HLA-A, -B, -C, -DRB1 and -DQB1 alleles and haplotypes in 951 Southeast Asia Malays from Peninsular Malaysia

A total of 951 Southeast Asia Malays from Peninsular Malaysia were genotyped for HLA-A, -B, -C -DRB1, and -DQB1 loci using polymerase chain reaction sequence-specific oligonucleotide probe hybridization methods. In this report, there were significant deviation from Hardy-Weinberg proportions for the HLA-A (p < 0.0001), -B (p < 0.0001), -DRB1 (p < 0.0001) and -DQB1 (p < 0.01) loci. Minor deviations from HWEP were detected for HLA-C (p = 0.01). This genotype data was available in Allele Frequencies Network Database (AFND) Gonzalez-Galarza et al. (2015).     

HLA-DQA1, DQB1 and DRB1 alleles associated with Takayasu arteritis in the Chinese Han population

Takayasu arteritis (TA) is a chronic large-vessel vasculitis of unknown etiology. Human leukocyte antigen (HLA) alleles play an important role in the development of TA. Sequence specific primer-polymerase chain reaction was used to detect 10 alleles of the HLA-DQA1 gene and 13 alleles of the HLA-DQB1, -DRB1 gene. A significant increase in the frequencies of DRB1¹07 (Pc < 0.01, OR = 3.44, CI: 2.15–5.52) was observed among TA patients compared with the control group. The significantly increased frequencies of the haplotype DQA1¹03:01-DQB1¹03:01-DRB1¹07 (Corrected P-values < 0.01) were observed in TA patients. But in the analysis of clinical manifestations, there are no significant associations with the HLA-DRB1¹07 allele.     

HLA-A68 and HLA-B15 alleles correlate with poor immune response among AIDS patients on combined antiretroviral therapy

Around 15–30% of AIDS patients fail to recover their CD4⁺ T cell levels following combined antiretroviral therapy despite successful inhibition of HIV-1 replication. The exact reasons for this immune recovery failure are not completely understood. HLA alleles are among the candidate that may explain this failure. A total of 65 adult AIDS patients, with viral load of <50 copies per ml were investigated. Viral load and CD4 T cells counts were performed following standard techniques. HLA genotyping was performed using PCR-SSP technique. The Statistical Package for Social Sciences (SPSS version 19) was used for data processing and analysis. A significantly higher proportion of poor immune responders were carrying HLA-A68 (4.8% compared to 25.0%, P = 0.025) and HLA-B15 (2.4% compared to 20.8%, P = 0.023). The etiological fraction (Efe%) among carriers of HLA-A68 was 57.89% (95% CI = 26.79, 75.79) and was 61.35% (95% CI = 35.33, 76.91) among carriers of HLA-B15.     

Diversities of HLA-A, -B, -C, -DRB1 and -DQB1 loci in Chinese Kazak population and its genetic relatedness dissection with multiple populations: a comparative study

Studying the allele and haplotype distributions of human leukocyte antigen (HLA) loci at 2nd-field level in different populations was important. Allele and haplotype frequencies of HLA-A, -B, -C, -DRB1 and -DQB1 loci in 110 unrelated healthy Kazak individuals living in Xinjiang (China) were analyzed using polymerase chain reaction sequence based typing. Thirty HLA-A, 48 HLA-B, 24 HLA-C, 34 HLA-DRB1 and 18 HLA-DQB1 alleles were detected at the 2nd-field level in the Kazak population. Frequencies of HLA alleles, genotypes, and haplotypes were calculated, and some exhibited significantly different distributions among different populations. A neighbor-joining (NJ) tree, heatmap, multidimensional scaling (MDS) and principal component analysis (PCA) were used to explore the genetic relationships between the Kazak population and 32 reference populations distributed in Asia, Africa, America and Europe using frequency data of HLA-A, -B, -C and -DRB1 loci. The NJ tree, heatmap, and MDS of the 33 populations were constructed based on pairwise D_A values of populations obtained by the HLA-A, -B, -C and -DRB1 allele frequencies. Different PCA plots were constructed based on the allele frequencies of HLA-A, -B, -C and -DRB1 or estimated haplotypic frequencies of HLA-A, -B, -C loci. The data obtained in the present research can be used for research on HLA-related diseases or paternity relationships, and aid to finding the best matched donors in stem cell transplantation for Kazak individuals.     

IL28B gene variants and glucose metabolism in Type 2 Diabetes

Type 2 Diabetes (T2D) develops, when β-cell insulin response fails to compensate for insulin resistance. Recent studies reported associations between the IL28B polymorphisms (rs12979860 and rs8099917) and T2D development in Hepatitis C virus (HCV) patients. To identify possible association with T2D independent from virus infection, we investigated both IL28B polymorphisms in T2D patients and healthy controls (HC). No association was found comparing the genotype and allele frequencies of both IL28B polymorphisms between T2D patients and HC. However, higher glucose levels were found in T2D patients carrying the IL28B CT/TT rs12979860 and GT/GG rs8099917 HCV risk genotypes compared to those with the protective CC and TT genotype (p = 0.06 and p = 0.02, respectively). Moreover, T2D patients with CT/TT rs12979860 HCV risk genotypes possessed significantly higher HbA1c levels than CC carriers (p = 0.04). In conclusion, the IL28B HCV risk genotypes may influence glucose homeostasis in T2D patients without HCV.     

NGS-based typings for 7 HLA loci in three populations from Rio de Janeiro,RJ, Brazil

We investigated HLA class I (HLA-A, -B, and -C) and class II (HLA-DRB1, -DQB1, -DPA1, and -DPB1) alleles by NGS-based typing among 759 Brazilian individuals from three populations in the Rio de Janeiro city based on their self-declared skin color (Caucasian, N = 521, AFND-ID: 3730; Parda, N = 170, AFND-ID: 3728; Black, N = 68, AFND-ID: 3727) to calculate allelic and haplotypic frequencies, plus linkage disequilibrium. Only HLA-DRB1 locus deviated from Hardy-Weinberg equilibrium (in Caucasian and Black populations). The three populations shared the most frequent allele on HLA-A, -C, -DRB1, -DPA1, and -DPB1. Genotype and frequency data are available in the Allele Frequencies Net Database.     

Role of ITPA and SLC28A2 genes in the prediction of anaemia associated with protease inhibitor plus ribavirin and peginterferon in hepatitis C treatment

BackgroundAnaemia is a common side-effect of ribavirin (RBV) use that overwhelms management of hepatitis C when protease inhibitors are added.AimTo assess the pharmacogenomic impact of candidate genes SLC28A2, SLC28A3 and ITPA on anaemia in patients receiving triple therapy.MethodsPatients (n = 161) with chronic hepatitis C genotype 1 treated with telaprevir (n = 95) or boceprevir (n = 66) were included. Using RT-PCR we genotyped ITPA (rs1127354, rs7270101) and SLC28A3 (rs56350726, rs10868138) and SLC28A2 (rs11854484). Clinically significant anaemia (CSA) was diagnosed when at least one of the following criteria was observed: (a) haemoglobin <8.5 g/dL during treatment; (b) blood transfusion required; (c) erythropoietin administered.ResultsCSA occurred in 44% (69/157) of patients and was associated with SLC28A2 rs11854484 [CC/CT genotypes: 33% (26/78) vs. TT genotype: 56% (36/64); p = 0.006]. Further, the needed for blood transfusion was related to genotype [CC: 0% (0/18) vs. CT: 13% (8/61) vs. TT: 27% (17/64); p = 0.016]. Similarly, ITPA rs1127354 genotypes [AA/AC: 19% (3/16) vs. CC: 45% (61/135; p = 0.060] were linked to CSA. In multivariate analysis, SLC28A2 rs11854484 TT genotype (OR:2.33;95%CI:1.10–4.95; p = 0.027), female sex (OR:2.54;95% CI:1.13–5.71;p = 0.024) and Hb drop at week 4) OR: 1.36; 95CI%: 1.11–1.67; p = 0.003) were independently associated with CSA. Similarly, ITPA rs1127354 genotypes [AA/AC: 16% (3/19) vs. CC: 63% (85/134); p = 0.0001] and ITPA rs6051702 genotypes [CC/CA: 46% (26/57) vs. CC: 65% (60/93); p = 0.023] were related to Hb drop of >3g/dL at week 4.ConclusionsIn patients receiving first generation protease inhibitors, genotype SLC28A2 rs11854484 predicts CSA, and helps to identify a subgroup of patients with better tolerance of triple therapy.     

Involvement of genes encoding apoptosis regulatory factors (FAS,FASL, TRAIL,BCL2, TNFR1 and TNFR2) in the pathogenesis of autoimmune thyroid diseases

Apoptosis is necessary for the maintenance of self-tolerance by eliminating autoreactive immune cells in the periphery. To clarify the association between the pathogenesis of autoimmune thyroid disease (AITD) and genes encoding apoptosis regulatory factors, we genotyped the FAS −1377G/A, −670A/G, FASL −844C/T, TRAIL −716C/T, BCL2 −938C/A, +127G/A, TNFR1 −383A/C and TNFR2 +676T/G polymorphisms. The frequencies of the FASL −844CC and BCL2 −938AA genotypes were significantly lower in AITD patients than in control subjects (P = 0.0101 and 0.0307, respectively). The frequency of the TNFR2 +676TT genotype was significantly lower in Graves’ disease (GD) patients than in controls (P = 0.0284). The serum sFasL level was significantly higher in GD and Hashimoto’s disease (HD) patients than in control subjects (P = 0.0003 and 0.0017, respectively). The serum sFasL levels in control subjects were significantly lower than those in intractable GD, GD in remission, and HD without treatment (P = 0.0310, 0.0007 and 0.0002, respectively). The serum sFasL levels in HD with treatment were significantly lower than those in HD without treatment (P = 0.0490). The polymorphisms in genes encoding apoptosis regulatory factors (FASL, BCL2) and serum levels of sFasL may be associated with immune dysregulation.     

Anti-Tax antibody levels in asymptomatic carriers,oligosymptomatic carriers,patients with rheumatologic disease or with HAM/TSP do not correlate with HTLV-1 proviral load

BackgroundHTLV-1 infects millions of people around the world and induces myelopathy (HAM/TSP), adult T-cell leukemia (ATL) or other inflammatory or rheumatologic diseases. The host–virus interaction causes asymptomatic carriers to develop HAM/TSP. Biomarkers are needed to predict patients who are at risk for HAM/TSP. Tax is highly immunogenic and is a major target protein recognized by cytotoxic T lymphocytes. Anti-Tax antibodies are involved in HAM/TSP pathogenesis.ObjectivesTo assess anti-Tax IgG reactivity with a flow cytometry assay (FCA) using an infection/transfection system with Vaccinia virus and pLW44/Tax-expressing Tax and to correlate the anti-Tax response and the HTLV-1 proviral load.Study design: We enrolled 81 individuals: 9 HTLV-1 seronegative (NP) and 72 HTLV-1 positive (23 HTLV-1 asymptomatic carriers (AC), 12 oligosymptomatic patients (OL), 7 with rheumatologic diseases (DR) and 30 with HAM/TSP (HT)). Anti-Tax reactivity was assessed by FCA, and HTLV-1 proviral load was measured with real time PCR.ResultsThe HT and DR groups showed greater anti-Tax IgG reactivity (p < 0.001 and p < 0.05 comparing HT to the OL and AC group, respectively; p < 0.05 comparing DR to the OL group), and the reactivity in the DR + HT group was significantly different when compared to the AC group (p < 0.05) and to the OL group (p < 0.001). The proviral load was higher in the HT group compared to the OL (p < 0.001) and in the HT + DR group compared to OL (p < 0.001). There was no correlation between anti-Tax IgG reactivity and proviral load in any of the HTLV-1-infected groups.ConclusionThese findings suggest that although anti-Tax IgG reactivity and the HTLV-1 proviral load are important markers of the development of HTLV-1-associated diseases, their levels are not correlated.     

Genetic polymorphisms of interleukin 20 (IL-20) in patients with ulcerative colitis

Interleukin (IL)-20 belongs to the IL-10 family and is a potent immunomodulatory cytokine with implications for pathogenesis in the inflammatory bowel disease (IBD). The interleukin 20 gene is located within a 200 kb region of q31-32 locus of chromosome 1. No previous studies have reported this novel association between ulcerative colitis (UC) and IL-20 polymorphisms. In the present work, we evaluated the role of IL-20 gene polymorphisms as susceptibility markers for UC. Three polymorphisms of IL-20 gene (rs2981573, rs2232360, rs1518108) were genotyped by 5′ exonuclease TaqMan genotyping assays on an ABI Prism 7900 HT Fast Real-Time PCR system in a group of 198 Mexican Mestizo patients with UC and 698 ethnically matched healthy unrelated individuals with no family history of UC. We found significant decreased frequencies of two IL-20 genotypes: GG (rs2981573) [10.6% vs. 17.6%, p = 0.017, OR = 0.55, 95% CI: 0.33–0.93] and GG (rs2232360) [10.6% vs. 17.6%, p = 0.017, OR = 0.55, 95% CI: 0.33–0.93] in UC patients as compared to healthy controls. No significant differences of gene frequencies were found between UC patients and healthy controls in the rs1518108 polymorphism. In the subgroup analysis, no differences were found between the IL-20 genotypes and the clinical characteristics of UC. The results suggest that the GG genotypes of the IL-20 polymorphisms (rs2981573 and rs2232360) might have an important role in the development of UC in the Mexican population.     

Effort-reward imbalance,overcommitment, and cellular immune measures among white-collar employees

We investigated whether chronic job stress, i.e., effort-reward imbalance (ERI) and overcommitment is associated with cellular immunity among 190 male and 157 female white-collar daytime employees (mean age 38; range 22–69 years). Participants provided a blood sample for the measurement of circulating immune (natural killer (NK), B, and T) cell counts and NK cell cytotoxicity (NKCC) and completed a questionnaire survey during April to June 2002. Stepwise multiple linear regression analyses revealed that NK cells were associated with effort (β = −.230; p = .013), reward (β = .169; p = .047), and ERI (β = −.182; p = .047) scores but not with overcommitment in men; reward score was positively associated with NKCC (β = .167; p = .049) and inversely associated with B cells (β = −.181; p = .030). No significant associations were found in women. Although the picture remains less clear in women, our findings suggest a potential immunological pathway linking adverse working conditions and stress-related disorders in men.     

Stronger Toll-like receptor 1/2, 4, and 7/8 but less 9 responses in peripheral blood mononuclear cells in non-infectious exacerbated asthmatic children

Toll-like receptors (TLR) initiate innate and often affect adaptive immune response. This study aimed to determine if TLR response and T regulatory cell (Treg) function in peripheral blood mononuclear cells (PBMC) correlate with clinical severity in non-infectious asthma. TLR1–9 expression and representative response cytokine TNF-α, IL-6, and IFN-β secretions were analyzed after stimulation by TLR1–9 ligands from 17 non-infectious asthmatic children. TNF-α production was higher in TLR1/2 (median 385.4 vs. 250.3 pg/ml in 1 μg/ml Pam3CSK4, p = 0.0078), TLR4 (2392.4 vs. 1355.9 in 1 μg/ml LPS; p = 0.0005), and TLR7/8 (10,776.2 vs. 4237.0 pg/ml in 1 μg/ml R848, p = 0.0079) of patients in exacerbation than those in convalescence and healthy controls despite equal TLR expression. TNF-α production stimulated by TLR9 agonist was significantly lower in exacerbation (17.7 vs. 34.9 pg/ml in 1 μg/ml ODN2216, p = 0.0175), while IL-6 production had similar patterns but was significantly lower in TLR3 signaling (119.7 vs. 245.0 pg/ml in 0.1 μg/ml poly(I:C), p = 0.0033). IFN-β production by TLR3 agonist also decreased in exacerbation but not statistically significant. Six older children showed decreased FOXP3 percentage in CD4 + CD25^high and decreased suppression capability in exacerbation but restored in stabilization (82.8% vs. 90.0%, p = 0.0061 and 60.9% vs. 81.7%, p = 0.0071; respectively). In conclusion, normalizing imbalanced TLR signaling and enhancing Treg cell capability may guide possible therapeutic strategies for non-infectious asthma in exacerbation.     

Genetic polymorphisms in TNFSF13 and FDX1 are associated with IgA nephropathy in the Han Chinese population

IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide, and its pathogenesis is influenced by both genetic and environmental factors. In this study, we evaluated 23 tag single-nucleotide polymorphisms (tSNPs) in 21 IgAN-associated genes, in 200 subjects with IgAN and 310 healthy gender- and age-matched unrelated control subjects with no history of renal disease or hypertension. Using the co-dominant model, we found that two genotypes of rs3803800 in TNFSF13 were associated with an increased risk of IgAN: “GA” (OR = 1.03, 95% CI = 0.71–1.51, p = 0.018) and “AA” (OR = 2.45, 95% CI = 1.29–4.65, p = 0.018). The “AA” genotype was also associated with an increased risk of IgAN in the recessive model (OR = 2.41, 95% CI = 1.30–4.46, p = 0.018), as was the genotype “AA” rs10488764 in FDX1 (OR = 1.88, 95% CI = 1.01–3.53, p = 0.048). Interestingly, we found that the allele “A” of rs3803800 in TNFSF13 is associated with a decreased risk of IgAN in females (OR = 0.43, 95% CI = 0.20–0.95, p = 0.009), but with an increased risk in males (OR = 1.78, 95% CI = 0.86–3.66, p = 0.009). Our findings, combined with previously reported results, suggest that TNFSF13 and FDX1 have potential roles in IgAN in the Han Chinese population. This information may be useful in the development of early prognostics for IgAN.     

Next generation HLA typing and haplotypes by descent in Gaza individuals

Forty-two individuals from the Gaza Strip were typed by Next Generation Sequencing (NGS) for HLA-A, -B, -C and -DRB1. Haplotypes were established by descent and only one haplotype was found to occur more than once; HLA-A*23:01 ~ B*41:01 ~ DRB1*07:01. The allele and haplotype frequencies and the individual genotypes are deposited at www.allelefrequencies.net (AFND) under population name Gaza and population ID number 3664 Dos Santos et al. (2016) [1].     

HLA-DPB1 matching in unrelated hematopoietic stem cell transplantation program contributes to a higher incidence of disease relapse

The impact of patient/donor matching for HLA-A, -B, -C, -DRB1 and -DQB1 genes in hematopoietic stem cell transplantation (HSCT) is well-recognized, but typing for additional genes, such as HLA-DPB1, is still controversial. Based on defined T-cell epitope (TCE) groups, all HLA-DPB1 mismatches can be classified as permissive or non-permissive. In this retrospective study we analysed 82 patient-matched unrelated donor (MUD) pairs who underwent HSCT, and explored the impact of HLA-DPB1 matches, permissive and non-permissive mismatches on transplantation outcomes. Patient-MUD pairs matched for HLA-DPB1 alleles in univariate analysis were associated with a significantly higher incidence of disease relapse compared to pairs who were permissive/non-permissive HLA-DPB1 mismatched according to the TCE3 and TCE4 algorithms (P = 0.025 and P = 0.026, respectively), although the significance was lost in multivariate analysis. The analysis did not reveal any significant influence of HLA-DPB1 alleles on overall survival (OS), non-relapse mortality (NRM) or graft-versus-host disease (GvHD) incidence. In conclusion, our study presents evidence that HLA-DPB1 matching influenced the relapse rate in patients after HSCT so the HLA-DPB1 alleles should be implemented in the MUD search algorithm as a transplantation determinant.     

PTPN22 polymorphisms,but not R620W,were associated with the genetic susceptibility of systemic lupus erythematosus and rheumatoid arthritis in a Chinese Han population

ObjectivesThe present study aimed to detect a possible association between PTPN22 gene polymorphisms and rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) in a Chinese Han population.Methods7 PTPN22 SNPs were genotyped in 358 patients with RA and 713 patients with SLE, as well as 564 RA controls and 672 SLE controls by Restriction Fragment Length Polymorphism (RFLP). Association analyses were conducted on the whole data set. Significant relationships were also examined between clinical features and SNPs for both RA and SLE.ResultsRs2476601 was lack of polymorphism with a ⩽0.1% frequency in both SLE and RA patients and healthy controls in our study. The two SNPs rs1217414 and rs3811021 of PTPN22 shown strong association with both SLE (rs1217414T: p_adj = 6.07e−004, OR = 0.57; rs3811021C: p_adj = 4.68e−005, OR = 0.65) and RA (rs1217414T: p_adj = 2.01e−008, OR = 0.26; rs3811021C: p_adj = 0.028, OR = 0.70). And the rs3765598 revealed a strong risk factor for SLE (p = 9.38e−009, p_adj = 6.57e−008, OR = 1.93), but not for RA (p = 0.48, OR = 1.12). Moreover, protective haplotype ACTTC in RA (p = 7.73e−016, p_adj = 5.51−015, OR[95%CI] = 0.02[0.002–0.10]) and SLE (p = 8.29e−018, p_adj = 5.80e−017, OR[95%CI] = 0.11[0.06–0.21]) were observed. In addition, the distribution of risk haplotypes ACGTC and GCTTT in RA (ACGTC: p = 0.0006, p_adj = 0.004, OR[95%CI] = 1.85[1.29–2.63]; GCTTT: p = 2.62e−005, p_adj = 1.85e−004, OR[95%CI] = 2.40[1.57–3.65]) and SLE (ACGTC: p = 0.0006, p_adj = 0.004, OR[95%CI] = 1.85[1.29–2.63]; ACGTC: p = 7.74e−011, p_adj = 6.81e−010, OR[95%CI] = 2.21[1.12–3.34]; GCTTT: p = 2.40[1.57–3.65], p_adj = 2.26e−006, OR[95%CI] = 2.64[1.79–3.87]) were significant different from that in controls. Furthermore, significant association was observed between the PTPN22 rs3765598 and antinuclear antibodies 1 (ANA1) in SLE.ConclusionsOur data provide strong evidence that the rs1217414 and rs3811021 in PTPN22 gene might be common protective factors contributed to SLE and RA susceptibility in the Chinese Han population. While, the rs3765598 might increase the genetic susceptibility of SLE, but not RA.     

Relationship between perilipin gene polymorphisms and body weight and body composition during weight loss and weight maintenance

BackgroundGenetic variation in the perilipin (PLIN) gene may play a role in the etiology and treatment of obesity.ObjectiveTo examine different polymorphisms in the PLIN gene in relation to body-weight regulation.Methods118 subjects followed a 6 wk VLCD, followed by 1 year weight maintenance. Body-weight (BW), body-composition, leptin concentration, and polymorphisms of the PLIN gene: PLIN1:rs2289487, PLIN4:rs894160, PLIN6:rs1052700, PLIN5:rs2304795 and PLIN7:rs 2304796 were determined.ResultsBW loss during VLCD was 7.0 ± 3.1 kg (p < 0.05), and BW regain was 3.7 ± 1.4 kg (p < 0.05), including changes in body mass index (BMI), waist-circumference, body-composition and leptin concentrations (p < 0.05).Linkage disequilibria were observed between PLIN1 and PLIN4: D' > 0.9, r² = 0.72; PLIN5 and PLIN7: D' > 0.9, r² = 0.85.In men, body weight, BMI, waist circumference, body fat, leptin concentrations were significantly lower for the haplotype of PLIN1 (C-alleles) and PLIN4 (A-alleles). In women weight loss and loss of fat mass were larger for the haplotype of PLIN1 (C-alleles) and PLIN4 (A-alleles). For PLIN6 genotypes body weight and body fat were lower for homozygotes of the minor allele (T/T) in the men; in the women leptin concentrations were lower.The haplotype of PLIN5 and PLIN7 consisting of A/G and G/G of PLIN5 and A/A of PLIN7 showed a reduction in FM: 5.9 ± 0.6 kg vs 3.1 ± 0.4 kg, % body fat: 5.5 ± 0.6% vs 2.2 ± 0.2%, and leptin: 20.5 ± 10.8 ng/ml vs 12.9 ± 6.7 ng/ml over time in the women (p < 0.05).ConclusionSince the haplotype of the minor alleles PLIN1–4, PLIN5–7 and PLIN6, was related to body-weight regulation at a lower level of body-weight in the men as well in the women we conclude that the PLIN1–4, 6, and 5–7 locus appears as a genetic influencer of obesity risk in humans.     

TBX6-associated congenital scoliosis (TACS) as a clinically distinguishable subtype of congenital scoliosis: further evidence supporting the compound inheritance and TBX6 gene dosage model

PurposeTo characterize clinically measurable endophenotypes, implicating the TBX6 compound inheritance model.MethodsPatients with congenital scoliosis (CS) from China(N = 345, cohort 1), Japan (N = 142, cohort 2), and the United States (N = 10, cohort 3) were studied. Clinically measurable endophenotypes were compared according to the TBX6 genotypes. A mouse model for Tbx6 compound inheritance (N = 52) was investigated by micro computed tomography (micro-CT). A clinical diagnostic algorithm (TACScore) was developed to assist in clinical recognition of TBX6-associated CS (TACS).ResultsIn cohort 1, TACS patients (N = 33) were significantly younger at onset than the remaining CS patients (P = 0.02), presented with one or more hemivertebrae/butterfly vertebrae (P = 4.9 × 10^‒8), and exhibited vertebral malformations involving the lower part of the spine (T8–S5, P = 4.4 × 10^‒3); observations were confirmed in two replication cohorts. Simple rib anomalies were prevalent in TACS patients (P = 3.1 × 10^‒7), while intraspinal anomalies were uncommon (P = 7.0 × 10^‒7). A clinically usable TACScore was developed with an area under the curve (AUC) of 0.9 (P = 1.6 × 10^‒15). A Tbx6^{-/mh (mild-hypomorphic)} mouse model supported that a gene dosage effect underlies the TACS phenotype.ConclusionTACS is a clinically distinguishable entity with consistent clinically measurable endophenotypes. The type and distribution of vertebral column abnormalities in TBX6/Tbx6 compound inheritance implicate subtle perturbations in gene dosage as a cause of spine developmental birth defects responsible for about 10% of CS.     

Rate and predictors of serum HCV-RNA >6 million IU/mL in patients with chronic hepatitis C

BackgroundBaseline serum HCV-RNA predicts sustained virological response in chronic hepatitis C patients treated with antiviral therapy. A threshold at 6 million IU/mL has been proposed to best discriminate treatment outcomes on sofosbuvir-based regimens. In comparison with the general population, immunosuppressed individuals exhibit greater viral load values.ObjectivesTo estimate the rate and predictors of serum HCV-RNA above 6 million IU/mL in chronic hepatitis C patients on care outside clinical trials.Study designSerum HCV-RNA values recorded from all chronic hepatitis C patients consecutively attended at our clinic during the last decade were analyzed. Testing had been performed using the COBAS TaqMan HCV test v2.0.ResultsA total of 816 individuals with detectable serum HCV-RNA were identified. The main characteristics of this population were as follows: mean age 48.6 years-old; 73.4% males; mean ALT 82.6 IU/L; mean HCV-RNA 6.02 log IU/mL; 80.6% HCV genotypes 1 or 4; 34.9% advanced liver fibrosis; 35.4% IL28B-CC alleles. HIV coinfection in 78.7%, of whom 91% were on antiretroviral therapy.Overall, 127 (15.6%) had serum HCV-RNA values >6 million IU/mL. This high viremia was found in 18.2% of HIV-positive versus 5.7% of HIV-negative subjects (p < 0.001). In multivariate analysis, serum HCV-RNA >6 million IU/mL was only significantly associated with HIV coinfection (OR: 4.03; 95% CI: 1.98–8.19, p < 0.01) and HCV genotypes 1 or 4 (OR: 1.88; 95% CI: 1.05–3.37, p = 0.03).ConclusionsSerum HCV-RNA >6 million IU/mL is roughly seen in 6% of chronic hepatitis C monoinfected patients, and increases up to 18% in HIV coinfection.     

Is Parkinson disease associated with lysosomal integral membrane protein type-2?: Challenges in interpreting association data

Several genetic risk factors have been identified for Parkinson disease (PD), including mutations in glucocerebrosidase (GBA1). Recently, two single nucleotide polymorphisms (SNPs) described as SCARB2 SNPs were reported to be associated with PD. SCARB2 is an attractive candidate gene for PD as it encodes for lysosomal integral membrane protein type 2 (LIMP-2), a protein involved in transporting glucocerebrosidase from the ER to the lysosome. The first SNP, rs6812193, located 64 kb upstream of SCARB2, was identified in a Parkinson disease Genome Wide Association study of Americans with European ancestry (p = 7.6 × 10^? 10, OR = 0.84), but was not replicated in a study in the Han Chinese. The second SNP, rs6825004, located within intron 2 of SCARB2 was reported in an association study of Parkinson disease in Greece (p = 0.02, OR = 0.68). We explored whether the two SNPs impact SCARB2 expression or LIMP-2 protein levels, testing fifteen control samples. First, the genotypes for each subject were determined for both SNPs using a Taqman assay. Then, RNA and protein were extracted from the corresponding cell pellets. Neither the relative RNA expression by real-time PCR, nor LIMP-2 levels on Western blots correlated with SNP genotype. Thus, these two reported SNPs may not be related to SCARB2 and demonstrate the challenges in interpreting some association studies. While LIMP-2 could still play a role in PD pathogenesis, this study does not provide evidence that the SNPs identified are in fact related to LIMP-2.