Two novel susceptibility loci for type 2 diabetes mellitus identified by longitudinal exome-wide association studies in a Japanese population

Recent genome-wide association studies identified genetic variants that confer susceptibility to type 2 diabetes mellitus (T2DM). However, few longitudinal genome-wide association studies of this metabolic disorder have been reported to date. Therefore, we performed a longitudinal exome-wide association study of T2DM, using 24,579 single nucleotide polymorphisms (SNPs) and repeated measurements from 6022 Japanese individuals. The generalized estimating equation model was applied to test relations of SNPs to three T2DM-related parameters: prevalence of T2DM, fasting plasma glucose level, and blood glycosylated hemoglobin content. Three SNPs that passed quality control were significantly (P < 2.26 × 10^? 7) associated with two of the three T2DM-related parameters in additive and recessive models. Of the three SNPs, rs6414624 in EVC and rs78338345 in GGA3 were novel susceptibility loci for T2DM. In the present study, the SNP of GGA3 was predicted to be a genetic variant whose minor allele frequency has recently increased in East Asia.     

Association of Interleukin 6 gene polymorphisms with genetic susceptibilities to spastic tetraplegia in males: A case-control study

BackgroundCerebral palsy (CP) is a group of non-progressive motor impairment and permanent disorders causing limitation of activity and abnormal posture. It may be caused by infection (such as chorioamnionitis), asphyxia or multiple genetic factors. The Interleukin 6 gene (IL6) was suggested to be involved in the susceptibilities to CP risk as a kind of proinflammatory cytokine.ObjectiveTo explore the genetic association between the polymorphisms of the IL6 gene and CP in the Chinese population.MethodsA total of 542 CP patients and 483 healthy control children were recruited in this study to detect five single nucleotide polymorphisms (rs1800796, rs2069837, rs2066992, rs2069840, and rs10242595) in the IL6 locus. Genotyping of SNPs was performed by the MassArray platform-based genotyping approach. The SHEsis program was applied to analyze the genotyping data.ResultsOf the five selected SNPs, no significant allelic and genotypic association was found between CP patients and controls. However, subgroup analysis found significant differences in allele frequencies between spastic tetraplegia in males compared with controls at rs1800796 (OR = 1.39, P = 0.033, P = 0.099 after SNPSpD correction) and rs2069837 (OR = 1.58, P = 0.012, P = 0.035 after SNPSpD correction). The frequencies of the C allele of rs1800796 and the A allele of rs2069837 were greater in males with spastic tetraplegia than in the controls. The two SNPs haplotype rs1800796 (G) – rs2069837 (G) were also associated with a decreased risk of spastic tetraplegia in males (OR = 0.619, P = 0.009, P = 0.027 after Bonferroni correction).ConclusionGenetic variation of the IL6 gene may influence susceptibility to spastic tetraplegia in males and its role in cerebral palsy deserves further evaluation in a large-scale and well-designed study.     

Breast cancer susceptibility loci in association with age at menarche,age at natural menopause and the reproductive lifespan

Background: Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) associated with breast cancer risk. Some of these loci have unknown functional significance and may mediate the effects of hormonal exposures on breast cancer risk. We examined relationships between breast cancer susceptibility variants and menstrual/reproductive factors using data from two population-based studies. Methods: The first analysis was based on a sample of 1328 women age 20–74 who participated as controls in a case–control study of breast cancer conducted in three U.S. states. We evaluated the associations between age at menarche, age at natural menopause and the reproductive lifespan with 13 previously identified breast cancer variants. Associations were also examined with a genetic score created as the sum of at-risk alleles across the 13 variants. For validation, significant results were evaluated in a second dataset comprised 1353 women age 43–86 recruited as part of a cohort study in Wisconsin. Results: Neither the genetic score nor any of the 13 variants considered individually were associated with age at menarche or reproductive lifespan. Two SNPs were associated with age at natural menopause; every increase in the minor allele (A) of rs17468277 (CASP8) was associated with a 1.12 year decrease in menopause age (p = 0.02). The minor allele (G) of rs10941679 (5p12) was associated with a 1.01 year increase in age at natural menopause (p = 0.01). The results were not replicated in the validation cohort (B = −0.61, p = 0.14 and B = −0.01, p = .0.98, respectively). Conclusions: The evaluated variants and reproductive experiences may work through separate pathways to influence breast cancer risk.     

Case-control study of rhinoconjunctivitis associated with IL5RA polymorphisms in Japanese women: The Kyushu Okinawa Maternal and Child Health Study

BackgroundEpidemiological research on the relationship between single nucleotide polymorphisms (SNPs) in the IL5RA gene and allergic disorders is limited. We examined the relationship between IL5RA SNPs and risk of rhinoconjunctivitis in young adult Japanese women.MethodsIncluded were 393 women who met the criteria of the International Study of Asthma and Allergies in Childhood (ISAAC) for rhinoconjunctivitis. Controls were 767 women without rhinoconjunctivitis according to the ISAAC criteria who had not been diagnosed with allergic rhinitis by a doctor. Adjustment was made for age, region of residence, presence of older siblings, smoking, and education.ResultsCompared with the CC genotype of SNP rs6771148, the CG genotype, but not the GG genotype, was significantly associated with a reduced risk of rhinoconjunctivitis: the adjusted OR for the CG genotype was 0.76 (95% CI: 0.58–0.99). No evident associations were found between SNPs rs17882210, rs3804797, rs334809, rs9831572, or rs17881144 and rhinoconjunctivitis. The ACTAGA haplotype of rs17882210, rs3804797, rs334809, rs9831572, rs6771148, and rs17881144 was significantly inversely associated with rhinoconjunctivitis (crude OR = 0.58, 95% CI: 0.37–0.88) while the GTAGCA haplotype was significantly positively related to rhinoconjunctivitis (crude OR = 1.74, 95% CI: 1.14–2.65). No significant interactions affecting rhinoconjunctivitis were observed between any of the six SNPs and smoking.ConclusionThis is the first study to show significant associations between IL5RA SNP rs6771148, the ACTAGA haplotype, and the GTAGCA haplotype and the risk of rhinoconjunctivitis. We did not find evidence for interactions affecting rhinoconjunctivitis between any of the IL5RA SNPs and smoking.     

Novel gene variants predict serum levels of the cytokines IL-18 and IL-1ra in older adults

Activation of inflammatory pathways measured by serum inflammatory markers such as interleukin-18 (IL-18) and interleukin-1 receptor antagonist (IL-1ra) is strongly associated with the progression of chronic disease states in older adults. Given that these serum cytokine levels are in part a heritable trait, genetic variation may predict increased serum levels. Using the Cardiovascular Health Study and InCHIANTI cohorts, a genome-wide association study was performed to identify genetic variants that influence IL-18 and IL-1ra serum levels among older adults. Multiple linear regression models characterized the association between each SNP and log-transformed cytokine values. Tests for multiple independent signals within statistically significant loci were performed using haplotype analysis and regression models conditional on lead SNP in each region. Multiple SNPs were associated with these cytokines with genome-wide significance, including SNPs in the IL-18-BCO gene region of chromosome 2 for IL-18 (top SNP rs2250417, P = 1.9 × 10^–32) and in the IL-1 gene family region of chromosome 2 for IL-1ra (rs6743376, P = 2.3 × 10^–26). Haplotype tests and conditional linear regression models showed evidence of multiple independent signals in these regions. Serum IL-18 levels were also associated with a region on chromosome 2 containing the NLRC4 gene (rs12989936, P = 2.7 × 10^–19). These data characterize multiple robust genetic signals that influence IL-18 and IL-1ra cytokine production. In particular, the signal for serum IL-18 located on chromosome two is novel and potentially important in inflammasome triggered chronic activation of inflammation in older adults. Replication in independent cohorts is an important next step, as well as molecular studies to better understand the role of NLRC4.     

ERCC1 haplotypes modify bladder cancer risk: A case–control study

Bladder cancer risk is highly influenced by environmental and/or predisposing genetic factors. In the last decades growing evidence of the major role played by DNA repair systems in the developing of bladder cancer has been provided. To better investigate the involvement of DNA repair genes previously reported to be significantly associated with bladder cancer risk, we examined in a case–control study (456 cases and 376 hospital controls) 36 single nucleotide polymorphisms (SNPs) in 10 DNA repair genes, through a better gene coverage and a deep investigation of the haplotype role. A single SNP analysis showed a significantly increased risk given by XRCC1-rs915927 G allele (OR = 1.55, CI 95% 1.02–2.37 for dominant model) and a protective effect of the rare alleles of 3 ERCC1 SNPs: rs967591 (OR = 0.66, CI 95% 0.46–0.95), rs735482 (OR = 0.62, CI 95% 0.42–0.90) and rs2336219 (OR = 0.63, CI 95% 0.43–0.93). Haplotype analysis revealed that cases had a statistically significant excess of XRCC3-TAGT and ERCC1-GAT haplotypes, whereas ERCC1-AAC, MGMT-TA, XRCC1-TGCC and ERCC2-TGAA haplotypes were significantly underrepresented. Together with other published data on large case–control studies, our findings provide epidemiological evidence supporting a link between DNA repair gene variants and bladder cancer development, and suggest that the effects of high-order interactions should be taken into account as modulating factors affecting bladder cancer risk. A detailed characterization of DNA repair genetic variation is warranted and might ultimately help to identify multiple susceptibility variants that could be responsible for joint effects on the risk.     

ADIPOQ gene polymorphisms and cancer risk: A meta-analysis

The results of studies investigating the association between ADIPOQ gene polymorphisms and risk of cancer have been inconsistent and often contradictory. The present meta-analysis was conducted in order to overcome the limitations of any individual study and to provide a more precise overall effect estimate. Relevant studies were identified by searching PubMed and Embase for articles published through May 2012. The strength of the relationship between the ADIPOQ gene and risk of cancer was assessed using odds ratios (ORs). Either a fixed-effects or a random-effects model was used to calculate the overall risk estimates. Fifteen studies were included and five SNPs were considered. A significant association was found between SNP rs2241766 and risk of cancer in the recessive genetic model (OR: 0.768, 95% CI: [0.626, 0.942], P = 0.011); a significant relationship was also found between SNP rs1501299 and risk of cancer in both an allele contrast (OR: 0.141, 95%CI: [0.113, 0.176], P < 0.001) and the dominant genetic model (OR: 0.904, 95%CI: [0.830, 0.985], P = 0.021); no association was found with the rs266729, rs822395, or rs822396 SNPs. Adjusted ORs were also considered, but no statistically significant association was found in homozygote contrasts for any of the five SNPs after adjustment. Our results suggest that two polymorphisms, SNP rs2241766 and SNP rs1501299, of the ADIPOQ gene may be associated with reduced risk of cancer. However, the overall strength of association is mild to moderate, and additional well-designed studies are needed to confirm the present conclusion.     

Vitamin D receptor variants and the malignant melanoma risk: A population-based study

Background: There is continuing interest in identifying low-penetrance genes which are associated with an increased susceptibility to common types of cancer, including malignant melanoma. Methods: We sought to examine the association between four VDR common variants (rs1544410, rs731236, rs10735810, rs4516035) and the risk of melanoma in the Polish population. We also determined the prevalence of compound carriers of VDR and known MM genetic risk factors MC1R and CDKN2A (A148T) variants. We examined 763 unselected melanoma cases, 763 healthy adults matched for sex and age with the melanoma cases and 777 newborns. Results: None of the VDR variants alone or as compound carriers of two or more of the VDR genotypes were associated with MM risk. There were no major differences between the prevalences of the examined variants among patients with MM on UV-exposed and UV-non exposed skin areas, as well as among early-onset and late-onset cases. We found no association between VDR and MC1R or between VDR and CDKN2A common variants. A statistically significant over-representation of one VDR haplotype: rs731236_A + rs1544410_T (OR = 3.2, p = 0.02) was detected. Linkage disequilibrium of rs1544410 and rs731236 was confirmed. Conclusion: To answer the question, whether VDR can be regarded as melanoma susceptibility gene, additional, large multi-center association studies have to be performed.     

Genetic variations of NOD2 and MD2 genes in hepatitis B virus infection

Objectives: Nucleotide oligomerization domain 2 (NOD2) and myeloid differentiation protein 2 (MD-2) have crucial roles in the innate immune system. NOD2 is a member of the NOD-like receptor (NLR) family of pattern recognition receptors (PRRs), while MD-2 is a co-receptor for Toll-like receptor 4 (TLR4), which comprises another group of PRRs. Genetic variations in the NOD2 and MD-2 genes may be susceptibility factors to viral pathogens including hepatitis B virus (HBV). We investigated whether polymorphisms at NOD2 (rs2066845 and rs2066844) or at MD-2 (rs6472812 and rs11466004) were associated with susceptibility to HBV infection and advancement to related liver complications in a Saudi Arabian population. Methods: A total of 786 HBV-infected patients and 600 healthy uninfected controls were analyzed in the present study. HBV-infected patients were categorized into three groups based on the clinical stage of the infection: inactive HBV carriers, active HBV carriers, and patients with liver cirrhosis + hepatocellular carcinoma (HCC). Results: All four SNPs were significantly associated with susceptibility to HBV infection although none of the SNPs tested in NOD2 and MD-2 were significantly associated with persistence of HBV infection. We found that HBV-infected patients that were homozygous CC for rs2066845 in the NOD2 gene were at a significantly increased risk of progression to HBV-related liver complications (Odds Ratio = 7.443 and P = 0.044). Furthermore, haplotype analysis found that the rs2066844-rs2066845 C-G and T-G haplotypes at the NOD2 gene and four rs6472812-rs11466004 haplotypes (G-C, G-T, A-C, and A-T) at the MD-2 gene were significantly associated with HBV infection in the affected cohort compared to those found in our control group. Conclusion: We found that the single nucleotide polymorphisms rs2066844 and rs2066845 at NOD2 and rs6472812 and rs11466004 at MD-2 were associated with susceptibility to HBV infection in a Saudi population.     

Paget’s disease of bone is not associated with common polymorphisms in interleukin-6, interleukin-8 and tumor necrosis factor alpha genes

BackgroundCytokines, specially interleukin (IL)-6, play an important role in the differentiation and activation of osteoclasts and might be involved in osteoblast stimulation in Paget’s disease of bone (PDB).ObjectivesThe aim of this study was to investigate the association of polymorphisms in IL-6, IL-8 and tumor necrosis factors-alpha (TNFA) genes among Spanish patients with PDB.MethodsWe studied four single nucleotide polymorphisms (−174 G > C IL-6, −251 T > A IL-8, −238 G > A TNFA and −308 G > A TNFA) in 172 PDB patients and 150 healthy controls. Distribution of alleles and pro-inflammatory genotypes were studied for association with the presence of the disease and with clinical and laboratory data, as well as the response to bisphosphonate treatment in PDB patients.ResultsWe found no statistically significant association between genotype and allele distribution of any of the cytokines polymorphism studied and PDB. No association between the clinical and therapeutic characteristics of PDB and the investigated polymorphism were found.ConclusionsThis study does not support the hypothesis that the analyzed IL6, IL8 and TNFA polymorphism are associated with PDB.     

Marked differences of haplotype tagging SNP distribution,linkage, and haplotype profile of IL23 receptor gene in Roma and Hungarian population samples

Polymorphisms of the interleukin-23 receptor (IL23R) gene have been found to play an important role in the development of several autoimmune diseases. We examined five susceptible (rs10889677, rs1004819, rs2201841, rs11805303, rs11209032), one protective (rs7517847) and two neutral variants (rs7530511, rs1884444) of the IL23R gene in pooled DNA of healthy Roma (Gipsy) and Hungarian population samples. Our aim was to determine the genetic variability of the major haplotype tagging polymorphisms, and the haplotype profile of IL23R between the two groups. We analyzed 273 healthy Roma and 253 Hungarian DNA samples using PCR/RFLP assay. Comparing the five susceptible conferring alleles, there were significant increase (p < 0.05), while in the protective alleles, there were decrease in the allele frequencies in Roma population (p < 0.05). One of the neutral alleles showed increase, the another one did not differ between the two groups. The haplotype analysis of the SNPs revealed fundamentally different association types of SNPs in the two groups; moreover, the frequencies of the various haplotypes also exhibited strong differences, as of ht4 and ht5 haplotypes were significantly higher, whereas the frequencies of ht2 and ht3 haplotypes were significantly lower in the Roma population than in Hungarians (p < 0.05). The data presented here show profound differences in the IL23R genetic profiles in the Roma population, that likely has also clinical implications in respect their possible role in the development of certain immunological diseases.     

An intronic polymorphism of IRF4 gene influences gene transcription in vitro and shows a risk association with childhood acute lymphoblastic leukemia in males

The interferon regulatory factor (IRF) family of DNA-binding proteins regulates expression of interferon-inducible genes with roles in the immune response and carcinogenesis. IRF4 is involved in the differentiation of B and T cells and is overexpressed in B-cell malignancies as a result of c-REL (NF-κB) hyperactivation. IRF4 polymorphisms are associated with susceptibility to chronic lymphoid leukemia (CLL) and non-Hodgkin lymphoma (NHL). We examined 13 IRF4 SNPs in 114 cases of childhood acute lymphoblastic leukemia (ALL) and 388 newborn controls from Wales (U.K.) using TaqMan assays. IRF4 intron 4 SNP rs12203592 showed a male-specific risk association (OR = 4.4, 95% CI = 1.5 to 12.6, P = 0.007). Functional consequences of the C > T substitution at this SNP were assessed by cell-based reporter assays using three different cell lines. We found a repressive effect of the rs12203592 wildtype allele C on IRF4 promoter activity (P < 0.001) but no repression by the variant allele in any cell line tested. Thus, homozygosity for the rs12203592 variant allele would result in increased IRF4 expression. This increase would be compounded by high levels of NF-κB activity in males due to the absence of estrogen. IRF4 differs from other IRFs in its anti-interferon activity which interferes with immune surveillance. We propose that a detailed study of IRF4 can provide information on the mechanism of the sex effect and the role of immune surveillance in childhood ALL development.     

Novel functional variants locus in PLCE1 and susceptibility to esophageal squamous cell carcinoma: Based on published genome-wide association studies in a central Chinese population

A novel functional single nucleotide polymorphism (SNP) rs2274223 located in the phospholipase C epsilon 1 (PLCE1) gene was found to be associated with the risk of esophageal squamous cell carcinoma (ESCC) by three large-scale genome-wide association studies (GWAS) in Chinese populations. In the present study, we validated this finding and also explored the risk of ESCC associated with other two unreported potentially functional SNPs (rs17417407 G > T and rs2274224 C > G) of PLCE1 in a population-based case–control study to investigate the association between these three potentially functional SNPs in PLCE1 and susceptibility to ESCC. A total of 381 ESCC cases and 420 controls matched by age and sex were recruited and successfully genotyped for three SNPs (rs17417407, rs2274223 and rs2274224) of the PLCE1 in a central Chinese population. SNP rs2274223 was independently associated with increased risk of ESCC (adjusted odds ratio [OR], 2.80; 95% confidence interval [95% CI], 1.45–5.39 for GG vs. AA), and SNP rs2274224 was found to be associated with decreased risk of ESCC (adjusted OR, 0.65; 95% CI, 0.46–0.91 for CG vs. CC). The combined effects of risk alleles for three SNPs (rs17417407T, rs2274223G and rs2274224G) were found to be associated with elevated risk of ESCC in a dose-dependent effect manner (P_trend = 0.005). The G_rs17417407A_rs2274223C_rs2274224 haplotype decreased the risk of ESCC (adjusted OR, 0.76; 95% CI, 0.62–0.93), meanwhile the G_rs17417407G_rs2274223C_rs2274224 and T_rs17417407G_rs2274223C_rs2274224 haplotypes could increase the risk of ESCC (adjusted OR, 1.75; 95% CI, 1.33–2.18 and OR, 2.51; 95% CI, 1.15–2.49). Gene–environment interaction analysis presented a best model consisted of four factors (rs2274223, rs2274224, family history, and smoking) with testing balance accuracy (TBA): 0.66 and cross validation consistency (CVC): 7/10, which could increase the esophageal cancer risk in the “high risk group” with 3.67-fold (OR: 3.67, 95% CI: 2.74–4.92), compared to the “low risk group”. Our results further confirmed that genetic variations in PLCE1 may contribute to ESCC risk associated with tobacco exposure in a central Chinese population. Further functional studies are needed to validate our results.     

Association between polymorphisms of matrix metalloproteinase 11 (MMP-11) and Kawasaki disease in the Korean population

AimsThis study was conducted to investigate the associations between single nucleotide polymorphisms (SNPs) of matrix metalloproteinases (MMPs) and Kawasaki disease (KD) in the Korean population.Main methodsA total 0f 101 KD patients and 306 healthy controls were examined. MMP7 (rs10502001, G/A, Arg77His), MMP11 (rs738792, T/C, Ala38Val), MMP12 (rs652438, A/G, Ile357Val) and MMP26 (rs2499953, A/G, Lys43Glu) genes were genotyped from the genomic DNA using direct sequencing. The results were then analyzed using logistic regression models, adjusting for gender as covariates.Key findingsThe four SNPs were in Hardy–Weinberg equilibrium. Only the MMP11 polymorphism (rs738792) was associated with KD. The SNP (rs738792) showed a statistically significant association with KD in the codominant (OR = 1.61, 95% CI = 1.11–2.34, P = 0.011) and dominant (OR = 1.92, 95% CI = 1.21–3.06, P = 0.006) models. However, there was no association between polymorphisms of other MMP genes and KD.SignificanceOverall, the results of this study indicate that MMP11 polymorphism may be associated with KD in the Korean population.     

Duffy antigen receptor genetic variant and the association with Interleukin 8 levels

The aim of this study is to identify loci associated with circulating levels of Interleukin 8 (IL8). We investigated the associations of 121,445 single nucleotide polymorphisms (SNPs) from the Illumina 200 K CardioMetabochip with IL8 levels in 1077 controls from the Stockholm Heart Epidemiology Program (SHEEP) study, using linear regression under an additive model of inheritance.Five SNPs (rs12075A/G, rs13179413C/T, rs6907989T/A, rs9352745A/C, rs1779553T/C) reached the pre-defined threshold of genome-wide significance (p < 1.0 × 10⁻⁵) and were tested for in silico replication in three independent populations, derived from the PIVUS, MDC-CC and SCARF studies. IL8 was measured in serum (SHEEP, PIVUS) and plasma (MDC-CC, SCARF). The strongest association was found with the SNP rs12075 A/G, Asp42Gly (p = 1.6 × 10⁻⁶), mapping to the Duffy antigen receptor for chemokines (DARC) gene on chromosome 1. The minor allele G was associated with 15.6% and 10.4% reduction in serum IL8 per copy of the allele in SHEEP and PIVUS studies respectively. No association was observed between rs12075 and plasma IL8.Conclusion: rs12075 was associated with serum levels but not with plasma levels of IL8. It is likely that serum IL8 represents the combination of levels of circulating plasma IL8 and additional chemokine liberated from the erythrocyte DARC reservoir due to clotting. These findings highlight the importance of understanding IL8 as a biomarker in cardiometabolic diseases.     

Interactions between IL17A, IL23R, and STAT4 polymorphisms confer susceptibility to intestinal Behcet's disease in Korean population

AimsAlthough polymorphisms in IL23R have recently been proposed to predispose to Behcet's disease (BD), associations between IL23R polymorphisms and intestinal BD have yet to be elucidated. We therefore performed a study to evaluate whether IL17A, IL23R, and STAT4 polymorphisms are associated with susceptibility to intestinal BD in the Korean population.Main methodsSingle nucleotide polymorphisms (SNP) in the IL17A, IL23R, and STAT4 genes were analyzed using DNA sequencing, denaturing high performance liquid chromatography, and TaqMan genotyping assays.Key findingsIndividual polymorphism analysis revealed that the TT genotype of IL17A rs8193036 (odds ratio (OR) 2.10, 95% confidence interval (CI) (1.12–3.92), p = 0.021), and GG + GT genotype of IL23R rs1884444 (OR 1.92, 95% CI (1.03–3.57), p = 0.034) was associated with the development of intestinal BD. When these two genotypes were combined, the risk of BD increased compared to that of patients with no-risk or one-risk genotype (OR 2.21, 95% CI (1.13–4.34), p = 0.021). Furthermore, statistically significant gene–gene interactions were observed between G149R in IL23R vs. rs11685878 in STAT4, rs2275913 in IL17A vs. rs7574865 in STAT4, and rs11889341 in STAT4 vs. rs2275913 in IL17A. The haplotypes of IL17A had a positive association with intestinal BD risks, whereas those of IL23R were protective for disease development.SignificanceOur results indicate that the interaction of specific IL17A, IL23R, and STAT4 SNPs modulate susceptibility to intestinal BD in the Korean population, suggesting that the IL-17/23 axis plays a significant role in disease pathogenesis.     

Association between interleukin 15 receptor, alpha (IL15RA) polymorphism and Korean patients with ossification of the posterior longitudinal ligament

ObjectivesRecently, a number of evidences have been reported concerning the genetic factor involved in the development of ossification of the posterior longitudinal ligament (OPLL). The purpose of this study was to investigate single nucleotide polymorphisms (SNPs) of the interleukin 15 receptor, alpha (IL15RA) gene as a risk factor in Korean patients with OPLL.DesignTo investigate the genetic association, two coding SNPs (rs2296139, Thr73Thr; rs2228059, Asn182Thr) in IL15RA were genotyped in 166 OPLL patients and 230 control subjects. SNPStats, SNPAnalyzer, and Helixtree programs were used for association analysis.ResultsIn the present study, we found the association between a missense SNP (rs2228059) and the risk of OPLL in codominant (p = 0.0028, OR = 1.58, 95% CI = 1.17–2.14), dominant (p = 0.0071, OR = 1.82, 95% CI = 1.17–2.82), and recessive models (p = 0.036, OR = 1.79, 95% CI = 1.04–3.09). The frequency of rs2228059 allele was significantly associated with the susceptibility of OPLL (p = 0.0043, OR = 1.52, 95% CI = 1.14–2.02). After Bonferroni correction, the missense SNP (rs2228059, Asn182Thr) still had significant correlations (p = 0.0056 in codominant model; p = 0.0142 in dominant model; p = 0.0086 in allele analysis). Haplotype variation in IL15RA was associated with OPLL (global haplotype test, p = 0.025).ConclusionsThese results suggest that IL15RA polymorphism may be associated with the susceptibility of OPLL in Korean population.