Genetic Association of Human Leukocyte Antigens with Chronicity or Resolution of Hepatitis B Infection in Thai Population

Background

Previous studies showed that single nucleotide polymorphisms (SNPs) in the HLA-DP, TCF19 and EHMT2 genes may affect the chronic hepatitis B (CHB). To predict the degree of risk for chronicity of HBV, this study determined associations with these SNPs.

Methods

The participants for this study were defined into 4 groups; HCC (n = 230), CHB (n = 219), resolved HBV infection (n = 113) and HBV uninfected subjects (n = 123). The HLA-DP SNPs (rs3077, rs9277378 and rs3128917), TCF19 SNP (rs1419881) and EHMT2 SNP (rs652888) were genotyped.

Results

Due to similar distribution of genotype frequencies in HCC and CHB, we combined these two groups (HBV carriers). The genotype distribution in HBV carriers relative to those who resolved HBV showed that rs3077 and rs9277378 were significantly associated with protective effects against CHB in minor dominant model (OR = 0.45, p<0.001 and OR = 0.47, p<0.001). The other SNPs rs3128917, rs1419881 and rs652888 were not associated with HBV carriers.

Conclusions

Genetic variations of rs3077 and rs9277378, but not rs3128917, rs1419881 and rs652888, were significantly associated with HBV carriers relative to resolved HBV in Thai population.     

Association of Genetic Variants with Primary Angle Closure Glaucoma in Two Different Populations

Purpose

A recent large genome-wide association study (GWAS) identified multiple variants associated with primary angle-closure glaucoma (PACG). The present study investigated the role of these variants in two cohorts with PACG recruited from Australia and Nepal.

Method

Patients with PACG and appropriate controls were recruited from eye clinics in Australia (n = 232 cases and n = 288 controls) and Nepal (n = 106 cases and 204 controls). Single nucleotide polymorphisms (SNPs) rs3753841 (COL11A1), rs1015213 (located between PCMTD1 and ST18), rs11024102 (PLEKHA7), and rs3788317 (TXNRD2) were selected and genotyped on the Sequenom. Analyses were conducted using PLINK and METAL.

Results

After adjustment for age and sex, SNP rs3753841 was found to be significantly associated with PACG in the Australian cohort (p = 0.017; OR = 1.34). SNPs rs1015213 (p = 0.014; OR 2.35) and rs11024102 (p = 0.039; OR 1.43) were significantly associated with the disease development in the Nepalese cohort. None of these SNPs survived Bonferroni correction (p = 0.05/4 = 0.013). However, in the combined analysis, of both cohorts, rs3753841 and rs1015213 showed significant association with p-values of 0.009 and 0.004, respectively both surviving Bonferroni correction. SNP rs11024102 showed suggestive association with PACG (p-value 0.035) and no association was found with rs3788317.

Conclusion

The present results support the initial GWAS findings, and confirm the SNP’s contribution to PACG. This is the first study to investigate these loci in both Australian Caucasian and Nepalese populations.     

A Genetic Variant in the Promoter Region of miR-106b-25 Cluster Predict Clinical Outcome of HBV-Related Hepatocellular Carcinoma in Chinese

Background

MiR-106b-25 cluster, hosted in intron 13 of MCM7, may play integral roles in diverse processes including immune response, tumorigenesis and progression. A single nucleotide polymorphism (SNP), rs999885, is located in the promoter region of MCM7. Our previous study showed that the A to G base change of rs999885 may provide an increased risk for HCC in HBV persistent carriers by altering the expression of the miR-106b-25 cluster. However, it is unknown whether rs999885 is associated with prognosis of intermediate or advanced HBV-related hepatocellular carcinoma (HCC) patients.

Methods

The SNP, rs999885, was genotyped by using the TaqMan allelic discrimination Assay in 414 intermediate or advanced HCC patients. Log-rank test and Cox proportional hazard models were used for survival analysis.

Results

The variant genotypes of rs999885 were associated with a significantly decreased risk of death for intermediate or advanced HCC [additive model: adjusted hazard ratio (HR)  = 0.76,95% confidence intervals (CI)  = 0.59–0.97]. Further stepwise regression analysis suggested that rs999885 was an independently protective factor for the prognosis of HCC in the final model (additive model: adjusted HR  = 0.72, 95% CI  = 0.56–0.91, P = 0.007).

Conclusions

These findings indicate that the A to G base change of rs999885 may provide a protective effect on the prognosis of intermediate or advanced HCC in Chinese.     

Associations between a Polymorphism in the Pleiotropic GCKR and Age-Related Phenotypes: The HALCyon Programme

Background

The glucokinase regulatory protein encoded by GCKR plays an important role in glucose metabolism and a single nucleotide polymorphism (SNP) rs1260326 (P446L) in the gene has been associated with several age-related biomarkers, including triglycerides, glucose, insulin and apolipoproteins. However, associations between SNPs in the gene and other ageing phenotypes such as cognitive and physical capability have not been reported.

Methods

As part of the Healthy Ageing across the Life Course (HALCyon) collaborative research programme, men and women from five UK cohorts aged between 44 and 90+ years were genotyped for rs1260326. Meta-analysis was used to pool within-study genotypic associations between the SNP and several age-related phenotypes, including body mass index (BMI), blood lipid levels, lung function, and cognitive and physical capability.

Results

We confirm the associations between the minor allele of the SNP and higher triglycerides and lower glucose levels. We also observed a triglyceride-independent association between the minor allele and lower BMI (pooled beta on z-score = −0.04, p-value = 0.0001, n = 16,251). Furthermore, there was some evidence for gene-environment interactions, including physical activity attenuating the effects on triglycerides. However, no associations were observed with measures of cognitive and physical capability.

Conclusion

Findings from middle-aged to older adults confirm associations between rs1260326 GCKR and triglycerides and glucose, suggest possible gene-environment interactions, but do not provide evidence that its relevance extends to cognitive and physical capability.     

Analysis of PPARGC1B,RUNX3 and TBKBP1 Polymorphisms in Chinese Han Patients with Ankylosing Spondylitis: A Case-Control Study

Background

Susceptibility to and severity of ankylosing spondylitis (AS) are largely genetically determined. PPARGC1B, RUNX3 and TBKBP1 have recently been found to be associated with AS in patients of western European descent. Our purpose is to examine the influence of PPARGC1B, RUNX3 and TBKBP1 polymorphisms on the susceptibility to and the severity of ankylosing spondylitis in Chinese ethnic majority Han population.

Methods

Blood samples are drawn from 396 AS patients and 404 unrelated healthy controls. All the patients and the controls are Han Chinese and the patients are HLA-B27 positive. The AS patients are classified based on the severity of the disease. Twelve tag single nucleotide polymorphisms (tagSNPs) in PPARGC1B, RUNX3 and TBKBP1 are selected and genotyped. Frequencies of different genotypes and alleles are analyzed among the different severity AS patients and the controls.

Results

After Bonferroni correction, the rs7379457 SNP in PPARGC1B shows significant difference when comparing all AS patients to controls (p = 0.005). This SNP also shows significant difference when comparing normal AS patients to controls (p = 0.002). The rs1395621 SNP in RUNX3 shows significant difference when comparing severe AS patients to controls (p = 0.007). The rs9438876 SNP in RUNX3 shows significant difference when comparing normal AS patients to controls (p = 0.007). The rs8070463 SNP in TBKBP1 shows significant difference in genotype distribution when comparing severe AS patients to controls (p = 0.003).

Conclusions

The rs7379457 SNP in PPARGC1B is related to susceptibility to AS in Chinese Han population. The rs7379457 SNP in PPARGC1B, the rs1395621 and rs9438876 SNPs in RUNX3, and the rs8070463 SNP in TBKBP1 are related to the severity of AS in Chinese Han population.     

Cranialization of the Frontal Sinus for Secondary Mucocele Prevention following Open Surgery for Benign Frontal Lesions

Objective

To compare frontal sinus cranialization to obliteration for future prevention of secondary mucocele formation following open surgery for benign lesions of the frontal sinus.

Study Design

Retrospective case series.

Setting

Tertiary academic medical center.

Patients

Sixty-nine patients operated for benign frontal sinus pathology between 1994 and 2011.

Interventions

Open excision of benign frontal sinus pathology followed by either frontal obliteration (n = 41, 59%) or frontal cranialization (n = 28, 41%).

Main Outcome Measures

The prevalence of post-surgical complications and secondary mucocele formation were compiled.

Results

Pathologies included osteoma (n = 34, 49%), mucocele (n = 27, 39%), fibrous dysplasia (n = 6, 9%), and encephalocele (n = 2, 3%). Complications included skin infections (n = 6), postoperative cutaneous fistula (n = 1), telecanthus (n = 4), diplopia (n = 3), nasal deformity (n = 2) and epiphora (n = 1). None of the patients suffered from postoperative CSF leak, meningitis or pneumocephalus. Six patients, all of whom had previously undergone frontal sinus obliteration, required revision surgery due to secondary mucocele formation. Statistical analysis using non-inferiority test reveal that cranialization of the frontal sinus is non-inferior to obliteration for preventing secondary mucocele formation (P<0.0001).

Conclusion

Cranialization of the frontal sinus appears to be a good option for prevention of secondary mucocele development after open excision of benign frontal sinus lesions.     

Common Genetic Variants of Surfactant Protein-D (SP-D) Are Associated with Type 2 Diabetes

Context

Surfactant protein-D (SP-D) is a primordial component of the innate immune system intrinsically linked to metabolic pathways. We aimed to study the association of single nucleotide polymorphisms (SNPs) affecting SP-D with insulin resistance and type 2 diabetes (T2D).

Research Design and Methods

We evaluated a common genetic variant located in the SP-D coding region (rs721917, Met³¹Thr) in a sample of T2D patients and non-diabetic controls (n = 2,711). In a subset of subjects (n = 1,062), this SNP was analyzed in association with circulating SP-D concentrations, insulin resistance, and T2D. This SNP and others were also screened in the publicly available Genome Wide Association (GWA) database of the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC).

Results

We found the significant association of rs721917 with circulating SP-D, parameters of insulin resistance and T2D. Indeed, G carriers showed decreased circulating SP-D (p = 0.004), decreased fasting glucose (p = 0.0002), glycated hemoglobin (p = 0.0005), and 33% (p = 0.002) lower prevalence of T2D, estimated under a dominant model, especially among women. Interestingly, these differences remained significant after controlling for origin, age, gender, and circulating SP-D. Moreover, this SNP and others within the SP-D genomic region (i.e. rs10887344) were significantly associated with quantitative measures of glucose homeostasis, insulin sensitivity, and T2D, according to GWAS datasets from MAGIC.

Conclusions

SP-D gene polymorphisms are associated with insulin resistance and T2D. These associations are independent of circulating SP-D concentrations.     

Polymorphism rs11085226 in the Gene Encoding Polypyrimidine Tract-Binding Protein 1 Negatively Affects Glucose-Stimulated Insulin Secretion

Objective

Polypyrimidine tract-binding protein 1 (PTBP1) promotes stability and translation of mRNAs coding for insulin secretion granule proteins and thereby plays a role in β-cells function. We studied whether common genetic variations within the PTBP1 locus influence insulin secretion, and/or proinsulin conversion.

Methods

We genotyped 1,502 healthy German subjects for four tagging single nucleotide polymorphisms (SNPs) within the PTBP1 locus (rs351974, rs11085226, rs736926, and rs123698) covering 100% of genetic variation with an r²≥0.8. The subjects were metabolically characterized by an oral glucose tolerance test with insulin, proinsulin, and C-peptide measurements. A subgroup of 320 subjects also underwent an IVGTT.

Results

PTBP1 SNP rs11085226 was nominally associated with lower insulinogenic index and lower cleared insulin response in the OGTT (p≤0.04). The other tested SNPs did not show any association with the analyzed OGTT-derived secretion parameters. In the IVGTT subgroup, SNP rs11085226 was accordingly associated with lower insulin levels within the first ten minutes following glucose injection (p = 0.0103). Furthermore, SNP rs351974 was associated with insulin levels in the IVGTT (p = 0.0108). Upon interrogation of MAGIC HOMA-B data, our rs11085226 result was replicated (MAGIC p = 0.018), but the rs351974 was not.

Conclusions

We conclude that common genetic variation in PTBP1 influences glucose-stimulated insulin secretion. This underlines the importance of PTBP1 for beta cell function in vivo.     

Evidence for STAT4 as a Common Autoimmune Gene: rs7574865 Is Associated with Colonic Crohn's Disease and Early Disease Onset

Background

Recent studies demonstrated an association of STAT4 variants with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), indicating that multiple autoimmune diseases share common susceptibility genes. We therefore investigated the influence of STAT4 variants on the susceptibility and phenotype of inflammatory bowel diseases (IBD) in a large patient and control cohort.

Methodology/Principal Findings

Genomic DNA from 2704 individuals of Caucasian origin including 857 patients with Crohn''s disease (CD), 464 patients with ulcerative colitis (UC), and 1383 healthy, unrelated controls was analyzed for seven SNPs in the STAT4 gene (rs11889341, rs7574865, rs7568275, rs8179673, rs10181656, rs7582694, rs10174238). In addition, a detailed genotype-phenotype analysis was performed. Our analysis revealed an association of the STAT4 SNP rs7574865 with overall decreased susceptibility to CD (p = 0.047, OR 0.86 [95% CI 0.74–0.99]). However, compared to CD patients carrying the wild type genotype, the STAT4 SNP rs7574865 was significantly associated with early CD onset (p = 0.021) and colonic CD (p = 0.008; OR = 4.60, 95% CI 1.63–12.96). For two other STAT4 variants, there was a trend towards protection against CD susceptibility (rs7568275, p = 0.058, OR 0.86 [95% CI 0.74–1.00]; rs10174238, p = 0.057, OR 0.86 [95% CI 0.75–1.00]). In contrast, we did not observe any association with UC susceptibility. Evidence for weak gene-gene interaction of STAT4 with the IL23R SNP rs11209026 was lost after Bonferroni correction.

Conclusions/Significance

Our results identified the STAT4 SNP rs7574865 as a disease-modifying gene variant in colonic CD. However, in contrast to SLE and RA, the effect of rs7574865 on CD susceptibility is only weak.     

The Common Variant rs11646213 Is Associated with Preeclampsia in Han Chinese Women

Background

Preeclampsia, characterized by hypertension and proteinuria, is a multifactorial disease caused by complex interactions between environmental and genetic factors. A recent genome-wide association study of blood pressure reported an association between hypertension and rs11646213. This study evaluated the association between preeclampsia and rs11646213.

Methods

A total of 454 cases and 460 controls were recruited to participate in this study. The single nucleotide polymorphism (SNP) rs11646213 was genotyped by polymerase chain reaction (PCR) and direct sequencing.

Results

The allele frequency of rs11646213 was significantly different between the preeclampsia and control groups (P = 0.017, OR = 1.36, 95% CI = 1.06–1.76). Differences were particularly significant in the severe preeclampsia subgroup (P = 0.002, OR = 1.54, 95% CI = 1.17–2.03) and the early-onset preeclampsia subgroup (P = 0.004, OR = 1.57, 95% CI = 1.16–2.13). Genotyping analysis showed that the T allele of rs11646213 could confer a risk for preeclampsia, severe preeclampsia and early-onset preeclampsia.

Conclusions

Rs11646213 upstream of the CDH13 gene is associated with preeclampsia in Han Chinese women.     

Polymorphism of 9p21.3 Locus Is Associated with 5-Year Survival in High-Risk Patients with Myocardial Infarction

Objective

The rs10757278, rs1333049 and rs4977574 are single nucleotide polymorphisms (SNPs) of chromosome 9p21 locus associated with a prevalence of acute coronary syndromes (ACS). Reports concerning their association with long-term outcome after an ACS are equivocal. The aim of our study was to investigate the association of the 9p21.3 locus with 5-year overall mortality in patients with ST-elevation myocardial infarction (STEMI).

Materials and methods

We performed a retrospective analysis of data collected prospectively in 2 independent registries of consecutive patients with STEMI (derivation and validation group). Genotyping was performed with the TaqMan method. The analyzed end-point was total mortality.

Results

The derivation group comprised 589 patients: 25.3% female (n = 149), mean age 62.4±12.0 years, total 5-year mortality 16.6% (n = 98). When all the study group was analyzed, no significant differences in mortality were found between the genotypes. However, in high-risk patients (GRACE risk score ≥155 points, n = 238), homozygotes associated with higher risk for ACS had significantly better 5-year survival compared to other genotypes. The hazard ratio associated with the high-risk genotype (a homozygote of high risk for ACS or a heterozygote) was: HR = 2.2 (1.15–4.2) for the rs10757278 polymorphism, HR = 2.7 (95% CI 1.3–5.4) for the rs4977574 one and HR = 2.3 (1.2–4.5) for the rs1333049 one (Cox proportional hazards model). Survival analysis in the validation group (n = 365) showed a clear trend towards better prognosis in GG homozygotes of the rs10757278 SNP, which confirms our initial results (p = 0.09, log-rank test).

Conclusions

The 9p21.3 locus is associated with 5-year mortality in high-risk patients with STEMI. The genotypes associated with higher risk for ACS show a protective effect in terms of further survival (instead of a deteriorating prognosis, as reported previously). This finding, due to the very high size of the effect, could potentially be applied to clinical practice, if appropriate methods are elaborated.     

TRAF5 and TRAF3IP2 Gene Polymorphisms Are Associated with Beh?et's Disease and Vogt-Koyanagi-Harada Syndrome: A Case-Control Study

Background

TRAF5 and TRAF3IP2 have been reported to be associated with several autoimmune diseases. Behçet''s disease (BD) and Vogt-Koyanagi-Harada (VKH) syndrome are two autoimmune uveitis entities whereby both genetic and environmental factors are thought to be involved.

Objective

The role of TRAF5 and TRAF3IP2 in BD and VKH has not yet been reported and was therefore the subject of this study.

Methods

The study included 789 BD patients, 940 VKH patients and 1601 healthy unrelated individuals. Genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) or TaqMan® SNP Genotyping Assay. Real-Time PCR was used to detect mRNA expression from PBMCs obtained from healthy controls with (n = 22) or without (n = 79) stimulation. Levels of TNF-α, IL-6 and IL-8 in culture supernatants were measured by ELISA (n = 22).

Results

Three SNPs (rs6540679, rs12569232, rs10863888) of TRAF5 and rs13210247 of TRAF3IP2 were significantly associated with Behçet''s disease and VKH syndrome (corrected P values ranging from 9.45×10⁻¹² to 0.027). TRAF3IP2 rs33980500 and rs13190932 were not polymorphic in Han Chinese. Following stimulation by lipopolysaccharide (LPS), carriers of the GG genotype of rs6540679/TRAF5 had a higher TRAF5 mRNA expression (p = 0.004) and an increased TNF-α (p = 0.0052) and IL-6 (p = 0.0014) level compared with AA and AG genotype carriers.

Conclusion

This study provides evidence that TRAF5 and TRAF3IP2 genes are involved in the development of BD and VKH syndrome. Functional research suggested that TRAF5 gene polymorphisms may regulate TRAF5 expression and downstream inflammatory cytokines such as TNF-α and IL-6.     

Polymorphism Located between CPT1B and CHKB,and HLA-DRB1*1501-DQB1*0602 Haplotype Confer Susceptibility to CNS Hypersomnias (Essential Hypersomnia)

Background

SNP rs5770917 located between CPT1B and CHKB, and HLA-DRB1*1501-DQB1*0602 haplotype were previously identified as susceptibility loci for narcolepsy with cataplexy. This study was conducted in order to investigate whether these genetic markers are associated with Japanese CNS hypersomnias (essential hypersomnia: EHS) other than narcolepsy with cataplexy.

Principal Findings

EHS was significantly associated with SNP rs5770917 (P_allele = 3.6×10⁻³; OR = 1.56; 95% c.i.: 1.12–2.15) and HLA-DRB1*1501-DQB1*0602 haplotype (P _positivity = 9.2×10⁻¹¹; OR = 3.97; 95% c.i.: 2.55–6.19). No interaction between the two markers (SNP rs5770917 and HLA-DRB1*1501-DQB1*0602 haplotype) was observed in EHS.

Conclusion

CPT1B, CHKB and HLA are candidates for susceptibility to CNS hypersomnias (EHS), as well as narcolepsy with cataplexy.     

A Functional TNFAIP2 3'-UTR rs8126 Genetic Polymorphism Contributes to Risk of Esophageal Squamous Cell Carcinoma

Background

Accumulated evidences demonstrated that single nucleotide polymorphisms (SNPs) in mRNA 3''-untranslated region (3''-UTR) may impact microRNAs (miRNAs)-mediated expression regulation of oncogenes and tumor suppressors. There is a TNFAIP2 3''-UTR rs8126 T>C genetic variant which has been proved to be associated with head and neck cancer susceptibility. This SNP could disturb binding of miR-184 with TNFAIP2 mRNA and influence TNFAIP2 regulation. However, it is still unclear how this polymorphism is involved in development of esophageal squamous cell carcinoma (ESCC). Therefore, we hypothesized that the functional TNFAIP2 rs8126 SNP may affect TNFAIP2 expression and, thus, ESCC risk.

Methods

We investigated the association between the TNFAIP2 rs8126 variant and ESCC risk as well as the functional relevance on TNFAIP2 expression in vivo. Genotypes were determined in a case-control set consisted of 588 ESCC patients and 600 controls. The allele-specific regulation on TNFAIP2 expression by the rs8126 SNP was examined in normal and cancerous tissue specimens of esophagus.

Results

We found that individuals carrying the rs8126 CC or CT genotype had an OR of 1.89 (95%CI  = 1.23–2.85, P = 0.003) or 1.38 (95%CI  = 1.05–1.73, P = 0.017) for developing ESCC in Chinese compared with individual carrying the TT genotype. Carriers of the rs8126 CC and CT genotypes had significantly lower TNFAIP2 mRNA levels than those with the TT genotypes in normal esophagus tissues (P<0.05).

Conclusions

Our data demonstrate that functional TNFAIP2 rs8126 genetic variant is a ESCC susceptibility SNP. These results support the hypothesis that genetic variants interrupting miRNA-mediated gene regulation might be important genetic modifiers of cancer risk.     

Polymorphisms in ABC Transporter Genes and Concentrations of Mercury in Newborns – Evidence from Two Mediterranean Birth Cohorts

Background

The genetic background may influence methylmercury (MeHg) metabolism and neurotoxicity. ATP binding cassette (ABC) transporters actively transport various xenobiotics across biological membranes.

Objective

To investigate the role of ABC polymorphisms as modifiers of prenatal exposure to MeHg.

Methods

The study population consisted of participants (n = 1651) in two birth cohorts, one in Italy and Greece (PHIME) and the other in Spain (INMA). Women were recruited during pregnancy in Italy and Spain, and during the perinatal period in Greece. Total mercury concentrations were measured in cord blood samples by atomic absorption spectrometry. Maternal fish intake during pregnancy was determined from questionnaires. Polymorphisms (n = 5) in the ABC genes ABCA1, ABCB1, ABCC1 and ABCC2 were analysed in both cohorts.

Results

ABCB1 rs2032582, ABCC1 rs11075290, and ABCC2 rs2273697 modified the associations between maternal fish intake and cord blood mercury concentrations. The overall interaction coefficient between rs2032582 and log2-transformed fish intake was negative for carriers of GT (β = −0.29, 95%CI −0.47, −0.12) and TT (β = −0.49, 95%CI −0.71, −0.26) versus GG, meaning that for a doubling in fish intake of the mothers, children with the rs2032582 GG genotype accumulated 35% more mercury than children with TT. For rs11075290, the interaction coefficient was negative for carriers of TC (β = −0.12, 95%CI −0.33, 0.09), and TT (β = −0.28, 95%CI −0.51, −0.06) versus CC. For rs2273697, the interaction coefficient was positive when combining GA+AA (β = 0.16, 95%CI 0.01, 0.32) versus GG.

Conclusion

The ABC transporters appear to play a role in accumulation of MeHg during early development.     

A Non-Synonymous Coding Variant (L616F) in the TLR5 Gene Is Potentially Associated with Crohn's Disease and Influences Responses to Bacterial Flagellin

Background and Objectives

Although numerous studies have implicated TLR5, or its ligands, bacterial flagellins, in the pathogenesis of Crohn''s disease (CD), genome-wide association studies (GWAS) have not reported associations with the TLR5 gene. We aimed to examine potential CD-associated TLR5 variants and assess whether they modified inflammatory responses to bacterial flagellins.

Methods and Principal Results

A two-stage study was carried out. In stage 1, we genotyped tagging single-nucleotide polymorphisms (tag-SNPs) in the TLR5 gene in a sample of CD cases (<20 years of age, N = 566) and controls (N = 536). Single SNP and haplotype analysis was carried out. In Stage 2, we assessed the functional significance of potential CD-associated variant(s) vis-à-vis effects on the inflammatory response to bacterial flagellin using HEK293T cells. We observed marginal association between a non-synonymous coding SNP rs5744174 (p = 0.05) and CD. Associations between SNP rs851139 that is in high linkage disequilibrium (LD) with SNP rs5744174 were also suggested (p = 0.07). Haplotype analysis revealed that a 3 marker haplotype was significantly associated with CD (p = 0.01). Functional studies showed that the risk allele (616F) (corresponding to the C allele of SNP rs5744174) conferred significantly greater production of CCL20 in response to a range of flagellin doses than the comparator allele (616L).

Conclusions

Our findings suggest that a non-synonymous coding variation in the TLR5 gene may confer modest susceptibility for CD.     

IL28B Polymorphism Correlates with Active Hepatitis in Patients with HBeAg-Negative Chronic Hepatitis B

Background & Aims

The clinical relevance of single nucleotide polymorphisms (SNPs) near the IL28B gene is controversial in patients with hepatitis B virus (HBV) infection. This study aimed to investigate the role of viral and host factors, including IL28B genotypes, in the natural course of chronic hepatitis B (CHB).

Methods

The study enrolled consecutive 115 treatment-naive CHB patients. HBV viral loads, genotypes, precore and basal core promotor mutations, serum hepatitis B surface antigen (HBsAg) and interferon-gamma inducible protein 10 (IP-10) levels as well as four SNPs of IL28B were determined. Serial alanine transaminase (ALT) levels in the previous one year before enrollment at an interval of three months were recorded. Factors associated with active hepatitis, defined as persistent ALT >2× upper limit of normal (ULN) or a peak ALT level >5× ULN, were evaluated.

Results

The prevalence of rs8105790 TT, rs12979860 CC, rs8099917 TT, and rs10853728 CC genotypes were 88.3%, 87.4%, 88.4% and 70.9%, respectively. In HBeAg-positive patients (n = 48), HBV viral load correlated with active hepatitis, while in HBeAg-negative patients (n = 67), rs10853728 CC genotype (p = 0.032) and a trend of higher IP-10 levels (p = 0.092) were associated with active hepatitis. In multivariate analysis, high viral load (HBV DNA >10⁸ IU/mL, p = 0.042, odds ratio = 3.946) was significantly associated with HBeAg-positive hepatitis, whereas rs10853728 CC genotype (p = 0.019, odds ratio = 3.927) was the only independent factor associated with active hepatitis in HBeAg-negative population.

Conclusions

HBV viral load and IL28B rs10853728 CC genotype correlated with hepatitis activity in HBeAg-positive and HBeAg-negative CHB, respectively. Both viral and host factors play roles in disease activity during different phases of CHB.     

Sequence Analysis of Six Blood Pressure Candidate Regions in 4,178 Individuals: The Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Targeted Sequencing Study

Background

Genome-wide association studies (GWAS) identified multiple loci for blood pressure (BP) and hypertension. Six genes – ATP2B1, CACNB2, CYP17A1, JAG1, PLEKHA7, and SH2B3 – were evaluated for sequence variation with large effects on systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse pressure (PP), and mean arterial pressure (MAP).

Methods and Results

Targeted genomic sequence was determined in 4,178 European ancestry participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Common variants (≥50 minor allele copies) were evaluated individually and rare variants (minor allele frequency, MAF≤1%) were aggregated by locus. 464 common variants were identified across the 6 genes. An upstream CYP17A1 variant, rs11191416 (MAF = 0.09), was the most significant association for SBP (P = 0.0005); however the association was attenuated (P = 0.0469) after conditioning on the GWAS index single nucleotide polymorphism (SNP). A PLEKHA7 intronic variant was the strongest DBP association (rs12806040, MAF = 0.007, P = 0.0006) and was not in LD (r² = 0.01) with the GWAS SNP. A CACNB2 intronic SNP, rs1571787, was the most significant association with PP (MAF = 0.27, P = 0.0003), but was not independent from the GWAS SNP (r² = 0.34). Three variants (rs6163 and rs743572 in the CYP17A1 region and rs112467382 in PLEKHA7) were associated with BP traits (P<0.001). Rare variation, aggregately assessed in the 6 regions, was not significantly associated with BP measures.

Conclusion

Six targeted gene regions, previously identified by GWAS, did not harbor novel variation with large effects on BP in this sample.     

Plasma Level of Adrenomedullin Is Influenced by a Single Nucleotide Polymorphism in the Adiponectin Gene

Objective

Adrenomedullin (ADM) and adiponectin are both involved in inflammation and cardiovascular diseases. The plasma levels of these peptides are influenced by single nucleotide polymorphisms (SNPs) in the ADM and ADIPOQ genes respectively. There is some evidence that ADM may regulate adiponectin gene expression, but whether adiponectin can regulate ADM expression is unclear, and was therefore investigated.

Methods

Plasma ADM level was measured in 476 subjects in the Hong Kong Cardiovascular Risk Factor Prevalence Study-2 (CRISPS2). We genotyped them for 2 ADIPOQ SNPs that are known to be associated with plasma adiponectin level.

Results

The minor allele frequencies of ADIPOQ SNPs rs182052 and rs12495941 were 40.6% and 42.2% respectively. Plasma ADM level was significantly associated with rs182052 after adjusting for age and sex (β = 0.104, P = 0.023) but not with rs12495941 (β = 0.071, P = 0.120). In multivariate analysis, plasma ADM level increased with the number of minor alleles of rs182052 (P = 0.013). Compared to subjects with GG genotype, subjects with AA genotype had 17.7% higher plasma ADM level (95% CI: 3.6%–33.7%). Subgroup analysis revealed that the association was significant in diabetic patients (β = 0.344, P = 0.001) but not in non-diabetic subjects.

Conclusion

Plasma ADM level is related to SNP rs182052 in the ADIPOQ gene. Our findings provide new evidence of the interplay between these two important peptides in cardiovascular disease and diabetes. Knowing the genotype may help to refine the interpretation of these biomarkers.