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Associations of Apolipoprotein E and Low‐Density Lipoprotein J Periodont Res 2015; 50: 509–518 © 2014 John Wiley & Sons A/S. All rights reserved Published by John Wiley & Sons Ltd JOURNAL OF PERIODONTAL RESEARCH doi:10.1111/jre.12237 H. Gao*, Y. Tian*, H. Meng, J. Hou, Associations of L. Xu, L. Zhang, D. Shi, R. Lu, X. Feng, X. Wang, Z. Chen Department of Periodontology, Peking apolipoprotein E and University School and Hospital of Stomatology, Beijing, China low-density lipoprotein receptor-related protein 5 polymorphisms with dyslipidemia and generalized aggressive periodontitis in a Chinese population Gao H, Tian Y, Meng H, Hou J, Xu L, Zhang L, Shi D, Lu R, Feng X, Wang X, Chen Z. Associations of apolipoprotein E and low-density lipoprotein receptor- related protein 5 polymorphisms with dyslipidemia and generalized aggressive periodontitis in a Chinese population. J Periodont Res 2015; 50: 509–518. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Background and Objective: Dyslipidemia is associated with aggressive periodonti- tis, a condition characterized by the rapid destruction of the periodontium. Apo- lipoprotein E (APOE) and low-density lipoprotein receptor-related protein 5 (LRP5) are involved in immunomodulation and inflammatory activity. We eval- uated the association of LRP5 and APOE polymorphisms with serum lipid con- centrations and generalized aggressive periodontitis within a Chinese population. Material and Methods: Mean serum lipid concentrations were compared across LRP5 and APOE polymorphisms, among cases (n = 185) and controls (n = 138). Multivariable logistic regression was used to evaluate the independent and combined associations of LRP5 and APOE polymorphisms with generalized Huanxin Meng, BDS, MS, PhD, Peking aggressive periodontitis. University School and Hospital of Stomatology, 22, Zhongguancun Nandajie, Hai Dian District, Results: Compared with controls, individuals with generalized aggressive peri- Beijing 100081, China odontitis exhibited significantly lower serum total cholesterol (TC) and lower Tel: +86 10 82195522 high-density lipoprotein cholesterol (HDL-c). Individuals with LRP5 polymor- Fax: +86 10 62173402 e-mail: [email protected] phisms (rs682429-AA or rs312016-GG) exhibited higher TC, higher HDL-c and decreased odds for generalized aggressive periodontitis. Haplotype (A-G), deter- *These authors contributed equally to this mined by rs682429 and rs312016, was also associated with decreased odds for study. generalized aggressive periodontitis. Furthermore, individuals with the combined Key words: apolipoprotein E; generalized polymorphisms (LRP5-rs682429-AA and APOE-rs429358-CC/CT) had higher aggressive periodontitis; low-density lipoprotein receptor-related protein 5; serum lipid; single levels of low-density lipoprotein cholesterol, higher levels of TC and decreased nucleotide polymorphisms odds for generalized aggressive periodontitis. Accepted for publication August 23, 2014 510 Gao et al. Conclusion: Independently or combined with APOE, LRP5 polymorphisms may lead to dyslipidemia and are associated with generalized aggressive periodontitis. Dyslipidemia may be a risk indicator for generalized aggressive periodontitis in the Chinese population. Furthermore, two LRP5 polymorphisms (rs682429 and rs312016) might be useful for identifying subjects at higher risk of generalized aggressive periodontitis. Aggressive periodontitis is an uncom- APOE binds to cholesterol to form a As far as the researchers are aware, mon and severe form of periodontitis, highly hydrophilic lipoprotein, allow- no published studies have evaluated characterized by the rapid destruction ing efficient transportation in the the independent or combined associa- of the periodontium in otherwise blood (16), and mediates the binding tion of APOE and LRP5 polymor- healthy adolescents and young adults between the lipoprotein and the low- phisms with generalized aggressive (1). Although microbes are often cited density lipoprotein receptor (17). Of periodontitis. The purpose of the cur- as the primary causative agent of all the different APOE isoforms, the rent study is two-fold: (i) to evaluate aggressive periodontitis, the manifes- APOE e4 isoform is that which is the relationship between the APOE tation and progression of the disease most strongly associated with higher and LRP5 polymorphisms and serum results from the complex interactions lipid levels and increased risk of car- lipid concentrations; and (ii) to evalu- between oral bacteria, the host diovascular disease (18). Furthermore, ate the independent and combined response and behavioral factors. It APOE is involved in immunomodula- association of APOE (rs429358, has also been suggested that genetic tion and inflammatory activity (19); rs7412) and LRP5 (rs312016, factors seem to play an important role APOE polymorphisms have been rs682429) polymorphisms with gener- in predisposing individuals to peri- associated with a range of inflamma- alized aggressive periodontitis in a odontitis, which is supported by sev- tory and autoimmune diseases and Chinese population. eral genetic segregation analyses of disorders, including Alzheimer’s dis- families and a twin study of chronic ease (20), diabetic nephropathy (21), Material and methods periodontitis (2,3). severe hepatitis C infection (22), high Evidence is building that hyperlipid- levels of C-reactive protein (23) and Study population emia is a risk indicator for periodontal rheumatoid arthritis (16). disease (4–6). Studies have found that Similarly, low-density lipoprotein A total of 323 unrelated individuals severe periodontitis is associated with receptor-related protein 5 (LRP5) of Chinese ethnicity volunteered to lower levels of high-density lipopro- plays a regulatory role in cholesterol participate in this case–control study. tein cholesterol (HDL-c), higher levels metabolism (24) and is involved in the Each case received a full periodontal of low-density lipoprotein cholesterol clearance of APOE-containing lipo- examination and a set of full-mouth (LDL-c) and significantly higher levels proteins (25). Recent studies have radiographs were obtained. Two of plasma triglycerides (7–9). How- shown that APOE/LRP5 double- senior, experienced periodontists, who ever, contradictory findings have also knockout mice exhibited higher were calibrated, carried out all clinical been reported (10–12). plasma cholesterol levels that were examinations and diagnosis. The Nutrition is also an important risk 60% higher than the levels among kappa value of intrarater agreement factor for periodontitis, as poor nutri- APOE knockout mice (26,27). Fur- for the diagnosis of generalized tion may inhibit the immune response thermore, LRP5 is also a co-receptor aggressive periodontitis was estimated (13). Specifically, foods high in dietary of Wnt/b-catenin signaling (28), a for 50 individuals, whilst the kappa cholesterol or fatty acids may inhibit mechanism that might be involved in value for inter-rater agreement for the the immune response and accelerate the development of periodontitis (29). diagnosis of generalized aggressive the bactericidal effect on Porphyro- LRP5 polymorphisms have been asso- periodontitis was estimated for 20 monas gingivalis (14). Although the ciated with cholesterol level (30), bone individuals. The kappa values for in- importance of nutrition on the mineral density (31), osteoporosis trarater/inter-rater agreement were immune function has been estab- (32), diabetes mellitus (33), obesity 0.98 and 0.95, respectively. Patients lished, it remains unclear whether (34), bone fracture (35), Alzheimer’s with generalized aggressive periodon- abnormalities in lipid metabolism or disease (36) and tumors (28,37,38). As titis (cases) (n = 185) were recruited conditions related to dyslipidemia a result of the established relationship from the Clinic of Periodontology lead to periodontal disease or if peri- between periodontitis and osteoporo- Department, Peking University odontal disease leads to impaired lipid sis, diabetes mellitus and obesity School and Hospital of Stomatology, metabolism (15). (15,38), we suspect that LRP5 poly- from July 2001 to December 2012. Apolipoprotein E (APOE) plays an morphisms might also be associated We used the 1999 International Clas- important role in the uptake of lipids. with periodontitis. sification of Periodontal Diseases and APOE, LRP5 polymorphisms, generalized aggressive periodontitis and serum lipid 511 Conditions (1) as the diagnostic crite- terol (TC), triglyceride, HDL-c and MASSARRAY TYPER software version 3.4 ria for generalized aggressive peri- LDL-c levels, were measured using a (Sequenom). As a quality check of odontitis, which includes all of the biochemical analyzer (Hitachi 7060; our data, we sequenced more than following characteristics: (i) under Hitachi, Tokyo, Japan); fasting serum 5% of the samples (eight cases and 35 years of age; (ii) at least six teeth glucose levels were also measured using seven controls) using an ABI 3100 (at least three of which were not first a biochemical analyzer. DNA sequencer (Applied Biosystems, molars or incisors) with a probing Foster City, CA, USA); the genotype depth of ≥ 5 mm and clinical attach- concordance rate between duplicate Genotyping ment loss of ≥ 3 mm; (iii) no peri- samples was 100%. odontal treatments within the past The SEQUENOM MassARRAY 12 mo; (iv) female cases were not matrix-assisted laser desorption ioniza- Statistical analyses pregnant or lactating; and (v) clini- tion time-of-flight (MALDI-TOF) cally healthy, except for the presence mass spectrometry
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