LRRK2 Pro755Leu variant in ethnic Chinese population with Parkinson's disease

Neuroscience Letters 495 (2011) 35–38

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LRRK2 Pro755Leu variant in ethnic Chinese population with Parkinson’s disease Ling-yan Yao a , Ji-feng Guo a , Lei Wang a , Ren-he Yu c , Qi-ying Sun a , Qian Pan b , Kun Xia b , Bei-sha Tang a,b , Lu Shen a,∗ a

Department of Neurology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan 410008, PR China State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan 410008, PR China c School of Public Health Sciences, Central South University, Changsha, Hunan 410008, PR China b

a r t i c l e

i n f o

Article history: Received 16 November 2010 Received in revised form 2 March 2011 Accepted 8 March 2011 Keywords: Parkinson’s disease LRRK2 Pro755Leu Polymorphism Chinese Asia

a b s t r a c t Parkinson’s disease (PD) is a common neurodegenerative disease resulting from complex interaction involving genetic and environmental risk factors on background of aging. In terms of genetic risk factors, recent studies provided a growing number of evidence for the idea that certain polymorphisms in familiar Parkinsonism genes may contribute to risk for sporadic PD in populations of specific ethnic backgrounds. To address this issue, a case-control study was conducted to determine the prevalence of LRRK2 Pro755Leu variant in 401 patients with sporadic PD and 398 unrelated healthy controls in Han population from mainland China. Heterozygous LRRK2 Pro755Leu variant was found in four patients and two healthy controls, but no statistical differences in genotypic or allelic frequencies between PD and control groups (genotype: P = 0.686; allele: P = 0.687) were detected. Furthermore, to evaluate its role in ethnic Chinese population, a meta-analysis was performed on Pro755Leu in population of Chinese ancestry throughout Asia. And it was detected at a similar frequency in PD and control cohort (Z = 0.48, P = 0.63, odds ratio = 1.44, 95% CI: 0.32–6.40). Given these findings, it was quite reasonable to suppose that LRRK2 Pro755Leu variant rarely increased risk for PD in ethnic Chinese population in Asia. © 2011 Elsevier Ireland Ltd. All rights reserved.

Parkinson’s disease (PD) is a common neurodegenerative syndrome, characterized by resting tremor, rigidity, bradykinesia, and postural instability. The exact etiology of PD remained elusive, but mounting evidence suggested that environment, hereditary factors and progress of aging all had essential influences on the pathogenic mechanism of this disease. The LRRK2 gene, cloned in 2004 [22,39], was associated with autosomal dominant familial PD type eight (PARK 8), while its variants were also discovered in sporadic PD cases [25]. The patients with PARK8 shared similar clinical features with those suffering from sporadic PD, such as relatively late onset, four main symptoms of PD and good response to l-dopa. The information available to date suggested that the prevalence of LRRK2 polymorphisms varied remarkably across populations. For instance, Gly2019Ser was relatively common in populations from North America, Europe and North African Arab region, and those of Ashkenazi Jewish origin [2,4,6,12,15,20,21]. However, it did not occur at a detectable frequency in ethnic Chinese populations from Taiwan and Singapore [10,16,27,28]. Moreover, some variants in LRRK2 appeared to be susceptive for elevating risk for PD. Gly2385Arg, initially identified in one family from Taiwan [18],

∗ Corresponding author. Tel.: +86 731 84327623; fax: +86 731 84327332. E-mail addresses: [email protected], [email protected] (L. Shen). 0304-3940/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.neulet.2011.03.030

was significantly more frequent in sporadic PD patients than in controls in Taiwan, Singapore and some regions in mainland China [1,3,7,8,11,31]. It was therefore considered to be the firstly identified LRRK2 variant accounting for increased risk for PD in ethnic Chinese, and also in Japanese and Korean population throughout the Asia [9,14,37]. On the contrary, Gly2385Arg was rare or even absent in Malay, Indian, Norwegian or Caucasian populations [23,32,33]. The second recently hotspot variant in LRRK2 gene was Arg1628Pro, presenting in PD patients at higher frequency compared to controls in ethnic Chinese population in Taiwan, Singapore and some parts of mainland China [17,24,29,36,38], while this variant was hardly seen in Japan, Caucasian, Malay and Indian populations [24,30]. Pro755Leu (c.2264c>t, rs34410987) was reported to be a mutation responsible for PD in mainland China in 2006 [35], but the studies investigated in Taiwan and Singapore [7,26] showed that it was present with similar frequency in cases and controls, and was regarded as an irrelevant variant for increasing PD risk, which makes its role as a susceptible variant for PD in Chinese population still ambiguous to date. Here, we report the finding of our research on this contentious LRRK2 Pro755Leu, in a large sample involving 799 individuals from central part of mainland China. We also performed a meta-analysis of studies reporting data on Pro755Leu in ethnic Chinese population in Asia.

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L.-y. Yao et al. / Neuroscience Letters 495 (2011) 35–38

Table 1 Profile of analyzed samples. Patients Gender (male/female) Age at onset (years)a a b

238/163 54.86 ± 11.23

Controls

Statistic value

P-value

210/188 53.45 ± 13.02b

 = 3.519 t = 1.963

0.061 0.102

2

Data are mean ± SD. Age at sampling.

Fig. 1. PCR-restriction fragment length polymorphism (PCR-RFLP) assays of LRRK2 Pro755Leu variant. Samples 1–8 present the Pro755Leu variant allele which produces a novel BsmAI site, resulting into 193-, 79-, 14-bp fragments, whereas Samples 9–10 present the wild-type allele which can be digested into 272- and 14-bp fragments. The 14-bp fragment is too small to be detected, thus not showed in this figure.

Four hundred and one patients with sporadic PD were recruited from the Department of Neurology in Xiangya Hospital, Central South University, and all cases’ diagnosis fulfilled the United Kingdom PD Brain Bank Criteria [13]. All of them were Chinese Han population form the central part of mainland China and unrelated with each other. Three hundred and ninety-eight unrelated controls were matched with patients for age, gender, ethnicity and area of residence (Table 1). Approve by the Ethics Committee of Central South University was obtained. All individuals gave an informed consent in writing. The genotype of Pro755Leu was detected by PCR-restriction fragment length polymorphism (PCR-RFLP) assays (Fig. 1) and confirmed by sequencing analysis (Fig. 2). Sequences of primers, conditions of PCR-RFLP were based on a previous report [5].

Fig. 2. Sequencing analysis of LRRK2 Pro755Leu variant. (A) Homozygous genotype of the wild-type; (B) heterozygous genotype of the Pro755Leu variant (c.2264c>t).

Prevalence in age and gender between two groups were assessed by t-test. The genotypic and allelic frequencies and Hardy–Weinberg equilibrium in cases and controls were analyzed using the Chi-square test. A two-tailed P-value < 0.05 was considered significant. A meta-analysis of all studies reporting genotype data on Pro755Leu in PubMed (January 1, 2000, to September 1, 2010) was performed. Studies with a case-control design which screened Pro755Leu in PD patients and controls in ethnic Chinese population were recruited. All PD patients fit into the meta-analysis fulfilled acceptable diagnosis criteria [13]. Pooled estimates of the odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using both fixed-effects and random effects models. Statistical analysis was performed using the Statistical Package for the Social Sciences version 13.0 (SPSS Inc., IBM, Chicago, USA). Meta-analysis was done by the usage of Review Manager Version 4.2 (Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2008). The power analysis was estimated at the 0.05 level of significance, assuming an odd ratio of 2.0 or 2.5 and was performed by using Power and Precision 4 (Biostat, Englewood, USA). Heterozygous LRRK2 Pro755Leu variant was found in four patients (4/401 = 1.0%) and two healthy controls (2/398 = 0.5%). The overall call rate of samples is 100%. Cases and controls were both in concordance with Hardy–Weinberg equilibrium (case: P = 0.920; control: P = 0.960). There was no statistical difference in genotypic or allelic frequencies between case and control groups (Table 2). Three other studies on Pro755Leu for ethnic Chinese PD patients were recruited for meta-analysis, one in Taiwan [7], one in Singapore [26] and one in Nanjing, mainland China [35]. Characteristics of these studies included were demonstrated in detail (Table 3). There was a statistical heterogeneity among all included studies (P = 0.009, I2 = 74.0%) and therefore these data was analyzed under random effect model. The result of meta-analysis revealed that the frequency of Pro755Leu was similar in cases to the data in control (Z = 0.48, P = 0.63, odds ratio = 1.44, 95% CI: 0.32–6.40) (Fig. 3). LRRK2 gene, responsible for PARK8 type PD, encodes a putative protein kinase named dardarin [22]. LRRK2 contains several functional domains: armadillo and ankyrin repeats region, leucine-rich repeat (LRR) domain, ROC-GTP enzyme domain, C-terminal of Roc domain, tyrosine kinase-like family domain and WD40 domain. Albeit the pathological mechanism of LRRK2-related PARK8 type PD is unknown, it is believed that the alternation of certain high risk genetic variant may change the amino position and eventually have negative influence on its physiological functions. The Pro755Leu variant locates in the conserved ankyrin repeat region which is regarded to be relevant to protein to protein interactions [19], thus it is a putative “disruptor” of normal protein to protein interactive functions. Our study found a few of LRRK2 Pro755Leu heterozygous C/T carriers, but no statistical significance in carrier frequency between cases and controls (4/401 vs. 2/398) was obtained. This indicated that the Pro755Leu presented in the Han-Chinese population from the central part of mainland China in a relatively low frequency, and it might rarely be a potential genetic risk factor for PD. In the present studies involving Pro755Leu variant, our result is similar to the reports from Taiwan (1% of 608 cases) [7], Singapore (case vs. control = 2.0%:2.6%) [26] and Japan (case vs. control = 1.2%:1.6%)

L.-y. Yao et al. / Neuroscience Letters 495 (2011) 35–38

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Table 2 Genotype and allele distribution of LRRK2 c.2264c>t (p. Pro755Leu) in Chinese patients with Sporadic PD and controls from central part of mainland China. N

Patients Controls P-value OR (95% CI)c a b c

Genotype, n (%)

401 398

Allele, n (%)

TT

TC

CC

T

C

0(0) 0(0) 0.686a 1.995(0.363–10.954)a

4(1.0) 2(0.5)

397(99.0) 396(99.5)

4(0.5) 2(0.3) 0.687b 1.990(0.363–10.895)b

798(99.5) 794(99.7)

Comparison of (TT + TC)/CC genotypic frequency between patients and controls. Comparison of T/C allelic frequency between patients and controls. OR, odd ratio; CI, confidence interval.

Table 3 The summary of studies on LRRK2 c.2264c>t (p. Pro755Leu) for PD in ethnic Chinese population. Authors

Published (year)

Di Fonzo et al. [7] Wu et al. [35] Tan et al. [26] Current study Current meta-analysis a

2006 2006 2008 2010 2010

Region

Taiwan Nanjing, mainland of China Singapore Changsha, mainland of China Asia

Patients

Controls

Power (%) (frequency of carrier = 0.015, ˛ = 0.05)

N (carrier, n)

N (carrier, n)

ORa = 2.0

ORa = 2.5

585(7) 598(12) 204(4) 401(4) 1788(27)

349(10) 765(0) 235(6) 398(2) 1747(18)

26.1 41.7 12.3 22.2 83.7

47.8 70.0 23.7 42.8 98.3

OR = odd ratio.

Review: Comparison: Outcome: Study or sub-category A. Di Fonzo, et al T. Wu, et al E.K. Tan, et al Us

Meta-analysis of LRRK2 Pro755Leu variant for PD in ethnic Chinese population 01 Meta-analysis of LRRK2 Pro755Leu variant for PD in ethnic Chinese population 01 Meta-analysis of LRRK2 Pro755Leu variant for PD in ethnic Chinese population Patient n/N 7/585 12/598 4/204 4/401

Control n/N

OR (random) 95% CI

Weight %

10/349 0/765 6/235 2/398

31.23 15.72 28.50 24.54

1788 1747 Total (95% CI) Total events: 27 (Case), 18 (Control) 2 Test for heterogeneity: Chi-square= 11.53, df = 3 (P = 0.009), I = 74.0% Test for overall effect: Z = 0.48 (P = 0.63)

100.00

0.01

0.1

Favours treatment

1

10

OR (random) 95% CI 0.41 32.63 0.76 1.99

[0.15, [1.93, [0.21, [0.36,

1.09] 552.24] 2.74] 10.95]

1.44 [0.32, 6.40]

100

Favours control

Fig. 3. Meta-analysis of LRRK2 Pro755Leu in ethnic Chinese population. The result of meta-analysis revealed that the frequency of LRRK2 Pro755Leu variant was similar in cases to the data in control (Z = 0.48, P = 0.63, odds ratio = 1.44, 95% confidence interval: 0.32–6.40)

[34]. However, it is inconsistent with the investigation conducted in Nanjing [35], mainland China, in which no Pro755Leu carriers had been detected in 765 controls, whereas 12 heterozygous carriers in 598 patients. The possible explanation of these conflicting reports is that individual studies reported did not have sufficient statistical power to conclude anything with small effect as a result of their limited sample sizes. Given our findings, none of individual studies present a statistical power great than 80% to detect the association between P755L variant and PD (Table 3). In order to clarify the role of Pro755Leu as a susceptibility variant increasing risk for PD, we conducted a meta-analysis over this variant implicating 3535 individuals from four areas [7,26,35] in Asia. According to the meta-analysis data (odds ratio = 1.44, 95% CI: 0.32–6.40, P = 0.63), it is quite reasonable to support our inference that Pro755Leu may be an irrelevant polymorphism rather than a susceptive risk-elevating variant in ethnic Chinese population. Two Pro755Leu heterozygous carriers in control proband determined in our research were neurologically healthy, unrelated Chinese with no PD family history, one is a female at the age of 59, and the other one is a male at the age of 63. Considering the relatively late ages of these two control carriers, the possibility that

the presence of healthy carriers may be due to age-related incomplete penetrance of the variant was reduced, yet not reduced to none. In that case, the conclusion from a large epidemiologically matched case-control comprising 3535 individuals of ethnic Chinese we conducted is more convincing. Moreover, the result of our meta-analysis on Pro755Leu is consistent with the findings in our study of relatively small size. In conclusion, our study suggested that Pro755Leu may have insignificant influence on increasing risk for the onset of PD in ethnic Chinese population in Asia. Acknowledgements This work was supported by grants from the Major State Basic Research Development Program of China (973 Program) (2006cb500700) (Dr. Bei-sha Tang); the National High-Technology Research and Development Program of China (863 Program) (2006AA02A408) (Dr. Bei-sha Tang); National Natural Science Foundation of China (30370515, 30570638, 30770735) (Dr. Bei-sha Tang). We would like to thank the participating patients and donors for their cooperation.

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