” and the mind-boggling scientific article cited therein on “The Pharmacogenetics of Nicotine Dependence and Smoking Cessation Therapies”.

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About the Author
Joseph Gut - thasso Ph.D.; Professor in Pharmacology and Toxicology. Senior expert in theragenomic and personalized medicine and individualized drug safety. Senior expert in pharmaco- and toxicogenetics. Senior expert in human safety of drugs, chemicals, environmental pollutants, and dietary ingredients.

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