Genetic variation in catechol-<Emphasis Type="Italic">O</Emphasis>-methyltransferase (<Emphasis Type="Italic">COMT</Emphasis>) and obesity in the prostate,lung, colorectal,and ovarian (PLCO) cancer screening trial |
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Authors: | Sophia S Wang Lindsay M Morton Andrew W Bergen Elizabeth Z Lan Nilanjan Chatterjee Paul Kvale Richard B Hayes Stephen J Chanock Neil E Caporaso |
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Institution: | (1) Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, 6120 Executive Blvd., EPS/5104, MSC#7234, Rockville, MD 20852, USA;(2) Henry Ford Health System, Detroit, MI, USA;(3) Core Genotyping Facility, Advanced Technology Corporation, National Cancer Institute, NIH, DHHS, Gaithersburg, MD, USA |
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Abstract: | Catechol-O-methyltransferase (COMT) is an important modulator in the catabolism of extraneural dopamine, which plays an important role
in drug reward mechanisms. It is hypothesized that genetic variations in the COMT gene, which can result in a three to fourfold difference in COMT enzyme activity, may be associated with several reward-motivated
behaviors. The aim of our study was to examine the relationship between COMT polymorphisms with smoking, obesity and alcohol. Three single nucleotide polymorphisms (SNPs) in COMT were genotyped in 2,371 participants selected randomly from the screening arm of the PLCO Cancer Screening Trial after stratifying
by sex, age, and smoking status. Smoking, obesity, and alcohol consumption were assessed by questionnaire. SNP and haplotype
associations were estimated using odds ratios (ORs) and 95% confidence intervals (CIs) derived from conditional logistic regression
models, adjusted for race/ethnicity. The COMT Ex4-76C > G (Leu136Leu) polymorphism was statistically significantly associated with individuals who had >30% increases in
BMI from ages 20 to 50 years, compared to those with 0–5% increase in BMI (0–5%) over the same age period: (CC is referent;
ORCG = 1.42, ORGG = 1.46, P
trend = 0.06). By sex, the increased risk was further pronounced among females (ORCG = 1.50, ORGG = 2.10, P
trend = 0.03). Consistent with our analyses of single polymorphisms, individuals whose BMI increased >30% from ages 20 to 50 years
were more likely than individuals with 0–5% increases in BMI to possess COMT haplotypes COMT Ex3-104C > T–COMT Ex4-76 C > G–COMT Ex4-12 A > G] that included the variant allele for COMT Ex4-76 C > G: C-G-G (T-C-A is referent: ORC-G-G
= 1.33, 95% CI 1.01–1.77) and C-G-A (ORC-G-A = 1.79, 95% CI 0.72–4.49). We observed no association between any of the COMT polymorphisms with smoking behavior or alcohol intake. The COMT Ex4-76C > G (Leu136Leu) polymorphism appears to play a role in large increases in BMI. The null association with smoking
and alcohol and the pronounced association with increasing BMI among women further implicates COMT’s role in estrogen metabolism as a potentially culpable pathway. Our results support a need for comprehensive evaluation
of COMT variations and their functional relevance as COMT may be an important molecular target to evaluate for new treatments regarding
obesity. |
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