Original Article Sexually Dimorphic Association of the B-Cell CLL/Lymphoma 7B Gene Rs2237278 and Lipid-Associated Phenotypes

Int J Clin Exp Pathol 2016;9(12):12942-12958 www.ijcep.com /ISSN:1936-2625/IJCEP0035189 Original Article Sexually dimorphic association of the B-cell CLL/lymphoma 7B gene rs2237278 and lipid-associated phenotypes Tao Guo, Rui-Xing Yin, Hui Gao, Qing-Hui Zhang, Jian-Hua Huang, Wei-Jun Li Department of Cardiology, Institute of Cardiovascular Diseases, The First Affiliated Hospital, Guangxi Medical University, Nanning, Guangxi, China Received July 6, 2016; Accepted July 20, 2016; Epub December 1, 2016; Published December 15, 2016 Abstract: The biology basis for gender differences in cardiovascular diseases (CVDs) susceptibility seems ubiquitous especially for postmenopausal women, but little is known about the sexually dimorphic association of the B-cell CLL/lymphoma 7B gene (BCL7B) rs2237278 single nucleotide polymorphism (SNP) and environmental factors with lipid profiles in the Jing and Han populations. To study the contribution of BCL7B rs2237278 to both the establish- ment and persistence of gender differences in lipid profiles, genotyping was performed in 1148 of Jing (582 males and 566 females) and 1355 of Han (706 males and 649 females) participants using polymerase chain reaction and restriction fragment length polymorphism. Sexually dimorphic analysis showed that the genotype and allele frequencies of the BCL7B rs2237278 SNP were significantly different between males and females in Jing (CC, 67.87% vs. 61.31%; CT, 29.55% vs. 34.63%; TT, 2.58% vs. 4.06%; P = 0.047; T, 17.35% vs. 21.38%, P = 0.015) and Han populations (CC, 68.27% vs. 62.10%; CT, 29.32% vs. 34.36%; TT, 2.41% vs. 3.54%; P = 0.046; T, 17.07% vs. 20.72%; P = 0.015) populations. Females had higher serum triglyceride (TG) levels in Jing and lower high-density lipoprotein (HDL) cholesterol levels in Han than males. TT genotype of BCL7B rs2237278 SNP was a risk genotype for dyslipidemia, especially higher serum TG levels in sexually dimorphic group both of two populations and lower serum HDL-cholesterol levels in Jing females. Our findings provide evidence to support sexually dimorphic association between BCL7B rs2237278 SNP and serum lipid profiles may account, at least in part, for the female predominance of dyslipidemia susceptibility. Thus, although data are more limited, there is good reason to believe that cholesterol interventions for female are likely to be effective, particular in postmenopausal women. Keywords: Sexually dimorphic association, B-cell CLL/lymphoma 7B gene (BCL7B), single nucleotide polymorphism, lipids, environmental factors Introduction tion [10-14]. Although several studies have shown an improvement of prognosis in women Over the last decade, cardiovascular diseases over time [15, 16], overall outcomes remain have become the single largest cause of death worse for women compared with men [17], pro- and disability-adjusted life years (DALYs) in viding a strong rationale for focusing on the both men and women worldwide [1-3]. There is study of sex-based differences in the outcome a growing body of recently published genetic of hyperlipidemia [18, 19], especially hypertri- and epidemiological evidences which demon- glyceridemia [20]. American Heart Association strated a causal role of rising triglyceride (TG) (AHA) and numerous government and profes- levels (alongside with reducing of high-density sional organizations [21] have jointly developed lipoprotein cholesterol levels) [4] and TG-rich evidence-based guidelines to assist with lipid lipoproteins in the pathogenesis of atheroscle- assessment and treatment in high-risk women rosis and particularly coronary artery disease that take into consideration the quality, quanti- [5-9]. These data support the renewed interest ty, and generalizability of available data to in hypertriglyceridemia as a possible important women [22-24], because of high-risk women therapeutic target for cardiovascular risk reduc- benefit significantly and to a similar degree as BCL7B gene rs2237278 and lipid-associated phenotypes men from lipid-lowering therapy, especially their gender subgroups [40, 41]. This study, postmenopausal women [25-27]. therefore, was undertaken to detect the association of BCL7B rs2237278 SNP and several Human B-cell CLL/lymphoma 7B (BCL7) gene environmental factors with lipid profiles family [28, 29] consists of BCL7A, BCL7B, and between males and females in the Jing and BCL7C. A number of clinical studies have Han populations. reported that BCL7 family is involved in meta- bolic syndrome (MetS) incidence, progression, Methods and materials and development [30, 31]. BCL7B (Gene ID: 9275; MIM: 605846; Cytogenetic location: Ethical approval 7q-11.23; Genomic coordinates (GRCh38): 7:73,536,352-73,557,734) mutants exist that The study design was approved by the Ethics influence MetS and inflammatory markers Committee of the First Affiliated Hospital, forming a predisposing MetS genetic network Guangxi Medical University. Informed consent [32-34]. This gene encodes a member of the was taken from all participants. BCL7 family including BCL7A, BCL7B and BCL7C Subjects proteins. BCL7B contains a region that is highly similar to the N-terminal segment of BCL7A or Two groups of study population including 1148 BCL7C proteins. The BCL7A protein is encoded unrelated participants (582 males, 50.7% and by the gene known to be directly involved in a 566 females, 49.3%) of Jing and 1355 unrelat- three-way gene translocation in a Burkitt lym- ed subjects (706 males, 52.1% and 649 phoma cell line. This gene is located at a chro- females, 47.9%) of Han were randomly selected mosomal region commonly deleted in Williams’s from our previous stratified randomized sam- syndrome. It is highly conserved from C. ele- ples [42-44]. All participants were agricultural gans to human. Multiple alternatively spliced workers from Dongxing City, Guangxi Zhuang transcript variants have been found for this Autonomous Region, People’s Republic of gene. A GWAS analysis has identified the China. The participants’ age ranged from 15 to rs17145738 SNP in the intronic region of 80 years with the mean age of 57.14±14.21 BCL7B as TG-related loci in European popula- years in Jing males, 57.36±12.49 years in Jing tions [35, 36]. However, in Chinese population, females, 56.41±12.95 years in Han males, whether BCL7B rs2237278 SNP is associated 57.20±12.40 years in Han females; respective- with lipid profiles or whether it exhibits sex-spe- ly. The age distribution and gender ratio were cific association like the other reported BCL7B matched between the two groups. All partici- SNPs remains elusive. pants were essentially healthy with no history of coronary artery disease, stroke, diabetes, China has a majority population of Han ethnici- hyper- or hypo-thyroids, and chronic renal dis- ty and 55 officially recognized ethnic minorities ease. They were free from medications known [37]. The Jing ethnic group is one of several iso- to affect lipid profiles. lated minorities in the Guangxi Zhuang Auto- nomous Region, China. The Jing population is Epidemiological survey the only oceanic ethnic group in China, with a very small population size of 28,199 in 2010 The epidemiological survey was carried out [38]. In the early 16th century, the Jing ances- using internationally standardized methods, tors emigrated from Vietnam to China to first following a common protocol [42-44]. Infor- settle on the three islands of Wanwei, Wutou mation on demographics, socioeconomic sta- and Shanxin in Dongxing City, where almost all tus, and lifestyle factors was collected with of the Jing population now live [38]. We recently standardized questionnaires. Smoking status showed that Jing has much closer genetic rela- was categorized into groups of cigarettes per tionship with the other minorities in Guangxi day: < 20 and ≥ 20. Alcohol consumption was than with the Han nationality [39]. In addition, categorized into groups of grams of alcohol per several previous studies have revealed that the day: < 25 and ≥ 25. Several parameters such associations of variants in several lipid-related as blood pressure, height, weight, waist circum- genes and lipid profiles are significantly differ- ference were measured, and body mass index ent between the Jing and Han populations and (BMI, kg/m2) was calculated [45-47]. 12943 Int J Clin Exp Pathol 2016;9(12):12942-12958 BCL7B gene rs2237278 and lipid-associated phenotypes Biochemical measurements nology & Services Co., Ltd., People’s Republic of China. A fasting venous blood sample of 5 ml was drawn from the participants. The levels of total Diagnostic criteria cholesterol (TC), TG, high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein The normal values of serum TC, TG, HDL-C, LDL- cholesterol (LDL-C) in the samples were deter- C, ApoA1 and ApoB levels, and the ratio of mined by enzymatic methods with commercial- ApoA1 to ApoB in our Clinical Science Ex- ly available kits. Serum apolipoprotein (Apo) A1 periment Center were 3.10-5.17, 0.56-1.70, and ApoB levels were assessed by the immune- 1.16-1.42, 2.70-3.10 mmol/L, 1.20-1.60, 0.80- turbidimetric immunoassay [45-47]. 1.05 g/L, and 1.00-2.50; respectively [45-47]. Genotyping Statistical analysis Genomic DNA was isolated from peripheral The statistical analyses were performed with blood leukocytes using the phenol-chloroform the statistical software package SPSS 19.0 method. The BCL7B rs2237278 SNP was ge- (SPSS Inc., Chicago, Illinois). The quantitative notyped by polymerase chain reaction and res- variables were presented as mean ± standard triction fragment length polymorphism (PCR- deviation (serum TG levels were presented as RFLP). PCR amplification was performed using medians and interquartile ranges). Allele fre- 5’-GAGCGTGCCTCAGGTTAC-3’ as the forward quency was determined via direct counting, and 5’-GCAGGGATGCTGGAATGA-3’ as reversed and the Hardy-Weinberg equilibrium was veri- primer pair. Each amplification reaction was fied with the standard goodness-of-fit test. The performed in a total volume of 25 μl, 12.5 μl of genotype distribution between the groups was 2 × Taq PCR MasterMix (constituent: 0.1 U Taq analyzed by the chi-square test.

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