Association Study Of LOXL1 And VDR Gene With Benign Paroxysmal Positional Vertigo

BackgroundBenign paroxysmal positional vertigo(BPPV)is currently the most common type of positional vertigo.BPPV is characterized by short periods of vertigo,balance disorders and positional nystagmus associated with changes in head position.It may be accompanied by autonomic symptoms such as nausea,vomiting,sweating,and tachycardia.The neurological examination is mostly unremarkable and is usually not accompanied by hearing impairment or tinnitus.The average age of onset is 50 years,with a higher incidence in older age groups older than 65 years.The ratio of female to male prevalence is about 2-3:1.Some studies suggested that there is a familial aggregation of BPPV,but it cann’t make sure that this phenomenon is environmentally related or not.The diagnosis is based on these symptoms and the observation of the nystagmus by physical examinationt.It is reported that annual prevalence of BPPV to be 1.6%and the lifetime prevalence of BPPV to be 2.4%.Several studies have found an increased risk of falls,fractures,hypertension,and dementia in patients with BPPV.In addition,BPPV may cause physical and psychological distress during episodes of vertigo.As a result,BPPV severely reduces the quality of life of patients and affects the performance of daily activities.The current study about the occurrence of BPPV is related to otolith dislodgement.Otoliths are mainly composed of calcium carbonate crystals and organic glycoprotein cores with a density of about 2.7 g/cm3.Some studies have shown that otoliths share common features with bone tissue,and their formation is closely related to calcium ion metabolism.Vitamin D plays an important role in calcium regulation.Some studies have shown that vitamin D levels are low in patients with BPPV and that vitamin D supplementation can reduce vertigo attacks.The vitamin D receptor(VDR)is widely distributed in the semicircular canal of the inner ear,crista ampullaris,osteoblasts and osteoclasts,and may be involved in vestibular function.Mice with mutations in the vitamin D receptor has vestibular dysfunction,also suggesting the vitamin D receptor may be associated with the development of BPPV.Therefore,we hypothesized that the VDR gene might be the susceptibility gene of BPPV.A BPPV family study suggested that BPPV may be associated with the marker GATA151F03N of chromosome 15,which is involved in the expression of the LOXL1 gene.LOXL1 gene encodes a copper-dependent amino acid oxidase,which belongs to the LOXS family.The function of LOXS is to make collagen fiber and elastin form collagen cross-linking and interweave into a relatively stable network structure,which can resist the decomposition of elastin and the dissolution of collagen caused by proteolytic enzymes,increase the tensile strength,and play an important role in normal connective tissue function,tissue development and repair.Previous studies have focused on the role of LOXs in connective tissue disease,exfoliation syndrome,copper metabolic disorders,pelvic organ prolapse,osteomalacia and rickets,and the occurrence and metastasis of tumors.The main positive SNPs found are rs2165241,rs1048661,rs3825942,rs4461027,rs4886761 and rsl6958477,etc.but it is little study on LOXL1.ObjectiveThe main purpose of this study was to investigate the association between VDR and LOXL1 gene polymorphisms with BPPV in the Chinese population.MethodsPatients with idiopathic BPPV diagnosed in the Department of Neurology between July 2016 and March 2019 were selected as subjects in the case-control study.five tagSNPs of VDR gene(rs11574143,rs757343,rs1540339,rs2239186,rs10875695)and four tagSNPs of LOXL1 gene(rs4886761,rsl6958477,rs1078967,rs8041642)were selected for association analysis,Hardy-Weinberg equilibrium test and linkage disequilibrium test.We analyzed the correlation between VDR and LOXL1 gene with BPPV.Subgroup analysis was conducted to analyze the differences of allele and genotype frequency between male and female subgroups with the control group.Results1.This study included 1077 subjects(537 BPPV patients,540 healthy controls),there were no statistically significant differences in gender and age between the BPPV groups and control groups.2.The distribution of 4 SNPsof LOXL1 gene and 5 SNPs of VDR gene in the control group were consistent with Hard-Weinberg equilibrium(P>0.05).3.Correlation analysis of single loci and haplotypes showed that allele and genotype frequency of five SNPs of VDR gene did not have significant differences between BPPV group and control group(P>0.05).The allele and genotype distribution of rs 1078967 of the LOXL1 gene were significantly associated with benign paroxysmal positional vertigo(Pallele=0.001,OR=0.628[0.471--0.837],Pgeotype=0.004;FDR corrected Pallele=0.005,Pgeotype=0.013).In the dominant inheritance pattern,the frequency of TT+TC was 15.5%in the BPPV group and 23.3%in the control group.The difference between the two groups was significant.Individuals with TT+TC genotype had a lower risk of BPPV(P<0.001,OR=0.601[0.442-0.817]).There was no significant difference in allele distribution between BPPV group and control group for rs16958477 of LOXL1 gene(P=0.083).The genotype distribution of rs16958477 showed a significant correlation with benign paroxysmal positional vertigo(P=0.006,PFDR=0.013).Recessive genetic pattern analysis showed that the CC genotype frequency of the BPPV group was 3.2%,which was significantly higher than that of the control group(0.6%).The difference between the two groups was statistically significant.CC genotype was associated with an increased risk of BPPV(P=0.003,OR=5.852[1.705-20.08]).Rs4886761 and rs8041642 showed no significant correlation with BPPV after FDR correction.4.Linkage disequilibrium analysis showed that the D>0.95 of rs1 6958477 and rs1078967.the haplotype analysis showed that the difference of A-T haplotype between the BPPV group and the control group was statistically significant,and A-T haplotype reduced the risk of BPPV(P=0.001,OR=0.628[0.471-0.837]0,There was still significant difference after correction(P=0.004)4.Further gender subgroup analysis showed that the allele and genotype distribution frequencies of the five SNPs of the VDR gene were not significantly different between the BPPV and control groups in both the male and female subgroups(P>0.05).In the female subgroup the allele frequency of rs1078967 of the LOXL1 gene was significantly different between the case and control groups(P=9.34e-04,OR[95%CI]=0.556[0.391-0.79],PFDR=0.003).rs1078967 genotype frequency was also significantly different between the case and control groups significantly different(P=0.0035,χ2=11.54,PFDR=0.012).Genotype distribution of rsl695847 was significantly different between the two groups(P=0.006,χ2=9.951,PFDR=0.013).Allele frequencies of rs16958477 did not reach significant differences between the two groups(P>0.05).In the male subgroup,the allele and genotype frequencies of the four SNPs(rs4886761,rs16958477,rs1078967,rs8041642)of LOXL1 gene was no significant difference between the BPPV and control groups(P>0.05).Conclusions1.Single nucleotide polymorphisms of the LOXL1 are associated with benign paroxysmal positional vertigo.The T allele of rs1 078967 has a protective effect on the occurrence of BPPV.Under the dominant inheritance model,the TT genotype and TC genotype of rs1078967 can reduce the risk of BPPV.Under the recessive inheritance model,CC genotype of rs16958477 can increase the risk of BPPV.2.A-T haplotypes of rsl6958477 and rs1078967 reduce the risk of benign paroxysmal positional dizziness.3.VDR gene polymorphism may not be associated with the risk of benign paroxysmal positional vertigo.