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.     

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.     

Association of Genetic Markers with CSF Oligoclonal Bands in Multiple Sclerosis Patients

Objective

to explore the association between genetic markers and Oligoclonal Bands (OCB) in the Cerebro Spinal Fluid (CSF) of Italian Multiple Sclerosis patients.

Methods

We genotyped 1115 Italian patients for HLA-DRB1*15 and HLA-A*02. In a subset of 925 patients we tested association with 52 non-HLA SNPs associated with MS susceptibility and we calculated a weighted Genetic Risk Score. Finally, we performed a Genome Wide Association Study (GWAS) with OCB status on a subset of 562 patients. The best associated SNPs of the Italian GWAS were replicated in silico in Scandinavian and Belgian populations, and meta-analyzed.

Results

HLA-DRB1*15 is associated with OCB+: p = 0.03, Odds Ratio (OR) = 1.6, 95% Confidence Limits (CL) = 1.1–2.4. None of the 52 non-HLA MS susceptibility loci was associated with OCB, except one SNP (rs2546890) near IL12B gene (OR: 1.45; 1.09–1.92). The weighted Genetic Risk Score mean was significantly (p = 0.0008) higher in OCB+ (7.668) than in OCB− (7.412) patients. After meta-analysis on the three datasets (Italian, Scandinavian and Belgian) for the best associated signals resulted from the Italian GWAS, the strongest signal was a SNP (rs9320598) on chromosome 6q (p = 9.4×10⁻⁷) outside the HLA region (65 Mb).

Discussion

genetic factors predispose to the development of OCB.     

Association of LIN28B with Adult Adiposity-Related Traits in Females

Context

Pubertal timing is under strong genetic control and its early onset associates with several adverse health outcomes in adulthood, including obesity, type 2 diabetes and cardiovascular disease. Recent data indicate strong association between pubertal timing and genetic variants near LIN28B, but it is currently unknown whether the gene contributes to the association between puberty and adult disease.

Objective

To elucidate the putative genetic link between early puberty and adult disease risk, we examined the association of two genetic variants near LIN28B with adult body size and metabolic profiles in randomly ascertained adult Finnish males and females.

Methods

Two single nucleotide polymorphisms (SNPs), rs7759938, the lead SNP previously associated with pubertal timing and height, and rs314279, previously also associated with menarcheal age but only partially correlated with rs7759938 (r² = 0.30), were genotyped in 26,636 study subjects participating in the Finnish population survey FINRISK. Marker associations with adult height, weight, body mass index (BMI), hip and waist circumference, blood glucose, serum insulin and lipid/lipoprotein levels were determined by linear regression analyses.

Results

Both rs7759938 and rs314279 associated with adult height in both sexes (p = 2×10⁻⁶ and p = 0.001). Furthermore, rs314279 associated with increased weight in females (p = 0.001). Conditioned analyses including both SNPs in the regression model verified that rs314279 independently associates with adult female weight, BMI and hip circumference (p<0.005). Neither SNP associated with glucose, lipid, or lipoprotein levels.

Conclusion

Genetic variants near the puberty-associated gene LIN28B associate with adult weight and body shape in females, suggesting that the gene may tag molecular pathways influencing adult adiposity-related traits.     

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.     

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.     

Sequence Variation in DDAH1 and DDAH2 Genes Is Strongly and Additively Associated with Serum ADMA Concentrations in Individuals with Type 2 Diabetes

Background

Asymmetric dimethylarginine (ADMA), present in human serum, is an endogenous inhibitor of nitric oxide synthase and contributes to vascular disease. Dimethylarginine dimethylaminohydrolase (DDAH) is an ADMA degrading enzyme that has two isoforms: DDAHI and DDAHII. We sought to determine whether serum ADMA levels in type 2 diabetes are influenced by common polymorphisms in the DDAH1 and DDAH2 genes.

Methodology/Principal Findings

Relevant clinical parameters were measured and peripheral whole blood obtained for serum and genetic analysis on 343 participants with type 2 diabetes. Serum ADMA concentrations were determined by mass spectroscopy. Twenty six tag SNPs in the DDAH1 and 10 in the DDAH2 gene were genotyped in all subjects and tested for association with serum ADMA levels. Several SNPs and haplotypes in the DDAH genes were strongly associated with ADMA levels. Most significantly in the DDAH1 gene, rs669173 (p = 2.96×10⁻⁷), rs7521189 (p = 6.40×10⁻⁷), rs2474123 (p = 0.00082) and rs13373844 (p = 0.00027), and in the DDAH2 gene, rs3131383 (p = 0.0029) and the TGCCCAGGAG haplotype (p = 0.0012) were significantly associated with ADMA levels. Sub-analysis by diabetic retinopathy (DR) status revealed these variants were associated with ADMA levels predominantly in participants without DR. Combined analysis of the most strongly associated SNPs in DDAH1 (rs669173) and DDAH2 (rs3131383) revealed an additive effect (p = 1.37×10⁻⁸) on ADMA levels.

Conclusions/Significance

Genetic variation in the DDAH1 and 2 genes is significantly associated with serum ADMA levels. Further studies are required to determine the pathophysiological significance of elevated serum ADMA in type 2 diabetes and to better understand how DDAH gene variation influences ADMA levels.     

Genetic Variants in the Fat and Obesity Associated (FTO) Gene and Risk of Alzheimer's Disease

Background

Recent studies showed that polymorphisms in the Fat and Obesity-Associated (FTO) gene have robust effects on obesity, obesity-related traits and endophenotypes associated with Alzheimer''s disease (AD).

Methods

We used 1,877 Caucasian cases and controls from the NIA-LOAD study and 1,093 Caribbean Hispanics to further explore the association of FTO with AD. Using logistic regression, we assessed 42 SNPs in introns 1 and 2, the region previously reported to be associated with AD endophenotypes, which had been derived by genome-wide screenings. In addition, we performed gene expression analyses of neuropathologically confirmed AD cases and controls of two independent datasets (19 AD cases, 10 controls; 176 AD cases, 188 controls) using within- and between-group factors ANOVA of log₁₀ transformed rank invariant normalized expression data.

Results

In the NIALOAD study, one SNP was significantly associated with AD and three additional markers were close to significance (rs6499640, rs10852521, rs16945088, rs8044769, FDR p-value: 0.05<p<0.09). Two of the SNPs are in strong LD (D′>0.9) with the previously reported SNPs. In the Caribbean Hispanic dataset, we identified three SNPs (rs17219084, rs11075996, rs11075997, FDR p-value: 0.009<p<0.01) that were associated with AD. These results were confirmed by haplotype analyses and in a metaanalysis in which we included the ADNI dataset. FTO had a significantly lower expresssion in AD cases compared to controls in two independent datasets derived from human cortex and amygdala tissue, respectively (p = 2.18×10−5 and p<0.0001).

Conclusions

Our data support the notion that genetic variation in Introns 1 and 2 of the FTO gene may contribute to AD risk.     

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.     

FCGR2B and FCRLB Gene Polymorphisms Associated with IgA Nephropathy

Background

IgA nephropathy (IgAN) is a complex syndrome characterized by deposition of IgA and IgA containing immune complexes (ICs) composed of IgG and complement C3 proteins in the mesangial area of glomeruli. The low-affinity receptors for the Fc region of IgG (FcγRs) are involved in autoantibody/immune complex-induced organ injury as well as ICs clearance. The aim of the study was to associate multiple polymorphisms within FCGR gene locus with IgAN in a large Chinese cohort.

Patients and Methods

60 single nucleotide polymorphisms (SNPs) spanning a 400 kb range within FCGR gene locus were analyzed in 2100 DNA samples from patients with biopsy proven IgAN and healthy age- and sex-matched controls from the same population in Chinese.

Results

Among the 60 SNPs investigated, 15 gene polymorphisms within FCGR gene locus (25%) were associated with susceptibility to IgAN. The most significantly associated SNPs within individual genes were FCGR2B rs12118043 (p = 8.74*10⁻³, OR 0.76, 95% CI 0.62–0.93), and FCRLB rs4657093 (p = 2.28*10⁻³, OR 0.77, 95% CI 0.65–0.91). Both conditional analysis and linkage disequilibrium analysis suggested they were independent signals associated with IgAN. Associations between FCGR2B rs12118043 and proteinuria (p = 3.65×10⁻²) as well as gross hematuria (p = 4.53×10⁻²), between FCRLB rs4657093 and levels of serum creatinine (p = 2.67×10⁻²) as well as eGFR (p = 5.41*10⁻³) were also observed. Electronic cis-expression quantative trait loci analysis supported their possible functional significance, with protective genotypes correlating lower gene expressions.

Conclusion

Our data from genetic associations and expression associations revealed potentially pathogenic roles of Fc receptor gene polymorphisms in IgAN.     

CTLA4 Gene Polymorphisms Influence the Incidence of Infection after Renal Transplantation in Chinese Recipients

Background

Immunosuppressive therapy is usually administered following renal transplantation to protect the graft from rejection. However, this often causes complications such as infections to occur. Single nucleotide polymorphisms (SNPs) within the CTLA4 gene, such as −1772T/C (rs733618), +49A/G (rs231775) and +6230 G/A (rs3087243), can affect graft rejection and the long-term clinical outcome of organ transplantation. The role of CTLA4 SNPs in T cell-mediated immunity in renal transplantation and association with infection after transplantation is unknown.

Methods

In this study, the risk of infection according to CTLA4 SNPs was investigated in 304 patients who received kidney graft transplants between 2008 and 2012.

Results

The frequency of the rs4553808 GG genotype was significantly higher in recipients with viral infection (14.89%) than in those without infections (3.50%) (Bonferroni-adjusted p = 0.005). A significant difference (p = 0.001) in patients with the rs4553808 GG genotype from those with the AA+AG genotypes was found in the viral cohort using the log-rank test. A significant association was found between the rs4553808 genotype and onset of viral infection in transplant recipients (p = 0.001). The frequencies of the CGTAG and CGCAG haplotypes were significantly higher in the viral infection group (9.6% and 5.3%) than in the non-viral infection group (3.8% and 1.4%) (p = 0.0149 and p = 0.0111). No association between any CTLA4 SNP and bacterial infection was found. Multivariate analyses revealed that one risk factor, the use of antibody induction therapy (p = 0.007), was associated with bacterial infection, and two risk factors, antibody use (p = 0.015) and recipient rs4553808 genotype (p = 0.001), were associated with viral infection.

Conclusions

The rs4553808 GG genotype may be a risk factor for viral infection in kidney transplantation. The CTLA4 haplotypes CGTAG and CGCAG were partially associated with the development of viral infection in Chinese kidney transplant recipients.     

Risk of Ovarian Cancer and Inherited Variants in Relapse-Associated Genes

Background

We previously identified a panel of genes associated with outcome of ovarian cancer. The purpose of the current study was to assess whether variants in these genes correlated with ovarian cancer risk.

Methods and Findings

Women with and without invasive ovarian cancer (749 cases, 1,041 controls) were genotyped at 136 single nucleotide polymorphisms (SNPs) within 13 candidate genes. Risk was estimated for each SNP and for overall variation within each gene. At the gene-level, variation within MSL1 (male-specific lethal-1 homolog) was associated with risk of serous cancer (p = 0.03); haplotypes within PRPF31 (PRP31 pre-mRNA processing factor 31 homolog) were associated with risk of invasive disease (p = 0.03). MSL1 rs7211770 was associated with decreased risk of serous disease (OR 0.81, 95% CI 0.66–0.98; p = 0.03). SNPs in MFSD7, BTN3A3, ZNF200, PTPRS, and CCND1A were inversely associated with risk (p<0.05), and there was increased risk at HEXIM1 rs1053578 (p = 0.04, OR 1.40, 95% CI 1.02–1.91).

Conclusions

Tumor studies can reveal novel genes worthy of follow-up for cancer susceptibility. Here, we found that inherited markers in the gene encoding MSL1, part of a complex that modifies the histone H4, may decrease risk of invasive serous ovarian cancer.     

Genetic Variations in the KCNJ5 Gene in Primary Aldosteronism Patients from Xinjiang,China

Background

Primary aldosteronism (PA) is the most common endocrine form of secondary hypertension, and one of the most common subtypes of sporadic PA is aldosterone-producing adenoma (APA). Recently, two somatic mutations of the KCNJ5 gene were implicated in APA, and two germline mutations were associated with familial hyperaldosteronism III.

Objectives

This case-control study was designed to investigate the relationship between genetic variations in the KCNJ5 gene and sporadic PA patients in Xinjiang, China.

Methods

Five common single nucleotide polymorphisms (SNPs) of the KCNJ5 gene (rs6590357, rs4937391, rs3740835, rs2604204, and rs11221497) were detected in patients with sporadic PA (n = 235) and essential hypertension (EH; n = 913) by the TaqMan polymerase chain reaction method.

Results

The EH group and the PA group showed significant differences in the distributions of genotypes and alleles of rs4937391 and rs2604204 in total and male subjects (P<0.05), as well as rs3740835 in male subjects (P<0.05). However, only the association between the rs2604204 genotype and male sporadic PA remained significant after Bonferroni’s correction (P<0.01). Furthermore, logistic regression analysis demonstrated that the CC genotype of rs2604204 was a risk factor for male patients with sporadic PA, after adjusting for age and body mass index (odds ratio = 2.228, 95% CI: 1.300–3.819, P = 0.004).

Conclusion

The genetic variant rs2604204 of KCNJ5 is associated with sporadic PA in Chinese males, suggesting that KCNJ5 may be involved in the pathogenesis of sporadic PA in these particular patients.     

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.     

Polymorphisms in the Non-Muscle Myosin Heavy Chain Gene (MYH9) Are Associated with Lower Glomerular Filtration Rate in Mixed Ancestry Diabetic Subjects from South Africa

Objective

Though single nucleotide polymorphisms (SNPs) in the non-muscle myosin gene (MYH9) have been reported to explain most of the excess risk of nondiabetic chronic kidney disease (CKD), in African-Americans, some studies have also shown associations with diabetic end-stage renal disease. We investigated the association of MYH9 SNPs with renal traits in a mixed-ancestry South African population prone to diabetes.

Research Design and Methods

Three SNPs known to be associated with CKD (rs4821480, rs5756152 and rs12107) were genotyped using Taqman assay in 716 adults (198 with diabetes) from the Bellville-South community, Cape Town. Glomerular filtration rate was estimated (eGFR) and urinary albumin/creatinine ratio (ACR) assessed. Multivariable regressions were used to relate the SNPs with renal traits.

Results

Mean age was 53.6 years, with the expected differences observed in characteristics by diabetic status. Significant associations were found between rs575152 and serum creatinine, and eGFR in the total population, and in diabetic participants (all p≤0.003), but not in non-diabetics (all p≥0.16), with significant interactions by diabetes status (interaction-p≤0.009). The association with ACR was borderline in diabetic participants (p = 0.05) and non-significant in non-diabetics (p = 0.85), with significant interaction (interaction p = 0.02). rs12107 was associated with fasting-, 2-hour glucose and HbA1c in diabetic participants only (interaction-p≤0.003), but not with renal traits.

Conclusion

MYH9 SNPs were associated with renal traits only in diabetic participants in this population. Our findings and other studies suggest that MYH9 may have a broader genetic risk effect on kidney diseases.     

Genetic Variations in ADIPOQ Gene Are Associated with Chronic Obstructive Pulmonary Disease

Background

Adiponectin is reported to be related to the development of chronic obstructive pulmonary disease (COPD). Genetic variants in the gene encoding adiponectin (ADIPOQ) have been reported to be associated with adiponectin level in several genome–wide linkage and association studies. However, relatively little is known about the effects of ADIPOQ gene variants on COPD susceptibility. We determined the frequencies of single-nucleotide polymorphisms (SNPs) in ADIPOQ in a Chinese Han population and their possible association with COPD susceptibility.

Methods

We conducted a case–control study of 279 COPD patients and 367 age- and gender-distribution-matched control subjects. Seven tagging SNPs in ADIPOQ, including rs710445, rs16861205, rs822396, rs7627128, rs1501299, rs3821799 and rs1063537 were genotyped by SNaPshot. Association analysis of genotypes/alleles and haplotypes constructed from these loci with COPD was conducted under different genetic models.

Results

The alleles or genotypes of rs1501299 distributed significantly differently in COPD patients and controls (allele: P = 0.002, OR = 1.43 and 95%CI = 1.14–1.79; genotype: P = 0.008). The allele A at rs1501299 was potentially associated with an increased risk of COPD in all dominant model analysis (P = 0.009; OR: 1.54; 95%CI: 1.11–2.13), recessive model analyses (P = 0.015; OR: 1.75; 95% CI: 1.11–2.75) and additive model analyses (P = 0.003; OR: 2.11; 95% CI: 1.29–3.47). In haplotype analysis, we observed haplotypes AAAAACT and GGACCTC had protective effects, while haplotypes AGAACTC, AGGCCTC, GGAACTC, GGACACT and GGGCCTC were significantly associated with the increased risk of COPD.

Conclusions

We conducted the first investigation of the association between the SNPs in ADIPOQ and COPD risk. Our current findings suggest that ADIPOQ may be a potential risk gene for COPD. Further studies in larger groups are warranted to confirm our results.     

The Association between Genetic Variations of CHI3L1, Levels of the Encoded Glycoprotein YKL-40 and the Lipid Profile in a Danish Population

Background

The inflammatory biomarker YKL-40 seems to play a role in atherosclerosis and is elevated in patients with obesity, cardiovascular disease and type 2 diabetes. Single nucleotide polymorphisms (SNPs) of the YKL-40 encoding gene, CHI3L1, are associated with inter-individual YKL-40 levels. One study has described an association between a promoter polymorphism of CHI3L1 and levels of low density lipoprotein. The objective of this study was to evaluate the influence of YKL-40 on lipid parameters by determining the association between polymorphisms of CHI3L1, serum YKL-40 and levels of the differentiated lipid profile in a Danish general population.

Methodology/Principle Findings

12 SNPs of CHI3L1 were genotyped, and serum YKL-40 and parameters of the lipid profile were measured in 2,656 Danes. Lipid profile and genotypes were available in another Danish population (n = 6,784) for replication. Cholesterol and triglyceride levels increased with increasing YKL-40 quartile (both p<0.0001), and YKL-40 correlated with triglyceride levels (β = 0.15, p<0.0001). Low density lipoprotein levels increased slightly from the 1^st to the 3^rd quartile (p = 0.006). The highest YKL-40 quartile was associated with a greater risk of hypercholesterolemia compared to the lowest YKL-40 quartile (odds ratio 1.36, p = 0.009). Minor homozygosity of rs12123883 was associated with higher triglyceride levels (p = 0.022) and a higher prevalence of low high density lipoprotein (p = 0.012), but these associations could not be confirmed in the replication population.

Conclusions/Significance

Serum YKL-40 correlates with triglyceride levels in a representative group of the general Danish population. No consistent associations between SNPs of CHI3L1 and lipid levels could be documented.     

FADS Gene Polymorphisms Confer the Risk of Coronary Artery Disease in a Chinese Han Population through the Altered Desaturase Activities: Based on High-Resolution Melting Analysis

Objective

We explored the desaturase activities and the correlation of fatty acid desaturases (FADS) gene single nucleotide polymorphisms (SNPs) with plasma fatty acid in coronary artery disease (CAD) patients in a Chinese Han population.

Methods

Plasma fatty acids were measured by gas chromatography in CAD patients (n = 505) and a control group (n = 510). Five SNPs in the FADS gene were genotyped with high-resolution melting (HRM) methods.

Results

After adjustment, D6D activity, assessed as arachidonic acid (AA, C20:4n-6)/linoleic acid (LA, C18:2n-6), was higher in CAD patients (p<0.001). D9D activity, which was estimated as the ratio of palmitoleic acid (C16:1)/palmitic acid (C16:0) or oleic acid (C18:1n-9) to stearic acid (C18:0), was also increased (p<0.001). The genotype distributions of rs174537 G>T and rs174460 C>T were different between the two groups. The rs174537 T allele was associated with a lower risk of CAD [OR 0.743, 95% CI (0.624, 0.884), p = 0.001]. Carriers of the rs174460 C allele were associated with a higher risk of CAD [OR 1.357, 95% CI (1.106, 1.665), p = 0.003].

Conclusions

We firstly report that the rs174460 C allele is associated with a higher risk of CAD, and confirm that the rs174537 T allele is associated with a lower risk of CAD. Our results indicate that FADS gene polymorphisms are likely to influence plasma fatty acid concentrations and desaturase activities.