Polymorphisms of caffeine metabolism and estrogen receptor genes and risk of Parkinson's disease in men and women

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Abstract

Caffeine intake has been associated with a decreased risk of Parkinson's disease (PD) in men but the effect in women is less clear, and appears to be modified by use of post-menopausal estrogens. In a nested case–control study within the Nurses Health Study (NHS) and the Health Professionals Follow-up Study (HPFS), we examined associations between single nucleotide polymorphisms (SNPs) of caffeine metabolizing genes (CYP1A2 and NAT2) and estrogen receptors (ESR1 and ESR2), their interaction with caffeine intake and hormone replacement therapy (PMH) use (collected prospectively) and risk of PD. We matched 159 female cases to 724 controls and 139 male cases to 561 controls on birth year, source of DNA (blood or buccal smear), age and sex. The CYP1A2 rs762551 polymorphism (lower enzyme inducibility) was marginally associated with an increased risk of PD (RR, for increasing number of minor alleles = 1.34; 95% CI 1.02, 1.78 in women, but not in men. None of the NAT2 (classified as slow vs. fast acetylator), ESR1 or ESR2 polymorphisms were significantly associated with an altered risk of PD. Marginally significant interactions were observed between caffeine intake and the ESR1 polymorphism rs3798577 (p = 0.07) and ESR2 polymorphism rs1255998 (p = 0.07). The observed increased risk of PD among female but not male carriers of the rs762551 polymorphism of CYP1A2 and the interactions of caffeine with ESR1 rs3798577 and ESR2 rs1255998 may provide clues to explain the relationship between gender, caffeine intake, estrogen status and risk of PD and need to be replicated.

Introduction

Caffeine intake has been associated with a significantly reduced risk of Parkinson's disease (PD) in men in several cohort [1], [2] and case–control studies [3]. In women, the association appears to be modified by use of post-menopausal hormones: non-users of PMH are at a decreased risk of Parkinson's disease, whereas among users of PMH, caffeine has been associated with increased risk of PD [4]. In an attempt to understand the mechanisms behind the protective effect of caffeine on the risk of PD and the interaction with estrogen, we studied polymorphisms of genes involved in caffeine and estrogen metabolism.

Caffeine is metabolized to paraxanthine primarily by the P450 CYP1A2 enzyme, which is responsible for more than 90% of caffeine metabolism [5]. CYP1A2 also metabolizes estrogen [6]. Individuals carrying the (−163A  C) variant of CYP1A2 (rs762551) have lower CYP1A2 activity, presumably because this polymorphism reduces the enzyme inducibility [7].

Another enzyme involved in caffeine clearance is NAT2, whose function is to catalyze the transformation of a broad range of xenobiotics [8]. Carriers of mutant alleles are slow acetylators and metabolize less efficiently certain endogenous compounds, including caffeine [8]. This enzyme has previously been studied with relation to risk of PD and in gene-environment interaction studies [9], but with mixed results.

The observation in a mouse model of Parkinson disease that estrogen prevents the neuroprotective effects of low and moderated doses of caffeine [10] supports the hypothesis that the difference in the observed effect of caffeine in men and women is explained by an interaction with estrogen. Therefore, polymorphisms in estrogen receptors could modify the association between caffeine and risk of PD in women. Two estrogen receptors have been identified, estrogen receptor alpha (ESR1), which is primarily responsible for sexual development with functions in the endometrium and the hypothalamus [11], and estrogen receptor beta (ESR2), with functions in the kidney, brain, bone, heart, lungs, intestinal mucosa, prostate, and endothelial cells [11]. An association between ESR1 and risk of PD has been reported in some [12] but not all [13] studies. There are no data, however, on possible interactions between these genes and either caffeine or use of post-menopausal hormones.

We here report the results of a nested case–control study among participants in the Nurses Health Study (NHS) and the Health Professionals Follow-up Study (HPFS) conducted to examine whether polymorphisms of the caffeine metabolizing genes NAT2 and CYP1A2, and of the estrogen receptors ESR1 and ESR2 are associated with altered risk of PD, and whether these polymorphisms interact with caffeine intake or PMH in determining PD risk.

Section snippets

Study population

Participants in this study were men and women who provided a blood or buccal smear sample from amongst those enrolled in the NHS and HPFS. The NHS began in 1976 when 121,700 nurses aged 30–55 returned mailed questionnaires regarding lifestyle factors and disease history. The HPFS began in 1986 when 51,529 male health professionals (dentists, optometrists, pharmacists, osteopaths, podiatrists and veterinarians) aged 40–75 years returned similar questionnaires. Biennial questionnaires are mailed

Results

The polymorphisms examined in this study are listed in the online appendix Table 1S. Genotype and allele frequencies were similar between cases and controls for all SNPs in this study (Table 1, Table 2, Table 3).

All the SNPs except ESR1 rs1801132 in women and all SNPs in men confirmed to the Hardy-Weinberg equilibrium (HWE). The ESR1 rs1801132 polymorphism in women violated the HWE assumption (p = 0.0005), and was removed from subsequent analyses.

The overall relative risk associated with each

Discussion

We report a marginally increased risk of PD with increasing number of minor alleles (C allele) of the CYP1A2 rs762551 polymorphism. The CYP1A2 enzyme is part of the cytochrome P450 system. It is a hepatic enzyme primarily responsible for the metabolism of a number of substances, including drugs, caffeine, environmental toxins and estrogens [19]. This enzyme is responsible for more than 90 percent of caffeine metabolism [20]. In humans, the first step in the biotransformation of caffeine, the

Ethics

These studies [NHS and HPFS] were approved by the Human Subjects Research Committees at Harvard School of Public Health and Brigham and Women's Hospital.

Acknowledgements

This work was funded by NIH grant R01 NS048517. Natalia Palacios is supported by the Training Program in Environmental Epidemiology, NIH Kirshstein National Research Service Award, T32 ES07069. K. Simon is supported by NIH Kirshstein National Research Service Award T32 ES16645-01.

The authors would like to thank Eilis O'Reilly for statistical and programming help.

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