The NOD2 p.Leu1007fsX1008 Mutation (rs2066847) Is a Stronger Predictor of the Clinical Course of Crohn's Disease than the FOXO3A Intron Variant rs12212067

Background

Very recently, a sub-analysis of genome-wide association scans revealed that the non-coding single nucleotide polymorphism (SNP) rs12212067 in the FOXO3A gene is associated with a milder course of Crohn''s disease (CD) (Cell 2013;155:57–69). The aim of our study was to evaluate the clinical value of the SNP rs12212067 in predicting the severity of CD by correlating CD patient genotype status with the most relevant complications of CD such as stenoses, fistulas, and CD-related surgery.

Methodology/Principal Findings

We genotyped 550 CD patients for rs12212067 (FOXO3A) and the three common CD-associated NOD2 mutations rs2066844, rs2066847, and rs2066847 and performed genotype-phenotype analyses.

Results

No significant phenotypic differences were found between the wild-type genotype TT of the FOXO3A SNP rs12212067 and the minor genotypes TG and GG independently from NOD2 variants. The allele frequency of the minor G allele was 12.7%. Age at diagnosis, disease duration, body mass index, surgery rate, stenoses, fistula, need for immunosuppressive therapy, and disease course were not significantly different. In contrast, the NOD2 mutant p.Leu1007fsX1008 (rs2066847) was highly associated with penetrating CD (p = 0.01), the development of fistulas (p = 0.01) and stenoses (p = 0.01), and ileal disease localization (p = 0.03). Importantly, the NOD2 SNP rs2066847 was a strong separator between an aggressive and a mild course of CD (p = 2.99×10⁻⁵), while the FOXO3A SNP rs12212067 did not separate between mild and aggressive CD behavior in our cohort (p = 0.35). 96.2% of the homozygous NOD2 p.Leu1007fsX1008 carriers had an aggressive disease behavior compared to 69.3% of the patients with the NOD2 wild-type genotype (p = 0.007).

Conclusion/Significance

In clinical practice, the NOD2 variant p.Leu1007fsX1008 (rs2066847), in particular in homozygous form, is a much stronger marker for a severe clinical phenotype than the FOXO3A rs12212067 SNP for a mild disease course on an individual patient level despite its important impact on the inflammatory response of monocytes.     

Role of HLA-DP Polymorphisms on Chronicity and Disease Activity of Hepatitis B Infection in Southern Chinese

Background and Aims

The association between HLA-DP single nucleotide polymorphisms (SNPs) and chronic hepatitis B virus (HBV) infection varies between different populations. We aimed to study the association between HLA-DP SNPs and HBV infection and disease activity in the Chinese population of Hong Kong.

Methods

We genotyped SNPs rs3077 (near HLA-DPA1) and rs9277378 and rs3128917 (both near HLA-DPB1) in 500 HBV carriers (hepatitis B surface antigen [HBsAg]-positive), 245 non-HBV infected controls (HBsAg- and antibody to hepatitis B core protein [anti-HBc]-negative), and 259 subjects with natural HBV clearance (HBsAg-negative, anti-HBc-positive). Inactive HBV carriers state was defined by HBV DNA levels <2,000 IU/ml and persistently normal alanine aminotransferase level for least 12 months.

Results

Compared to the non-HBV infected subjects, the HBV carriers had a significantly lower frequency of the rs3077 T allele (p = 0.0040), rs9277378 A allele (p = 0.0068) and a trend for lower frequency of rs3128917 T allele (p = 0.054). These alleles were associated with an increased chance of HBV clearance (rs3077: OR = 1.41, p = 0.0083; rs9277378: OR = 1.61, p = 0.00011; rs3128917: OR = 1.54, p = 0.00017). Significant associations between HLA-DP genotypes and HBV clearance were also found under different genetic models. Haplotype TAT was associated with an increased chance of HBV clearance (OR = 1.64, p = 0.0013). No association was found between these SNPs and HBV disease activity.

Conclusion

HLA-DP SNPs rs3077, rs9277378 and rs3128917 were associated with chronicity of HBV disease in the Chinese. Further studies are required to determine whether these SNPs influence the disease endemicity in different ethnic populations.     

Genetic Variation in the Interleukin-28B Gene Is Associated with Spontaneous Clearance and Progression of Hepatitis C Virus in Moroccan Patients

Background

Genetic variation in the IL28B gene has been strongly associated with treatment outcomes, spontaneous clearance and progression of the hepatitis C virus infection (HCV). The aim of the present study was to investigate the role of polymorphisms at this locus with progression and outcome of HCV infection in a Moroccan population.

Methods

We analyzed a cohort of 438 individuals among them 232 patients with persistent HCV infection, of whom 115 patients had mild chronic hepatitis and 117 had advanced liver disease (cirrhosis and hepatocellular carcinoma), 68 individuals who had naturally cleared HCV and 138 healthy subjects. The IL28B SNPs rs12979860 and rs8099917 were genotyped using a TaqMan 5′ allelic discrimination assay.

Results

The protective rs12979860-C and rs8099917-T alleles were more common in subjects with spontaneous clearance (77.9% vs 55.2%; p = 0.00001 and 95.6% vs 83.2%; p = 0.0025, respectively). Individuals with clearance were 4.69 (95% CI, 1.99–11.07) times more likely to have the C/C genotype for rs12979860 polymorphism (p = 0.0017) and 3.55 (95% CI, 0.19–66.89) times more likely to have the T/T genotype at rs8099917. Patients with advanced liver disease carried the rs12979860-T/T genotype more frequently than patients with mild chronic hepatitis C (OR = 1.89; 95% CI, 0.99–3.61; p = 0.0532) and this risk was even more pronounced when we compared them with healthy controls (OR = 4.27; 95% CI, 2.08–8.76; p = 0.0005). The rs8099917-G allele was also associated with advanced liver disease (OR = 2.34; 95% CI, 1.40–3.93; p = 0.0100).

Conclusions

In the Moroccan population, polymorphisms near the IL28B gene play a role both in spontaneous clearance and progression of HCV infection.     

DNA Methyltransferase Candidate Polymorphisms,Imprinting Methylation,and Birth Outcome

Background

Birth weight and prematurity are important obstetric outcomes linked to lifelong health. We studied a large birth cohort to look for evidence of epigenetic involvement in birth outcomes.

Methods

We investigated the association between birth weight, length, placental weight and duration of gestation and four candidate variants in 1,236 mothers and 1,073 newborns; DNMT1 (rs2162560), DNMT3A (rs734693), DNMT3B (rs2424913) and DNMT3L (rs7354779). We measured methylation of LINE1 and the imprinted genes, PEG3, SNRPN, and IGF2, in cord blood.

Results

The minor DNMT3L allele in the baby was associated with higher birth weight (+54 95% CI 10,99 g; p = 0.016), birth length (+0.23 95% CI 0.04,0.42 cm; p = 0.017), placental weight, (+18 95% CI 3,33 g; p = 0.017), and reduced risk of being in the lowest birth weight decile (p = 0.018) or requiring neonatal care (p = 0.039). The DNMT3B minor allele in the mother was associated with an increased risk of prematurity (p = 0.001). Placental size was related to PEG3 (p<0.001) and IGF2 (p<0.001) methylation. Birth weight was related to LINE1 and IGF2 methylation but only at p = 0.052. The risk of requiring neonatal treatment was related to LINE1 (p = 0.010) and SNRPN (p = 0.001) methylation. PEG3 methylation was influenced by baby DNMT3A genotype (p = 0.012) and LINE1 by baby 3B genotype (p = 0.044). Maternal DNMT3L genotype was related to IGF2 methylation in the cord blood but this effect was only seen in carriers of the minor frequency allele (p = 0.050).

Conclusions

The results here suggest that epigenetic processes are linked birth outcome and health in early life. Our emerging understanding of the role of epigenetics in health and biological function across the lifecourse suggests that these early epigenetic events could have longer term implications.     

Association of a Rare Haplotype in Kinesin Light Chain 1 Gene with Age-Related Cataract in a Han Chinese Population

Purpose

The causal genes for congenital cataract are good candidates for the genetic susceptibility for age-related cataract (ARC). The aim of this study was to investigate association between the polymorphisms in the causal genes for congenital cataract and ARC in a Chinese population. Meanwhile, we performed the replication study for previous identified risk genes for ARC.

Methods

We recruited 212 sporadic Han Chinese patients with age-related cataracts (ARC) and 172 normal controls in this study. We analyzed 31 SNPs from 13 genes which mostly possible contributes the progress of ARC in a Chinese population, comprising 212 cataract patients and 172 controls. Polymorphism-spanning fragments were amplified by using the multiplex polymerase chain reaction (PCR) and genotyped using primer extension method in MassARRAY platform. Allelic and haplotypic difference in the frequencies were estimated using the SHEsis software platform. P-value was adjusted by the Bonferroni correction.

Results

There was no difference in the frequencies of the genotype and allele of the all SNPs between the patients with ARC and the controls. In the haplotypic analysis, the haplotypes consisting of rs7154572, rs7150141 and rs12432994 in Kinesin Light Chain 1 Gene (KLC1) showed significant association with ARC (p = 0.000878). A rare haplotype CGT was more frequent in patients (p = 0.000106, and p = 0.00795 after corrected for 75 tests).

Conclusions

Our study provides evidence that the combined effect of three variants within the KLC1 gene may predispose to ARC, but the precise mechanism needs further investigating.     

IFNL4 ss469415590 Variant Shows Similar Performance to rs12979860 as Predictor of Response to Treatment against Hepatitis C Virus Genotype 1 or 4 in Caucasians

Objectives

The rs12979860 variant, linked to IL28B gene, predicts sustained viral response (SVR) to pegylated-interferon/ribavirin (pegIFN/RBV) therapy in Hepatitis C Virus genotype 1 or 4 (HCV-1/4)-infected patients. Recently, a functional variant, ss469415590, in linkage disequilibrium (LD) with rs12979860, has been discovered. Our objective was to assess the value of ss469415590 to predict SVR to pegIFN/RBV in Caucasian HCV-1/4-infected individuals and to compare its performance with that of rs12979860.

Methods

272 Caucasian HCV-1/4-infected patients who completed a course of pegIFN/RBV were genotyped for both rs12979860 and ss469415590 markers. Logistic regression models including factors with univariate association with SVR and each genetic marker were elaborated. The area under the receiver operating-characteristic curve (AUROC) was calculated for each model and both were compared.

Results

Both markers were in LD (r² = 0.82). For rs12979860, 66 (64.0%) CC versus 56 (33.1%) T allele carriers achieved SVR (Adjusted OR = 4.156, 95%CI = 2.388–7.232, p = 4.647×10⁻⁷). For ss469415590, 66 (66.0%) TT/TT versus 56 (32.5%) –G allele carriers (Adjusted OR = 4.783, 95%CI = 2.714–8.428, p = 6.153×10⁻⁸) achieved SVR. The AUROC of the model including rs12979860 was 0.742 (95%CI = 0.672–0.813) and of that based on ss469415590 was 0.756 (95%CI = 0.687–0.826) (p = 0.780).

Conclusions

The ss469415590 variant shows an equivalent performance to predict SVR to pegIFN/RBV than the rs2979860 in Caucasian HCV-1/4-infected patients.     

Influence of the C242T Polymorphism of the p22-phox Gene (CYBA) on the Interaction between Urinary Sodium Excretion and Blood Pressure in an Urban Brazilian Population

Background

Reactive oxygen species are implicated in the physiopathogenesis of salt-induced hypertension and the C242T polymorphism of the p22-phox gene has been associated with higher superoxide production. This study investigated the impact of this polymorphism on the relationship between urinary sodium excretion (USE) and blood pressure levels in an urban Brazilian population.

Methods

We cross-sectionally evaluated 1,298 subjects from the city of Vitoria-ES, located in the Southeast region of Brazil, by clinical history, physical examination, anthropometry, analysis of laboratory parameters, USE measurement and p22-phox C242T polymorphism genotyping.

Results

No significant differences in studied parameters were detected between the studied genotype groups (CC vs. CT+TT). Systolic blood pressure exhibited significant correlation with USE only in T allele carriers (r = 0.166; p<0.001), while diastolic blood pressure and hypertension status correlated with USE in both genotypes albeit more weakly in subjects with CC genotype (r = 0.098; p = 0.021 and r = 0.105; p = 0.013, respectively) than in T carriers (r = 0.236; p<0.001 and r = 0.213; p<0.001, respectively). Regression analyses adjusted for confounding factors showed that USE remained independently associated with systolic (p<0.001) and diastolic blood pressure (p<0.001) and hypertension status (p = 0.004) only in T allele carriers. Finally, higher diastolic and systolic blood pressure levels were detected in T allele carriers than in CC genotype individuals in the highest tertile of USE.

Conclusions

The p22-phox 242T allele is associated with higher blood pressure levels among subjects with higher USE in an urban Brazilian population.     

The Cannabinoid 1 Receptor (CNR1) 1359 G/A Polymorphism Modulates Susceptibility to Ulcerative Colitis and the Phenotype in Crohn's Disease

Background

Recent evidence suggests a crucial role of the endocannabinoid system, including the cannabinoid 1 receptor (CNR1), in intestinal inflammation. We therefore investigated the influence of the CNR1 1359 G/A (p.Thr453Thr; rs1049353) single nucleotide polymorphism (SNP) on disease susceptibility and phenotype in patients with ulcerative colitis (UC) and Crohn''s disease (CD).

Methods

Genomic DNA from 579 phenotypically well-characterized individuals was analyzed for the CNR1 1359 G/A SNP. Amongst these were 166 patients with UC, 216 patients with CD, and 197 healthy controls.

Results

Compared to healthy controls, subjects A/A homozygous for the CNR1 1359 G/A SNP had a reduced risk to develop UC (p = 0.01, OR 0.30, 95% CI 0.12–0.78). The polymorphism did not modulate CD susceptibility, but carriers of the minor A allele had a lower body mass index than G/G wildtype carriers (p = 0.0005). In addition, homozygous carriers of the G allele were more likely to develop CD before 40 years of age (p = 5.9×10⁻⁷) than carriers of the A allele.

Conclusion

The CNR1 p.Thr453Thr polymorphism appears to modulate UC susceptibility and the CD phenotype. The endocannabinoid system may influence the manifestation of inflammatory bowel diseases, suggesting endocannabinoids as potential target for future therapies.     

Maternal and Fetal Genetic Associations of PTGER3 and PON1 with Preterm Birth

Objective

The purpose of this study was to identify associations between maternal and fetal genetic variants in candidate genes and spontaneous preterm birth (PTB) in a Norwegian population and to determine the effect size of those associations that corroborate a previous study of PTB.

Methods

DNA from 434 mother-baby dyads (214 cases and 220 controls) collected from the Norwegian Mother and Child Cohort (MoBa) was examined for association between 1,430 single nucleotide polymorphisms in 143 genes and PTB. These results were compared to a previous study on European Americans (EA) from Centennial Women''s Hospital in Nashville, TN, USA. Odds ratios for SNPs that corroborated the Cenntennial study were determined on the combined MoBa and Centennial studies.

Results

In maternal samples the strongest results that corroborated the Centennial study were in the prostaglandin E receptor 3 gene (PTGER3; rs977214) (combined genotype p = 3×10⁻⁴). The best model for rs977214 was the AG/GG genotypes relative to the AA genotype and resulted in an OR of 0.55 (95% CI = 0.37–0.82, p = 0.003), indicating a protective effect. In fetal samples the most significant association in the combined data was rs854552 in the paraoxonase 1 gene (PON1) (combined allele p = 8×10⁻⁴). The best model was the TT genotype relative to the CC/CT genotypes, and resulted in an OR of 1.32 (95% CI = 1.13–1.53, p = 4×10⁻⁴).

Conclusions

These studies identify single locus associations with preterm birth for both maternal and fetal genotypes in two populations of European ancestry.     

The SNP rs3128965 of HLA-DPB1 as a Genetic Marker of the AERD Phenotype

Background

Two common clinical syndromes of acetylsalicylic acid (aspirin) hypersensitivity, aspirin-exacerbated respiratory disease (AERD) and aspirin-exacerbated cutaneous disease (AECD), were subjected to a genome-wide association study to identify strong genetic markers for aspirin hypersensitivity in a Korean population.

Methods

A comparison of SNP genotype frequencies on an Affymetrix Genome-Wide Human SNP array of 179 AERD patients and 1989 healthy normal control subjects (NC) revealed SNPs on chromosome 6 that were associated with AERD, but not AECD. To validate the association, we enrolled a second cohort comprising AERD (n = 264), NC (n = 238) and disease-control (aspirin tolerant asthma; ATA, n = 387) groups.

Results

The minor genotype frequency (AG or AA) of a particular SNP, rs3128965, in the HLA-DPB1 region was higher in the AERD group compared to the ATA or NC group (P = 0.001, P = 0.002, in a co-dominant analysis model, respectively). Comparison of rs3128965 alleles with the clinical features of asthmatics revealed that patients harboring the A allele had increased bronchial hyperresponsiveness to inhaled aspirin and methacholine, and higher 15-HETE levels, than those without the A allele (P = 0.039, 0.037, and 0.004, respectively).

Conclusions

This implies the potential of rs3128965 as a genetic marker for diagnosis and prediction of the AERD phenotype.     

Importance of Ethnicity,CYP2B6 and ABCB1 Genotype for Efavirenz Pharmacokinetics and Treatment Outcomes: A Parallel-Group Prospective Cohort Study in Two Sub-Saharan Africa Populations

Objectives

We evaluated the importance of ethnicity and pharmacogenetic variations in determining efavirenz pharmacokinetics, auto-induction and immunological outcomes in two African populations.

Methods

ART naïve HIV patients from Ethiopia (n = 285) and Tanzania (n = 209) were prospectively enrolled in parallel to start efavirenz based HAART. CD4+ cell counts were determined at baseline, 12, 24 and 48 weeks. Plasma and intracellular efavirenz and 8-hydroxyefvairenz concentrations were determined at week 4 and 16. Genotyping for common functional CYP2B6, CYP3A5, ABCB1, UGT2B7 and SLCO1B1 variant alleles were done.

Result

Patient country, CYP2B6*6 and ABCB1 c.4036A>G (rs3842A>G) genotype were significant predictors of plasma and intracellular efavirenz concentration. CYP2B6*6 and ABCB1 c.4036A>G (rs3842) genotype were significantly associated with higher plasma efavirenz concentration and their allele frequencies were significantly higher in Tanzanians than Ethiopians. Tanzanians displayed significantly higher efavirenz plasma concentration at week 4 (p<0.0002) and week 16 (p = 0.006) compared to Ethiopians. Efavirenz plasma concentrations remained significantly higher in Tanzanians even after controlling for the effect of CYP2B6*6 and ABCB1 c.4036A>G genotype. Within country analyses indicated a significant decrease in the mean plasma efavirenz concentration by week 16 compared to week 4 in Tanzanians (p = 0.006), whereas no significant differences in plasma concentration over time was observed in Ethiopians (p = 0.84). Intracellular efavirenz concentration and patient country were significant predictors of CD4 gain during HAART.

Conclusion

We report substantial differences in efavirenz pharmacokinetics, extent of auto-induction and immunologic recovery between Ethiopian and Tanzanian HIV patients, partly but not solely, due to pharmacogenetic variations. The observed inter-ethnic variations in efavirenz plasma exposure may possibly result in varying clinical treatment outcome or adverse event profiles between populations.     

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.     

Liver X Receptor Gene Polymorphisms in Tuberculosis: Effect on Susceptibility

Objectives

The Liver X receptors (LXRs), Liver X receptor A (LXRA) and Liver X receptor B (LXRB), regulate lipid metabolism and antimicrobial response. LXRs have a crucial role in the control of Mycobacterium tuberculosis (M.tb). Lacking LXRs mice is more susceptibility to infection M.tb, developing higher bacterial burdens and an increase in the size and number of granulomatous lesions. We aimed to assess the associations between single nucleotide polymorphisms (SNPs) in LXRs and risk of tuberculosis.

Methods

We sequenced the LXRs genes to detect SNPs and to examine genotypic frequencies in 600 patients and 620 healthy controls to investigate for associations with tuberculosis (TB) in the Chinese Han population. DNA re-sequencing revealed eight common variants in the LXRs genes.

Results

The G allele of rs1449627 and the T allele of rs1405655 demonstrated an increased risk of developing TB (p<0.001, p = 0.002), and the T allele of rs3758673, the T allele of rs2279238, and the C allele of rs1449626 in LXRA and the C allele of rs17373080, the G allele of rs2248949, and the C allele of rs1052677 in LXRB were protective against TB patients compared to healthy controls (p = 0.0002, p = 0.006, p<0.001, p = 0.004, p = 0.008, p = 0.003, respectively). All SNP genotypes were significantly associated with TB. An estimation of the frequencies of haplotypes revealed two potential risk haplotypes,GGCG in LXRB (p = 0.004,) and TTCG in LXRA (p<0.001, p = 0.004). Moreover, three protective haplotypes, TTAT and CCAT in LXRA and CATC in LXRB, were significantly “protective” (p = 0.008, p<0.001, p = 0.031) for TB. Furthermore, we determined that the LXRs SNPs were nominally associated with the clinical pattern of disease.

Conclusions

Our study data supported that LXRs play a fundamental role in the genetic susceptibility to TB and to different clinical patterns of disease. Thus, further investigation is required in larger populations and in additional areas.     

Common Genetic Variants of the Human Steroid 21-Hydroxylase Gene (CYP21A2) Are Related to Differences in Circulating Hormone Levels

Purpose

Systematic evaluation of the potential relationship between the common genetic variants of CYP21A2 and hormone levels.

Methods

The relationships of CYP21A2 intron 2 polymorphisms and haplotypes with diverse baseline and stimulated blood hormone levels were studied in 106 subjects with non-functioning adrenal incidentaloma (NFAI). The rationale for using NFAI subjects is dual: i) their baseline hormone profiles do not differ from those of healthy subjects and ii) hormone levels after stimulation tests are available.

Results

The carriers (N = 27) of a well-defined CYP21A2 haplotype cluster (c5) had significantly elevated levels of cortisol (p = 0.0110), and 17-hydroxyprogesterone (p = 0.0001) after ACTH stimulation, and 11-deoxycortisol after metyrapone administration (p = 0.0017), but the hormone values were in normal ranges. In addition, the carriers (N = 33) of the C allele of the rs6462 polymorphism had a higher baseline aldosterone level (p = 0.0006). The prevalence of these genetic variants of CYP21A2 did not differ between NFAI and healthy subjects.

Conclusions

The common CYP21A2 variants presumably exert the same effect on hormone levels in the healthy and disease-affected populations. Therefore, they may contribute to complex diseases such as some cardiovascular diseases, and may influence the genotype-phenotype correlation in patients with congenital adrenal hyperplasia (CAH) including the individual need for hormone substitution.     

Genetic Variants in PCSK1 Gene Are Associated with the Risk of Coronary Artery Disease in Type 2 Diabetes in a Chinese Han Population: A Case Control Study

Background

Insulin and glucagon-like peptide 1 (GLP-1), converted by proprotein convertase 1 (PC1/3) from proinsulin and proglucagon, are associated with type 2 diabetes (T2DM) and coronary artery disease (CAD). The aim of this study is to investigate the association of PCSK1 gene, which encodes PC1/3, with the risk of CAD in Chinese patients with T2DM.

Methods

We selected and genotyped 5 haplotype-tagging single nucleotide polymorphisms (SNPs) at PCSK1 gene (across 39873bp locus) in a case-control study of Chinese Han population involving 425 diabetic patients (62.1% male, mean age 63.2 years) with CAD as positive cases and 258 diabetic patients (44.2% male, mean age 62.0 years) without CAD as controls.

Results

The allele frequencies at rs3811951 were significantly different between cases and controls (30.7% vs. 37.2%), with the allele G associated with decreased risk for CAD (OR = 0.75, 95% CI = 0.59–0.94, p = 0.013). In recessive inheritance mode, the carriers of GG had a lower risk (OR = 0.50, 95%CI = 0.31–0.82, p = 0.005), even after adjusted for gender, age, BMI and smoking (OR = 0.43, 95%CI = 0.24–0.77, p = 0.004). The carriers of the minor allele A at rs156019 had a higher risk (OR = 1.66, 95%CI = 1.10–2.50, p = 0.016 after adjustment) in dominant inheritance mode. The SNP rs6234 was also significantly associated with CAD risk in women, with the carriers of the minor allele G at rs6234 associated with a reduced CAD risk in recessive inheritance mode (OR = 0.42, 95% CI = 0.18–0.95, p = 0.036 after adjustment).

Conclusions

Our results found that common genetic variants in PCSK1 were associated with CAD in Chinese patients with T2DM.     

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.     

The A Allele of the rs1990760 Polymorphism in the IFIH1 Gene Is Associated with Protection for Arterial Hypertension in Type 1 Diabetic Patients and with Expression of This Gene in Human Mononuclear Cells

Background

The rs1990760 polymorphism of interferon induced with helicase C domain 1 (IFIH1) has been associated with type 1 diabetes mellitus (T1DM). Here, we investigated whether this polymorphism is associated with T1DM or its clinical characteristics in a Brazilian population, and if IFIH1 gene expression in mononuclear cells from T1DM patients differs according to the genotypes of this polymorphism. A meta-analysis was also conducted to evaluate if the rs1990760 polymorphism is associated with T1DM.

Methods

Frequencies of the rs1990760 polymorphism were analyzed in 527 T1DM patients and in 517 healthy subjects. IFIH1 gene expressions according to genotypes were measured in a sub-sample of 26 T1DM patients by quantitative real-time PCR.

Results

Our data show the association of the A allele with risk to T1DM under a dominant model of inheritance [odds ratio (OR) = 1.421, P = 0.037], adjusting for ethnicity. The meta-analysis revealed significant association between the rs199760A allele and risk for T1DM for all analyzed inheritance models. Surprisingly, T1DM patients carrying the A allele showed lower levels of systolic (P = 0.001) and diastolic (P = 1×10⁻¹⁰) blood pressures as compared to G/G carriers. Furthermore, the A/A genotype seems to be associated with protection to arterial hypertension (AH) after adjustment for covariates (OR = 0.339, P = 0.019). IFIH1 gene expression in mononuclear cells from 26 T1DM patients did not differ among genotypes (P = 0.274). Nevertheless, IFIH1 gene expression was increased in mononuclear cells from T1DM patients with AH as compared with T1DM patients without AH [6.7 (1.7–2.0) vs. 1.8 (1.3–7.1) arbitrary units; P = 0.036]. The association with blood pressures and AH was not observed in patients with type 2 diabetes mellitus.

Conclusions

Our results indicate that the rs1990760 polymorphism is associated with T1DM. Interestingly, the rs1990760 A allele seems to be associated with protection for AH in T1DM patients. Further studies are needed to confirm the association with AH.     

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.     

PDYN rs2281285 Variant Association with Drinking to Avoid Emotional or Somatic Discomfort

Introduction

One of the proposed psychobiological pathways of craving attributes the desire for drinking in the context of tension, discomfort or unpleasant emotions, to “negative” (or “relief”) craving. The aim of this study was to replicate a previously reported association of the PDYN rs2281285 variant with negative craving using a different phenotyping approach.

Methods

The TaqMan® Genotyping Assay was used to genotype the rs2281285 variant in 417 German alcohol-dependent subjects. The presence of negative/relief craving was assessed by asking if participants ever ingested alcohol to avoid unwanted emotional or somatic discomfort.

Results

The minor allele of rs2281285 was associated with an increased risk of drinking to avoid/escape unwanted emotional or somatic events (OR = 2.29, 95% CI = 1.08–4.85, p = 0.0298).

Discussion

Despite the use of a different phenotyping approach to the measurement of negative craving, our results confirm the association between negative craving and PDYN rs2281285. Genetic markers of negative craving may help to identify subgroups of alcohol-dependent individuals vulnerable to relapse in the context of negative emotions or somatic discomfort, leading to the development of specifically tailored treatment strategies.     

Natural Killer KIR3DS1 Is Closely Associated with HCV Viral Clearance and Sustained Virological Response in HIV/HCV Patients

Aim

To evaluate the influence of the presence of the killer cell immunoglobulin-like receptor (KIR) 3DS1 on HCV treatment response in HIV/HCV genotype 1 co-infected patients

Methods

HIV/HCV co-infected patients were included. KIR3DS1, their specific HLA-B ligands and IL28B gene were genotyped. Reductions of plasma HCV RNA levels between baseline and week 1, week 2 and week 4 were analyzed for IL28B genotype and KIR3DS1 (HLA Bw4 or Bw6). Rapid and sustained virological response (RVR and SVR) rates were also analyzed.

Results

Sixty HIV/HCV genotype 1 co-infected patients were included. Patients with KIR3DS1 and Bw4 had higher rates of HCV viral decline than those who were not carriers of KIR3DS1 (week1: p = 0.01; week2: p = 0.038; week 4: p = 0.03). Patients carrying KIR3DS1/Bw4 had higher rates of RVR and SVR than those who did not carry KIR3DS1 (RVR: 46.15% versus 17.02%, p = 0.012; SVR: 63.6% versus 13 26.5%, p = 0.031). With respect to patients carrying the IL28B-CC genotype, those with KIR3DS1/Bw4 had greater rates of HCV viral clearance (week1: p<0.001; week2: p = 0.01; week 4: p = 0.02), RVR (p = 0.015) and SVR (p = 0.029) than those not carrying KIR3DS1.

Conclusion

Our results show that the KIR3DS1 genotype has a positive effect on HCV viral clearance during the first weeks of Peg-IFN/RBV treatment in HCV/HCV co-infected patients bearing genotype 1, and higher RVR and SVR rates.