In-vitro Comparison of Occluding Effect of Fluoride Varnish and Diode Laser Irradiation with Fluoride Varnish and Er,Cr:YSGG Laser Irradiation on Dentinal Tubules of the Cervical Root Area of the Tooth.

Background and purpose:Dentin hypersensitivity (DH) is a sharp, short dental pain which originates from exposed dentin surfaces in response to thermal, evaporative, tactile, osmotic, chemical or electrical stimuli. Research showed that dentin tubule occlusion can lead to pain remission. Our goal was to evaluate the dentinal tubules in the cervical area of root teeth that are occluded by fluoride varnish, diode laser irradiation, and erbium laser irradiation. Materials and methods: This is an in vitro single-blind study. Twenty-four samples of extracted third molars were divided into four groups: control (A), fluoride varnish (B), fluoride varnish and diode laser (C) and fluoride varnish and Er,Cr:YSGG laser (D). After applying varnish and different lasers, the tubule diameter and number of open tubules were examined by SEM. Data were analyzed by SPSS 23 software. Results:In this research, there was no significant difference between groups C and D (ñ=0.999), although there were substantially more open tubules in the control group than groups C (ñ=0.004) and D (ñ=0.003). The mean diameter of tubules in the four groups was statistically different (ñ <0.001), and the descending order of tubule diameter was A > B > C > D. Conclusion:Using diode and erbium laser in combination with sodium fluoride varnish had a significant effect on the reduction of dentinal tubule diameter and their occlusion; thus, these therapies can be used to treat dentin hypersensitivity.

Genomewide Association Studies of LRRK2 Modifiers of Parkinson's Disease.

OBJECTIVE: The aim of this study was to search for genes/variants that modify the effect of LRRK2 mutations in terms of penetrance and age-at-onset of Parkinson's disease. METHODS: We performed the first genomewide association study of penetrance and age-at-onset of Parkinson's disease in LRRK2 mutation carriers (776 cases and 1,103 non-cases at their last evaluation). Cox proportional hazard models and linear mixed models were used to identify modifiers of penetrance and age-at-onset of LRRK2 mutations, respectively. We also investigated whether a polygenic risk score derived from a published genomewide association study of Parkinson's disease was able to explain variability in penetrance and age-at-onset in LRRK2 mutation carriers. RESULTS: A variant located in the intronic region of CORO1C on chromosome 12 (rs77395454; p value = 2.5E-08, beta = 1.27, SE = 0.23, risk allele: C) met genomewide significance for the penetrance model. Co-immunoprecipitation analyses of LRRK2 and CORO1C supported an interaction between these 2 proteins. A region on chromosome 3, within a previously reported linkage peak for Parkinson's disease susceptibility, showed suggestive associations in both models (penetrance top variant: p value = 1.1E-07; age-at-onset top variant: p value = 9.3E-07). A polygenic risk score derived from publicly available Parkinson's disease summary statistics was a significant predictor of penetrance, but not of age-at-onset. INTERPRETATION: This study suggests that variants within or near CORO1C may modify the penetrance of LRRK2 mutations. In addition, common Parkinson's disease associated variants collectively increase the penetrance of LRRK2 mutations. ANN NEUROL 2021;90:82-94.

Novel compound heterozygous FBXO7 mutations in a family with early onset Parkinson's disease.

BACKGROUND: Mutations in the F-box protein 7 (FBXO7) gene result in autosomal recessive parkinsonism. This usually manifests as early-onset parkinsonian-pyramidal syndrome but patients exhibit high phenotypic variability. Here we describe the findings of a Yemeni family with two novel FBXO7 mutations. METHODS: Clinical data and DNA were available for three siblings with early-onset parkinsonism together with their parents and three unaffected siblings. A targeted next generation sequencing panel was used to screen the proband for mutations in 14 genes known to cause a parkinsonian disorder. In addition, SNCA, PARK2, PINK1, and PARK7 were screened for copy number variants. RESULTS: The proband carried two novel compound heterozygous FBXO7 mutations: a missense mutation in exon 1 (p.G39R; c.115G > A) and a frameshift mutation in exon 5 (p.L280fs; c.838del). The mutations segregated with disease in the family with the exception of a potentially pre-symptomatic individual whose age was below the age of onset in two of their three affected siblings. P.G39R occurred at a highly conserved amino acid residue and both mutations were predicted to be deleterious in silico. In contrast to most reported families, the phenotype in this pedigree was consistent with clinically typical Parkinson's disease (PD) with a lack of pyramidal signs and good response to dopaminergic therapy. CONCLUSIONS: Our study expands the phenotype associated with FBXO7 to include early-onset PD and broadens the list of causative mutations. These data suggest that FBXO7 should be included in clinical genetic testing panels for PD, particularly in patients with early onset or a recessive inheritance pattern.

Effects of ß2-Adrenergic Agonists on Risk of Parkinson's Disease in COPD: A Population-Based Study.

INTRODUCTION: Multiple studies have investigated the role of ß2 -adrenoreceptor agonists on the risk of Parkinson's disease (PD). However, whether ß2 -agonist use is associated with the risk of PD in patients with chronic obstructive pulmonary disease (COPD) has not been examined to date. OBJECTIVES: To examine the association between use of ß2 -agonist and the risk of PD in patients with COPD. METHODS: A case-control study nested within a cohort of patients with COPD using the British Columbia health administrative databases from 1997 to 2015 was performed. Among a cohort of patients with COPD, all cases of PD were identified, and matched each case to up to five controls by age and calendar time. The use of ß2 -agonists was assessed between the third and fourth year preceding the date of PD diagnosis, followed by additional two years of grace period (between the first and second year preceding PD incidence) to control for PD latency. The use of ß2 -agonists was categorized into three levels: regular use (≥ 1 dispensation for every 6 months), irregular use (dispensation in one to three 6-month periods), and no use. A conditional logistic regression model was used to estimate the rate ratio of PD according to ß2-agonist use, rigorously controlling for confounding variables. RESULTS: Among 242,218 COPD patients, 732 PD cases and 3660 controls were identified. Use of ß2 -agonists did not significantly affect the subsequent risk of PD (vs no use, adjusted rate ratios: regular use, 1.14 [95% CI: 0.93, 1.40, p=0.21], irregular use, 1.15 [95% CI: 0.92, 1.45, p=0.22]). Results remained consistent with competing risk sensitivity analysis. CONCLUSION: Use of ß2 -agonists does not appear to affect the risk of PD in a real-world COPD population.

Tumor necrosis factor inhibitors and risk of peripheral neuropathy in patients with rheumatic diseases.

IMPORTANCE: Tumor necrosis factor inhibitors (TNFi) are widely used in the treatment of a variety of autoimmune diseases. A number of case reports have linked TNFi to neurologic adverse events including peripheral neuropathy (PN) in patients with rheumatic diseases. OBJECTIVES: To quantify the risk of peripheral neuropathy with TNFi in patients with rheumatic diseases. DESIGN: Nested-Case Control study within a cohort of patients with rheumatic diseases. SETTING: PharMetrics Plus™ health claims database from the United States. PARTICIPANTS: From a random sample of 9,053,240 subjects from the PharMetrics Plus™ database a cohort of patients with rheumatic diseases who had two physician visit codes for rheumatoid arthritis, ankylosing spondylitis and psoriasis in addition to a medication used in the treatment of each condition from 2006 to 2016 was created. EXPOSURE: We created different risk periods of current use (day 0-60), recent use (day 61-180) and past use (day 180-365) from the index date. MAIN OUTCOME MEASURES: New cases of PN were identified from the rheumatic disease cohort. Each case was matched to 10 controls by calendar time and age using density based sampling. Rate ratios (RRs) for new users of TNFi were computed using conditional logistic regression adjusting for gender, vitamin B12 deficiency, fluoroquinolone use, HIV, viral hepatitis, chronic renal failure and diabetes. RESULTS: Among a cohort of 61,570 patients with rheumatic diseases 1358 cases of PN and 13,580 corresponding controls were identified. The adjusted rate ratio (RR) of PN among recent users of TNFi was 1.14 (95% CI:0.90-1.43). The RR for past use of TNFi was 2.77 (95% CI:1.67-4.58). Past users who used three or more prescriptions had a higher risk of PN 3.49 (1.63-7.49). The RRs did not change when the risk of PN with TNFi was compared to those taking methotrexate and one additional disease modifying anti rheumatic drug (DMARD) for recent and past use (RR = 0.95 [95% CI:0.72-1.24] and RR = 2.30 (1.37-3.87), respectively). CONCLUSIONS: Patients with rheumatic diseases who are past users of TNFi are at higher risk of developing PN compared to those taking methotrexate and one additional DMARD.

Diagnostic Validation for Participants in the Washington State Parkinson Disease Registry.

BACKGROUND: The Washington State Parkinson Disease Registry (WPDR) was created to facilitate recruitment for Parkinson's disease (PD) research studies conducted in the Pacific Northwest. The success of registries that rely on self-report is dependent on the accuracy of the information provided by participants, particularly diagnosis. OBJECTIVE AND METHODS: Our goal was to assess diagnostic accuracy within the WPDR cohort. We randomly selected and attempted to contact 168 of the 1,278 actively enrolled WPDR participants. Those who responded were invited to undergo an interview and neurological examination performed by a PD specialist. If an in-person assessment was not possible, we sought information collected during participation in prior research studies or from review of medical records. A diagnosis was considered "validated" if the individual met UK Parkinson's Disease Society Brain Bank (UKBB) clinical diagnostic criteria for PD. RESULTS: Data were ascertained for 106 participants; 77 underwent an in-person assessment, 21 had data available from a prior research study, and 8 provided access to medical records. Diagnostic accuracy within the overall sample was 93.4% (95% confidence interval (86.4%, 97.1%)). Seven patients did not fulfill UKBB criteria for the following reasons: early severe autonomic involvement (n=3), history of neuroleptic treatment (n=1), presence of the Babinski sign (n=1), or insufficient supportive criteria (n=2). CONCLUSIONS: Our results indicate that studies which use the WPDR for recruitment will rarely encounter patients who are misdiagnosed. This further supports the utility of the WPDR as an effective recruitment tool for PD research in the Pacific Northwest.

Risk of Parkinson's disease in patients with neovascular age-related macular degeneration.

PURPOSE: To examine the risk of developing Parkinson's Disease (PD) in patients who are newly diagnosed with neovascular age-related macular degeneration (nAMD). METHODS: This was a cohort study using the British Columbia (BC) Retinal Disease Database. Data from 2009 to 2013 was accessed. Rates of PD in patients prior to the diagnosis of nAMD were computed and compared to the rates of patients newly diagnosed with PD after the diagnosis of nAMD. RESULTS: The rate of PD prior to the diagnosis of nAMD was 1.42 per 100,000 person-years. The rate of PD after the diagnosis of nAMD was 2.88/100,000 person-years. The rate ratio was 2.03 (95% CI; 1.31-3.16). CONCLUSIONS: The findings suggest that patients who are diagnosed with nAMD are at a significantly higher risk of developing PD later in life. More studies are needed to identify the pathological mechanism between the two diseases.

Association of Antidepressant Use With Drug-Related Extrapyramidal Symptoms: A Pharmacoepidemiological Study.

BACKGROUND: Antidepressants are one of the most prescribed classes of medications. A number of case reports have linked these drugs to extrapyramidal symptoms (EPSs), but no large epidemiologic study to date has examined this association. We sought to quantify the association of EPSs with different antidepressants by undertaking a large pharmacoepidemiologic study. METHODS: A nested case-control study was conducted using a large health claims database in the United States from June 2006 to December 2015. Subjects with a diagnosis of primary Parkinson disease and those who received prescriptions of levodopa, ropinirole, pramipexole, domperidone, metoclopramide, entacapone, benztropine, selegiline, rasagiline, diphenhydramine, trihexyphenidyl, typical and atypical antipsychotics, and tricyclic antidepressants were excluded. Cases were followed to the first billing code for an extrapyramidal event or last date of enrollment in the cohort. For each case, 10 control subjects were matched by follow-up time, calendar time, and age through density-based sampling. Rate ratios were computed using conditional logistic regression adjusting for other covariates. RESULTS: We identified 3,838 subjects with EPSs compared with 38,380 age-matched control subjects. Rate ratios with respect to EPSs were as follows: duloxetine, 5.68 (95% confidence interval [CI], 4.29-7.53); mirtazapine, 3.78 (95% CI, 1.71-8.32); citalopram, 3.47 (95% CI, 2.68-4.50); escitalopram, 3.23 (95% CI, 2.44-4.26); paroxetine, 3.07 (95% CI, 2.15-4.40); sertraline, 2.57 (95% CI, 2.02-3.28); venlafaxine, 2.37 (95% CI, 1.71-3.29); bupropion, 2.31 (95% CI, 1.67-3.21); and fluoxetine, 2.03 (95% CI, 1.48-2.78). CONCLUSIONS: This observational study demonstrates a harmful association between the incidence of Parkinson disease or associated EPSs and use of the antidepressants duloxetine, mirtazapine, citalopram, escitalopram, paroxetine, sertraline, venlafaxine, bupropion, and fluoxetine.

Genetic Drivers of Kidney Defects in the DiGeorge Syndrome.

BACKGROUND: The DiGeorge syndrome, the most common of the microdeletion syndromes, affects multiple organs, including the heart, the nervous system, and the kidney. It is caused by deletions on chromosome 22q11.2; the genetic driver of the kidney defects is unknown. METHODS: We conducted a genomewide search for structural variants in two cohorts: 2080 patients with congenital kidney and urinary tract anomalies and 22,094 controls. We performed exome and targeted resequencing in samples obtained from 586 additional patients with congenital kidney anomalies. We also carried out functional studies using zebrafish and mice. RESULTS: We identified heterozygous deletions of 22q11.2 in 1.1% of the patients with congenital kidney anomalies and in 0.01% of population controls (odds ratio, 81.5; P=4.5×10-14). We localized the main drivers of renal disease in the DiGeorge syndrome to a 370-kb region containing nine genes. In zebrafish embryos, an induced loss of function in snap29, aifm3, and crkl resulted in renal defects; the loss of crkl alone was sufficient to induce defects. Five of 586 patients with congenital urinary anomalies had newly identified, heterozygous protein-altering variants, including a premature termination codon, in CRKL. The inactivation of Crkl in the mouse model induced developmental defects similar to those observed in patients with congenital urinary anomalies. CONCLUSIONS: We identified a recurrent 370-kb deletion at the 22q11.2 locus as a driver of kidney defects in the DiGeorge syndrome and in sporadic congenital kidney and urinary tract anomalies. Of the nine genes at this locus, SNAP29, AIFM3, and CRKL appear to be critical to the phenotype, with haploinsufficiency of CRKL emerging as the main genetic driver. (Funded by the National Institutes of Health and others.).

Risk of Gambling Disorder and Impulse Control Disorder With Aripiprazole, Pramipexole, and Ropinirole: A Pharmacoepidemiologic Study.

BACKGROUND: Recently, the US Food and Drug Administration issued a warning regarding the potential risk of gambling disorder, but large epidemiologic studies are lacking. METHODS: We used a large health claims database from the United States and conducted a nested case-control study. Cases were defined as subjects newly diagnosed with gambling disorder or impulse control disorder. For each case, 10 controls were selected and matched to cases by age and follow-up time and calendar time. Adjusted rate ratios were computed with conditional logistic regression. RESULTS: There are 355 cases of gambling disorder and 3550 controls along with 4341 cases of impulse control disorder and 43,410 corresponding controls. After adjusting for confounders, users of aripiprazole demonstrated an increased risk of pathologic gambling (rate ratio [RR], 5.23; 95% confidence interval [CI], 1.78-15.38) and impulse control disorder (RR, 7.71; 95% CI, 5.81-10.34). The risk was also elevated for pramipexole or ropinirole for both gambling disorder and impulse control disorder (RR, 7.61; 95% CI, 2.75-21.07; RR, 3.28; 95% CI, 2.31-4.66, respectively). CONCLUSIONS: Our study confirms an association between aripiprazole, pramipexole, or ropinirole and impulse control disorder and gambling disorder.

Risk of Extrapyramidal Adverse Events With Aripiprazole.

Aripiprazole is a unique atypical antipsychotic with partial agonist activity on the dopamine-2 (D2) receptor. This unique pharmacological profile of aripiprazole was thought to lead to a lower incidence of extrapyramidal symptoms (EPSs). However, recent case reports have alluded to an increase in the risk of EPS in aripiprazole users compared with nonusers of the drug. No epidemiologic studies to date have quantified this risk. We conducted a pharmacoepidemiologic study composed of a nested case-control study using a large health claims database (IMS Health) in the United States. In the nested case-control analysis, there were 5242 cases of EPS with 50,532 corresponding controls in the entire cohort. The odds ratio (OR) for EPS among those with any prescription of aripiprazole was 5.38 (95% confidence interval [CI], 3.03-9.57). The OR was lower among those taking 2 to 3 prescriptions (OR, 2.9; 95% CI, 1.07-7.85) but increased in those receiving greater than 4 prescriptions (OR, 8.64; 95% CI, 2.63-28.38). All risk periods were compared with those of subjects who had not used aripiprazole or other antipsychotics. For the secondary outcome of dyskinesia, the risk for aripiprazole was 8.50 (95% CI, 8.53-2.27-31.97) compared with that of nonusers. In conclusion, we found an increase in the risk of EPS and dyskinesias among users of aripiprazole.

Electroconvulsive therapy for depression in Parkinson's disease: systematic review of evidence and recommendations.

AIM: We performed a systematic review of evidence regarding treatment of depression in Parkinson's disease (PD) utilizing electroconvulsive therapy. METHODS: The search led to the inclusion of 43 articles, mainly case reports or case series, with the largest number of patients totaling 19. RESULTS: The analysis included 116 patients with depression and PD; depression improved in 93.1%. Where motor symptoms' severity was reported, 83% of patients improved. Cognition did not worsen in the majority (94%). Many patients experienced delirium or transient confusion, sometimes necessitating discontinuation of electroconvulsive therapy (ECT). Little is known about maintenance ECT in this population. CONCLUSION: ECT can benefit patients suffering from PD and depression. We recommend an algorithm for treatment of depression in PD, utilizing ECT sooner rather than later.

The Risk of Glioblastoma with TNF Inhibitors.

PURPOSE: To quantify the risk of glioblastoma (GBM) and its most aggressive form, glioblastoma multiforme (GBM-M), in patients treated with tumor necrosis factor (TNF) inhibitors. METHODS: Data from the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) and the World Health Organization (WHO) Collaborating Centre for International Drug Monitoring were used to perform a disproportionality analysis. We computed reporting odds ratios (RORs) and corresponding 95% confidence intervals for the association between use of TNF inhibitors (infliximab, adalimumab, etanercept, certolizumab, and golimumab) and GBM or GBM-M compared to all other drugs with adverse events reported in the databases. A harmful signal was deemed for a lower limit of the 95% confidence interval above 1. RESULTS: We identified 81 cases of GBM or GBM-M with adalimumab in the U.S. FDA FAERS and 49 cases in the WHO drug monitoring database. For infliximab, 40 and 32 cases were identified in the FAERS and WHO databases, respectfully. Infliximab had the highest association with GBM (WHO: ROR = 7.41 (5.19-10.57), FAERS: ROR = 2.80 [1.89-4.15]). Adalimumab was also highly associated with GBM (WHO: ROR = 3.54 [2.58-4.89], FAERS: ROR = 1.99 [1.41-2.80]). CONCLUSION: Several TNF inhibitors appear to be more strongly associated with GBM compared to other drugs in both the FAERS and WHO databases. Large epidemiologic studies are needed to confirm these findings. Although these results do not demonstrate a cause-and-effect relationship, they warrant further investigation by well-designed epidemiologic studies.

Clinical-Genetic Associations in the Prospective Huntington at Risk Observational Study (PHAROS): Implications for Clinical Trials.

IMPORTANCE: Identifying measures that are associated with the cytosine-adenine-guanine (CAG) expansion in individuals before diagnosis of Huntington disease (HD) has implications for designing clinical trials. OBJECTIVE: To identify the earliest features associated with the motor diagnosis of HD in the Prospective Huntington at Risk Observational Study (PHAROS). DESIGN, SETTING, AND PARTICIPANTS: A prospective, multicenter, longitudinal cohort study was conducted at 43 US and Canadian Huntington Study Group research sites from July 9, 1999, through December 17, 2009. Participants included 983 unaffected adults at risk for HD who had chosen to remain unaware of their mutation status. Baseline comparability between CAG expansion (≥37 repeats) and nonexpansion (<37 repeats) groups was assessed. All participants and investigators were blinded to individual CAG analysis. A repeated-measures analysis adjusting for age and sex was used to assess the divergence of the linear trend between the expanded and nonexpanded groups. Data were analyzed from April 27, 2010, to September 3, 2013. EXPOSURE: Huntington disease mutation status in individuals with CAG expansion vs without CAG expansion. MAIN OUTCOMES AND MEASURES: Unified Huntington's Disease Rating Scale motor (score range, 0-124; higher scores indicate greater impairment), cognitive (symbol digits modality is the total number of correct responses in 90 seconds; lower scores indicate greater impairment), behavioral (score range, 0-176; higher scores indicate greater behavioral symptoms), and functional (Total Functional Capacity score range, 0-13; lower scores indicate reduced functional ability) domains were assessed at baseline and every 9 months up to a maximum of 10 years. RESULTS: Among the 983 research participants at risk for HD in the longitudinal cohort, 345 (35.1%) carried the CAG expansion and 638 (64.9%) did not. The mean (SD) duration of follow-up was 5.8 (3.0) years. At baseline, participants with expansions had more impaired motor (3.0 [4.2] vs 1.9 [2.8]; P < .001), cognitive (P < .05 for all measures except Verbal Fluency, P = .52), and behavioral domain scores (9.4 [11.4] vs 6.5 [8.5]; P < .001) but not significantly different measures of functional capacity (12.9 [0.3] vs 13.0 [0.2]; P = .23). With findings reported as mean slope (95% CI), in the longitudinal analyses, participants with CAG expansions showed significant worsening in motor (0.84 [0.73 to 0.95] vs 0.03 [-0.05 to 0.11]), cognitive (-0.54 [-0.67 to -0.40] vs 0.22 [0.12 to 0.32]), and functional (-0.08 [-0.09 to -0.06] vs -0.01 [-0.02 to 0]) measures compared with those without expansion (P < .001 for all); behavioral domain scores did not diverge significantly between groups. CONCLUSIONS AND RELEVANCE: Using these prospectively accrued clinical data, relatively large treatment effects would be required to mount a randomized, placebo-controlled clinical trial involving premanifest HD individuals who carry the CAG expansion.

The RAB39B p.G192R mutation causes X-linked dominant Parkinson's disease.

OBJECTIVE: To identify the causal gene in a multi-incident U.S. kindred with Parkinson's disease (PD). METHODS: We characterized a family with a classical PD phenotype in which 7 individuals (5 males and 2 females) were affected with a mean age at onset of 46.1 years (range, 29-57 years). We performed whole exome sequencing on 4 affected and 1 unaffected family members. Sanger-sequencing was then used to verify and genotype all candidate variants in the remainder of the pedigree. Cultured cells transfected with wild-type or mutant constructs were used to characterize proteins of interest. RESULTS: We identified a missense mutation (c.574G > A; p.G192R) in the RAB39B gene that closely segregated with disease and exhibited X-linked dominant inheritance with reduced penetrance in females. The mutation occurred in a highly conserved amino acid residue and was not observed among 87,725 X chromosomes in the Exome Aggregation Consortium dataset. Sequencing of the RAB39B coding region in 587 familial PD cases yielded two additional mutations (c.428C > G [p.A143G] and c.624_626delGAG [p.R209del]) that were predicted to be deleterious in silico but occurred in families that were not sufficiently informative to assess segregation with disease. Experiments in PC12 and SK-N-BE(2)C cells demonstrated that p.G192R resulted in mislocalization of the mutant protein, possibly by altering the structure of the hypervariable C-terminal domain which mediates intracellular targeting. CONCLUSIONS: Our findings implicate RAB39B, an essential regulator of vesicular-trafficking, in clinically typical PD. Further characterization of normal and aberrant RAB39B function might elucidate important mechanisms underlying neurodegeneration in PD and related disorders.

Haptoglobin phenotype modifies serum iron levels and the effect of smoking on Parkinson disease risk.

INTRODUCTION: Haptoglobin is a hemoglobin-binding protein that exists in three functionally different phenotypes, and haptoglobin phenotype 2-1 has previously been associated with Parkinson disease (PD) risk, with mechanisms not elucidated. Some evidence is emerging that low levels of serum iron may increase PD risk. In this study we investigated whether PD patients have lower serum iron and ferritin than controls, and whether this is dependent on haptoglobin phenotype. We also investigated the effect of Hp phenotype as a modifier of the effect of smoking on PD risk. METHODS: The study population consisted of 128 PD patients and 226 controls. Serum iron, ferritin, and haptoglobin phenotype were determined, and compared between PD cases and controls. Stratified analysis by haptoglobin phenotype was performed to determine effect of haptoglobin phenotype on serum iron parameter differences between PD cases and controls and to investigate its role in the protective effect of smoking on PD risk. RESULTS: PD cases had lower serum iron than controls (83.28 ug/100 ml vs 94.00 ug/100 ml, p 0.006), and in particular among subjects with phenotype 2-1. The protective effect of smoking on PD risk resulted stronger in subjects with phenotype 1-1 and 2-2, and weakest among subjects with phenotype 2-1. Ferritin levels were higher in PD cases than controls among subjects of White ethnicity. CONCLUSIONS: Our results report for the first time that the haptoglobin phenotype may be a contributor of iron levels abnormalities in PD patients. The mechanisms for these haptoglobin-phenotype specific effects will have to be further elucidated.