SIRT1 is associated with a decrease in acute insulin secretion and a sex specific increase in risk for type 2 diabetes in Pima Indians

Genetic variation in SIRT1 affects obesity-related phenotypes in several populations. The purpose of this study was to determine whether variation in SIRT1 affects susceptibility to obesity or type 2 diabetes in Pima Indians, a population with very high prevalence and incidence rates of these diseases. Genotypic data from single nucleotide polymorphisms (SNPs) identified by sequencing regions of SIRT1 combined with SNPs in/near SIRT1 from a prior genome-wide association study determined that 4 tag SNPs (rs7895833, rs10509291, rs7896005, and rs4746720) could capture information across this gene and its adjacent 5′ region. The tag SNPs were genotyped in a population-based sample of 3501 Pima Indians (44% had diabetes, 58% female) for association with type 2 diabetes and BMI. Metabolic trait data and adipose biopsies were available on a subset of these subjects. Two tag SNPs, rs10509291 and rs7896005, were nominally associated with type 2 diabetes (P = 0.01, OR = 1.25 95%CI 1.05–1.48, and P = 0.02, OR = 1.17 95%CI 1.02–1.34, respectively; additive P values adjusted for age, sex, birth year, and family membership), but not BMI (adjusted P values 0.52 and 0.45, respectively). Among metabolically characterized subjects with normal glucose tolerance (N = 243), those carrying the diabetes risk allele (T) for rs10509291 and (G) for rs7896005 had a reduced acute insulin response (AIR) to an intravenous glucose bolus (adjusted P = 0.045 and 0.035, respectively). SIRT1 expression in adipose biopsies was negatively correlated with BMI (adjusted P = 0.00001). We conclude that variation in SIRT1 is nominally associated with reduced AIR and increased risk for type 2 diabetes. SIRT1 expression in adipose is correlated with BMI, but it remains unknown whether this is a cause or consequence of obesity.     

SIRT1 gene polymorphisms are associated with nondiabetic type 1 cardiorenal syndrome

Type 1 cardiorenal syndrome (CRS1) is characterized by acute cardiac disease (e.g., acute heart failure [AHF]), leading to acute kidney injury. Sirtuin 1 (SIRT1), an NAD⁺‐dependent deacylase, has been found to be associated with CRS1. To confirm whether a correlation exists between SIRT1 variants and the risk of CRS1, the association between the prevalence of CRS1 and single‐nucleotide polymorphisms (SNPs) within the SIRT1 gene was investigated in AHF patients. A total of 316 Chinese AHF participants (158 patients with CRS1 and 158 age‐ and sex‐matched controls) were recruited for the present observational study to investigate the association between nine common SIRT1 SNPs (i.e., rs7895833 G > A, rs10509291 T > A, rs3740051 A > G, rs932658 A > C, rs33957861 C > T, rs7069102 C > G, rs2273773 T > C, rs3818292 A > G, and rs1467568 A > G) and the susceptibility to CRS1. Significant differences in genotype distribution between the control and CRS1 groups were found for rs7895833 and rs1467568. After applying a Bonferroni adjustment, the A allele of rs7895833 was still found to be protective (p = 0.001; odds ratio [OR] = 0.77) against CRS1 in this study population. The AA genotype of rs7895833 and the GA genotype of rs1467568 were associated with a significantly reduced risk of CRS1 (OR = 0.23 and 0.49, respectively). rs7895833 and rs1467568 were further analyzed as a haplotype, and the GA haplotype (rs7895833‐rs1467568) exhibited a significant association with CRS1 (p = 0.008), while the AA haplotype showed a significant protective effect (p = 0.022). Our study showed that SIRT1 rs7895833 and rs1467568 polymorphisms had a significant effect on the risk of developing CRS1 in a population in China.     

Genetic association between CD44 polymorphisms and chronic hepatitis B virus infection in a Chinese Han population

Aims: This article aimed at discussing the association of chronic hepatitis B virus (HBV) infection with CD44 polymorphisms in Chinese Han population; meanwhile, the interaction of polymorphisms was also analyzed based on chronic HBV infection. Methods: The genotyping of CD44 polymorphisms was conducted by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 108 HBV infected and 130 healthy persons. The genotype distributions of CD44 rs187115, rs13347 in the control group were checked by Hardy-Weinberg equilibrium (HWE). The strength of the relevance between polymorphism and disease was measured by odds ratio (OR) with corresponding 95% confidence interval (CI) calculated by χ² test. The 2×4 crossover analysis method was used to conduct the interaction analysis of polymorphisms. Results: The genotype distributions in controls conformed to HWE. GG genotype and G allele frequencies in rs187115 were obviously higher in cases than the controls (P=0.02, 0.04). Compared with the common genotype CC, individual who carried mutant genotypes (CT and TT) of rs13347 had a significantly high risk to suffer from HBV infection (OR=1.99, P=0.02 for CT; OR=3.56, P=3.00×10^-3 for TT), furthermore, CT+TT genotype also showed a high susceptibility (OR=2.27, P=2.00×10^-3). Similarly, T allele of rs13347 increased 0.98 times risk in cases compared with controls (OR=1.98, 95% CI=1.34-2.92). The two polymorphisms in CD44 presented a positive interaction. Conclusion: CD44 polymorphisms are associated with chronic HBV infection as the risk factors, and the synergistic action is also found between the two polymorphisms.     

Genetic polymorphisms of G protein-coupled receptor 65 gene are associated with ankylosing spondylitis in a Chinese Han population: A case-control study

ObjectiveThis study aimed to assess the association between two tag single nucleotide polymorphisms (SNPs) (rs68177277 and rs11624293) of G protein-coupled receptor 65 (GPR65) gene and ankylosing spondylitis (AS) susceptibility in a Chinese Han population.Methods673 patients with AS diagnosed according to the modified New York criteria and 679 age- and gender-matched healthy controls were recruited. SNP genotyping for rs68177277 and rs11624293 polymorphisms were performed using the SNPscan technique. Disease activity was assessed by the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI).ResultsGenotype and allele distribution of rs11624293 but not rs68177277 were significantly different between AS and controls (p = 0.004 and p = 0.002). Compared to the wild-type T/T genotype and T allele at rs11624293, the frequencies of C/T genotype and C allele were significantly higher in AS than controls after adjusting for age and gender (OR = 1.527, 95%CIs: 1.190–1.958; OR = 1.515, 95%CIs: 1.183–1.942, respectively). Dominant and co-dominant model of rs11624293 were predictive of AS susceptibility. In AS patients, the genotype of rs11624293 was significantly associated with BASFI scores in those with low disease activity (BASDAI < 4, p = 0.007).ConclusionsThe results of our study suggest that rs11624293 polymorphism of GPR65 gene is associated with the susceptibility and severity of AS in Chinese Han population.     

Genetic analysis of the ELOVL6 gene polymorphism associated with type 2 diabetes mellitus

Recent animal studies have indicated that overexpression of the elongation of long-chain fatty acids family member 6 (Elovl6) gene can cause insulin resistance and β-cell dysfunction. These are the major factors involved in the development of type 2 diabetes mellitus (T2DM). To identify the relationship between single nucleotide polymorphisms (SNP) of ELOVL6 and T2DM pathogenesis, we conducted a case-control study of 610 Han Chinese individuals (328 newly diagnosed T2DM and 282 healthy subjects). Insulin resistance and islet first-phase secretion function were evaluated by assessment of insulin resistance in a homeostasis model (HOMA-IR) and an arginine stimulation test. Three SNPs of the ELOVL6 gene were genotyped with polymerase chain reaction-restriction fragment length polymorphism, with DNA sequencing used to confirm the results. Only genotypes TT and CT of the ELOVL6 SNP rs12504538 were detected in the samples. Genotype CC was not observed. The T2DM group had a higher frequency of the C allele and the CT genotype than the control group. Subjects with the CT genotype had higher HOMA-IR values than those with the TT genotype. In addition, no statistical significance was observed between the genotype and allele frequencies of the control and T2DM groups for SNPs rs17041272 and rs6824447. The study indicated that the ELOVL6 gene polymorphism rs12504538 is associated with an increased risk of T2DM, because it causes an increase in insulin resistance.     

Positive Association between GCKR rs780093 Polymorphism and Coronary Heart Disease in the Aged Han Chinese

Objective. Previous studies have confirmed that GCKR rs780093 polymorphism is associated with triglyceride (TG), a known risk factor of coronary heart disease (CHD). The goal of our study is to explore the association of GCKR rs780093 polymorphism with CHD in Han Chinese population. Methods and Results. A total of 568 CHD cases and 494 non-CHD controls were enrolled in the current case-control study. Genotyping was done using melting temperature shift (Tm-shift) approach. Our results also showed that GCKR rs780093 polymorphism was significantly associated with TG level (P = 0.0016). Although there was no significant association between cases and controls (P > 0.05), a breakdown analysis by age yielded a significant association of GCKR rs780093 polymorphism with CHD in individuals aged 65 and older (genotype: χ² = 6.86; df = 2; P = 0.03; allele: χ² = 4.11; df = 1; P = 0.04). Conclusion. Our findings confirmed the contribution of GCKR rs780093 polymorphism to TG metabolism and demonstrated GCKR rs780093 as a risk factor of CHD in individuals aged 65 and older.     

Genetic variants of OCT1 influence glycemic response to metformin in Han Chinese patients with type-2 diabetes mellitus in Shanghai

Aims/hypothesis: Genetic variation in OCT1 can influence the glycemic response to metformin. We evaluated the effects of the OCT1 single-nucleotide polymorphisms (SNPs), rs1867351, rs4709400, rs628031, and rs2297374, on metformin efficacy in type-2 diabetes mellitus (DM) patients. Methods: We performed a single-center prospective analysis of the distributions of these SNPs in a cohort of Han Chinese subjects in Shanghai, China (HCS), and evaluated the effects of each SNP on glycemic control in HCS DM patients following 3 months of incident metformin treatment. Results: The allele frequencies of rs4709400 and rs628031 in our HCS control group differed from those previously reported for Han Chinese subjects in Beijing (HCB), as well as those previously reported for Caucasians and Africans, whereas the allele frequencies of rs1867351 and rs2297374 were more similar to those in HCB subjects. The DM patients with the rs1867351 T/T or rs4709400 G/G genotype exhibited greater reductions in postprandial plasma glucose (PPG), compared to those with different genotypes of these SNPs. The DM patients with the rs2297374 C/T, rs4709400 G/G, or rs628031 G/G genotype exhibited greater reductions in fasting plasma glucose (FPG), and those with the rs1867351 T/T, rs628031 A/A, or rs2297374 C/T genotype exhibited greater reductions in HbA_1c , compared to those with different genotypes of these SNPs. Conclusions /interpretation: The rs1867351, rs4709400, rs628031, and rs2297374 SNPs of OCT1 have selective effects on FPG, PPG, and HbA_1c in HCS DM patients in response to metformin treatment. Future studies of these SNPs in larger samples of HCS DM patients are warranted.     

CX3CR1 polymorphisms and the risk of age-related macular degeneration

Background: Age-related macular degeneration (AMD), a most common eye disease, can lead to irreversible visual impairment. Age, genetic and environmental factors have been implicated in AMD. Chemokine (C-X3-C motif) receptor 1 (CX3CR1) gene polymorphisms could influence the susceptibility of AMD. Methods: We tested the association between AMD and single nocleotide polymorphisms (SNPs) of CX3CR1 gene (rs3732378 and rs3732379) in 102 cases and 115 controls from China. Genotypes were determined by MassArray genotyping assay method. Association between CX3CR1 gene polymorphisms and AMD were examined by χ² test and logistic regression. Results: Genotype distribution of CX3CR1 gene polymorphisms were in accordance with HWE examination. No obvious differences were observed in the genotypes of rs3732378 polymorphism between case and control groups (P>0.05), but A allele of it could increase the risk of AMD (P=0.025, OR=2.391, 95% CI=1.092-5.237). Both TT genotype and T allele of rs3732379 were significantly associated with the susceptibility of AMD (P=8.663, OR=8.663, 95% CI=1.044-71.874; P=0.021, OR=2.076, 95% CI=1.104-3.903). Age, gender and smoking status were used as common confounders to adjust the association between CX3CR1 gene polymorphism and AMD risk. Then we found that rs3732378 had no obvious association with AMD susceptibility. TT genotype of rs3732379 related to the occurrence of AMD, but the association was not significant (P=0.050, OR=8.274, 95% CI=1.002-69.963). T allele of rs3732379 might increase the susceptibility of AMD (P=0.029, OR=2.033, 95% CI=1.077-3.838). Conclusion: T allele of rs3732379 might have a positive association with the susceptibility of AMD.     

Association between the interaction of SMAD3 polymorphisms with body mass index and osteoarthritis susceptibility

Purpose: This study aimed to investigate the relationship between the interaction of SMAD3 polymorphisms (rs12102171 and rs2289263) with body mass index (BMI) and osteoarthritis (OA) susceptibility. Methods: This study involved 112 OA patients and 120 healthy people. The controls were frequency-matched with the cases by age and sex. Hardy-Weinberg equilibrium (HWE) was tested by χ² test in the control group. The rs12102171 and rs2289263 polymorphisms were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The relative risk of OA was represented by odds ratio (OR) with 95% confidence interval (CI) calculated by chi-squared test. Gene-environment interaction was analyzed by crossover analysis. Results: The TT genotype and T allele of SMAD3 rs12102171 polymorphism were more frequent in case than control groups (P=0.04 in both of two polymorphisms), which increased the risk of OA (OR=3.39, 95% CI=1.03-11.11 and OR=1.64, 95% CI=1.03-2.59). GG genotype and G allele were also the risk factors for OA (OR=3.22, 95% CI=1.09-9.51 and OR=1.57, 95% CI=1.02-2.42). The BMI had interactions with genotype CC and CT+TT of rs12102171 and TT and TG+GG of rs2289263 (rs12102171: OR=2.15, P=0.02 and OR=3.99, P=1.00×10^-3; rs2289263: OR=2.73, P=4.00×10^-3 and OR=4.67, P=0). Conclusions: CC and CT+TT and TT and TG+GG genotypes of SMAD3 rs12102171 and rs2289263 polymorphisms together with BMI may be susceptible factors to OA, and interactions there between can possibly confer risk to OA.     

Association between functional SIRT1 polymorphisms and the clinical characteristics of patients with autoimmune thyroid disease

Sirtuin1 (SIRT1) is a Class 3 nicotinamide adenine dinucleotide-dependent histone deacetylase (HDAC) that is thought to be implicated in the protection against autoimmune diseases. However, an association between SIRT1 and autoimmune thyroid disease (AITD) has not been reported. In this study, we selected four single nucleotide polymorphisms (SNPs) in the SIRT1 gene, rs12049646 T/C (termed SNP1), rs12778366 T/C (termed SNP2), rs3758391 T/C (termed SNP3), and rs4746720 T/C (termed SNP4). We genotyped each of these polymorphic sites in 185 patients with Graves’ disease (GD), including 76 patients with intractable GD and 57 patients with GD in remission; 151 patients with Hashimoto’s disease (HD), including 68 patients with severe HD and 54 patients with mild HD; and 96 healthy volunteers. SNP1 and SNP3 were genotyped by the PCR-RFLP method; SNP2 and SNP4 were genotyped using TaqMan® SNP genotyping assays. We also measured the levels of SIRT1 mRNA in CD4⁺ T cells from 18 control subjects, 16 patients with GD in remission and 14 patients with mild HD using a real-time PCR method. In patients with GD and HD, the C carriers (TC?+?CC genotypes) of SNP3 showed significantly higher titers of McAb than the TT genotype (p?=?0.0261 and p?=?0.0309, respectively). Additionally, the T carriers (TT?+?TC genotypes) of SNP4 showed significantly higher titers of McAb than the CC genotype in patients with GD (p?=?0.0079). In conclusion, the polymorphisms in the SIRT1 gene were associated with a greater production of thyroid autoantibodies.     

Association Study of ARL15 and CDH13 with T2DM in a Han Chinese Population

Several studies indicate that plasma adiponectin levels are associated with the risk of type 2 diabetes mellitus (T2DM) or T2DM risk factors in diverse populations. In addition to the adiponectin gene, several other genes have been postulated to influence plasma adiponectin levels. In this study, we investigated two single nucleotide polymorphisms (SNPs), rs4311394 and rs4783244, located intronically in the ADP-ribosylation factor-like protein 15 (ARL15) and the T-cadherin (CDH13) genes, respectively. These SNPs were detected in a Han Chinese population using a TaqMan assay and evaluated for association with T2DM as well as with individual metabolic traits. Allele frequencies for rs4311394 were significantly different in T2DM and nondiabetes (NDM) groups (χ² = 4.49, P = 0.034). However, neither allele nor genotype frequencies for rs4783244 were associated with T2DM (χ² = 0.33, P = 0.56 and χ² = 2.35, P = 0.31 respectively). The SNPs did not exhibit significant association with individual metabolic traits in the T2DM and NDM groups. Our results indicated that the G allele of the rs4311394 might be a susceptibility factor for T2DM in the Han Chinese population (odds ratio: 1.20; 95% confidence interval: 1.01-1.41).     

Sex-specific association of the SPTY2D1 rs7934205 polymorphism and serum lipid levels

The objective of the present study was to detect the association of the rs7934205 single nucleotide polymorphism (SNP) near the Suppressor of Ty, domain containing 1 gene (SPTY2D1) and serum lipid levels between males and females in the Mulao and Han populations. Genotyping of SPTY2D1 rs7934205 SNP was performed in 933 of Mulao and 865 of Han participants using polymerase chain reaction and restriction fragment length polymorphism. The T allele frequency was different between Mulao males and females (23.2% vs. 27.9%, P = 0.018). The genotype and allele frequencies were also different between Han males and females (P = 0.020 and P = 0.004; respectively). Serum levels of apolipoprotein (Apo) A1 in Mulao males; and total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), ApoA1 and ApoB in Mulao females were different between the CC and CT/TT genotypes (P < 0.05). Serum TC, ApoB levels in Han males, and ApoB levels in Han females were different between the CC and CT/TT genotypes (P < 0.05). The subjects with CT/TT genotype in both Mulao and Han males and females have more favorable lipid profiles than those with CC genotype. These findings suggest that the association between the SPTY2D1 rs7934205 SNP and serum lipid levels might have ethnic- and/or sex-specificity.     

Replication of the LINGO1 gene association with essential tremor in a North American population

A marker in the LINGO1 gene, rs9652490, showing significant genome-wide association with essential tremor (ET), was recently reported in an Icelandic population. To replicate this association in an independent population from North America, we genotyped 15 SNPs in the LINGO1 gene in 257 Caucasian ET cases (‘definite,'' ‘probable'' or ‘possible'') and 265 controls enrolled in an epidemiological study at Columbia University. We observed a marginally significant association with allele G of the marker rs9652490 (P=0.0569, odds ratio (OR)=1.33). However, for ‘definite'' or ‘probable'' ET, rs9652490 was significantly associated with ET (P=0.03, OR=1.41). Our subsequent analysis of early-onset ET (age at onset <40 years) revealed that three SNPs, rs177008, rs13313467 and rs8028808, were significantly associated with ET (P=0.028, OR=1.52; P=0.0238, OR=1.54; and P=0.0391, OR=1.55, respectively). These three SNPs represent a 2.3 kb haplotype. Finally, a meta-analysis of three published studies confirms allelic association with rs9652490 and two adjacent SNPs. Our study independently confirms that the LINGO1 gene is a risk factor for ET in a Caucasian population in North America, and further shows that those with early-onset ET are likely to be at high risk.     

Insulin-like growth factor 1 (IGF1) polymorphism is associated with Alzheimer's disease in Han Chinese

A review of pathogenic findings in Alzheimer's brains and the functional consequences of altered insulin-like growth factor 1 (IGF1) input to the brain suggest the association between Alzheimer's disease (AD) and the disrupted IGF1 signaling. Recently, the identification of polymorphism rs972936 that was associated with both an increased risk of AD and high circulating levels of IGF1 was reported in Southern European population. In order to evaluate the involvement of the IGF1 polymorphism in the risk of developing late-onset Alzheimer's disease (LOAD) in Chinese, we performed an independent case-control association study in a Han Chinese population (794 LOAD cases and 796 controls). There were significant differences in genotype and allele frequencies between LOAD cases and controls (genotype P = 0.006, allele P = 0.047). The T allele of rs972936 demonstrated a 1.16-fold risk for developing LOAD when compared with the C allele, which diverges to the report in the Caucasian population. After stratification by apolipoprotein E (APOE) ?4-carrying status, rs972936 polymorphism was only significantly associated with LOAD in non-ApoE ?4 allele carriers (genotype P = 0.002, allele P = 0.039). Multivariate logistic regression analysis also conferred this positive association between the SNP rs972936 and LOAD in the recessive and additive model after adjustment for age, gender, and the ApoE ?4 carrier status. These results suggest that IGF1 polymorphism has a possible role in changing the genetic susceptibility to LOAD in a Han Chinese population.     

−1722T/C polymorphism (rs733618) of CTLA-4 significantly associated with systemic lupus erythematosus (SLE): A comprehensive meta-analysis

This study was to determine whether −318C/T (rs5742909), −1722T/C (rs733618) and −1661A/G (rs4553808) of Cytotoxic T-lymphocyte antigen-4 (CTLA-4) are associated with systemic lupus erythematosus (SLE). The meta-analysis for −318C/T (rs5742909) included 1163 cases and 1520 controls, for −1722T/C (rs733618) included 1016 cases and 1078 controls, and for −1661A/G (rs4553808) included 637 cases and 774 controls. For −318C/T (rs5742909), statistically significant differences were not noted between cases and controls {fixed/random: OR: 1.103, 95% CI: (0.907–1.341), p = 0.326}. For −1661A/G (rs4553808), also no significant difference existed {fixed: OR: 1.024, 95% CI: (0.843–1.244), p = 0.812; random: OR: 1.077, 95% CI: (0.780–1.300), p = 0.958}. But −1722T/C (rs733618) was significantly associated with SLE both in allele {fixed: OR: 0.699, 95% CI: (0.602–0.811), p = 0.000; random: OR: 0.748, 95% CI: (0.565–0.990), p = 0.042} and in genotype {CC/(CT + TT)} meta-analysis {OR: 0.422, 95% CI: (0.297–0.598), p = 0.000}. Also, we subdivided the −1722T/C group (rs733618) into Asia and Mixed subgroups, in Asia subgroup, the SNP was significantly associated with SLE {fixed: OR: 0.628, 95% CI: (0.528–0.746), p = 0.000; random: OR: 0.641, 95% CI: (0.470–0.875), p = 0.005}, in the Mixed subgroup, this polymorphism was not associated with SLE {fixed: OR: 0.946, 95% CI: (0.707–1.267), p = 0.711; random: OR: 0.973, 95% CI: (0.606–1.560), p = 0.908}. These results suggest that there is evidence of association between the CLTA-4 and SLE, especially −1722T/C polymorphism (rs733618).     

Association analysis between genetic variants in interleukin genes among different populations with hyperuricemia in Xinjiang Autonomous Region

To investigate whether functional variants of five interleukin genes (IL-1β, IL-10, IL-8, IL-18 and IL-18RAP) are associated with susceptibility to hyperuricemia among different nationalities (including Uygur, Kazak and Han populations) in the Xinjiang Autonomous Region of China. A total of 884 hyperuricemia patients and 1316 matched controls were recruited from the First Affiliated Hospital of Xinjiang Medical University in Urumqi. After genotyping of rs4073 in IL-8, rs16944 in IL-1, rs187238 in IL-18, rs1800871 in IL-10 and rs13015714 in IL-18RAP by TaqMan allele discrimination assays, an association analysis was performed using the χ² test as well as a genotype-phenotype analysis. For the Uygur population, IL-8 rs4073, IL-18 rs187238 and IL-18RAP rs130154 polymorphisms were all associated with hyperuricemia (P<0.001 by genotype and P=0.008, OR 0.802 by allele for IL-8; P=0.01 by genotype and P=0.006, OR 1.332 by allele for IL-18 rs187238; P=0.007 by genotype and P=0.005, OR 1.27 by allele for IL-18RAP rs130154). For the Kazak population, only IL-18 rs187238 showed statistical significance with hyperuricemia (P=0.002 by genotype and P=0.007, OR 1.823 by allele). However, no differences were found between the five SNPs and hyperuricemia among the Han population. This study demonstrated genetic polymorphisms of different interleukin genes related to hyperuricemia vary in different nationalities in the Xinjiang Autonomous Region because of different geographical environments. IL-8, IL-1RL1 and IL-18 might be involved in the development of hyperuricemia in the Uygur population, whereas only IL-18 might be involved in the Kazak population.     

Switch from enzyme replacement therapy to oral chaperone migalastat for treating fabry disease: real-life data

The treatment options for Fabry disease (FD) are enzyme replacement therapy (ERT) with agalsidase alfa or beta, and the oral pharmacological chaperone migalastat. Since few data are available on the effects of switching from ERT to migalastat, we performed a single-center observational study on seven male Fabry patients (18–66 years) to assess the effects of the switch on renal, cardiac, and neurologic function, health status, pain, lyso-Gb3, α-Gal A activity and adverse effects. Data were retrospectively collected at time of diagnosis of FD (baseline, T0), and after 12 months of ERT (T1), and prospectively after 1 year of therapy with migalastat (T2). No patient died or reported renal, cardiac, or cerebrovascular events during the study period. The predefined measures for cardiac, renal and neurologic function, and FD-related symptoms and questionnaires were stable between baseline and the switch, and remained unchanged with migalastat. However, a significant improvement was observed in left ventricular mass index from baseline to T2 (p = 0.016), with a significative difference between the treatments (p = 0.028), and in median proteinuria from T2 vs T1 (p = 0.048). Moreover, scores of the BPI improved from baseline to T1, and remained stable with migalastat. Plasma lyso-Gb3 levels significantly decreased from baseline to T1 (P = 0.007) and T2 (P = 0.003), while did not significantly differ between the two treatments. α-Gal A activity increased from T0 to T2 (p < 0.0001). The frequency of adverse effects under migalastat and ERT was comparable (28% for both drugs). In conclusion, switching from ERT to migalastat is valid, safe and well tolerated.Subject terms: Genetics research, Drug regulation     

The FSHB ?211G>T variant attenuates serum FSH levels in the supraphysiological gonadotropin setting of Klinefelter syndrome

Klinefelter syndrome (47, XXY) is the most frequent genetic cause of male infertility and individuals share the endocrine hallmark of hypergonadotropic hypogonadism. Single-nucleotide polymorphisms located within the FSHB/FSHR gene were recently shown to impact serum follicle-stimulating hormone (FSH) levels and other reproductive parameters in men. The objective of this study was to analyse the effect of FSHB-211G>T (c.−280G>T, rs10835638) as well as FSHR c.2039G>A (rs6166) and FSHR c.−29G>A (rs1394205) on endocrine and reproductive parameters in untreated and testosterone-treated Klinefelter patients. Patients were retrospectively selected from the clientele attending a university-based andrology centre. A total of 309 non-mosaic Klinefelter individuals between 18 and 65 years were included and genotyped for the variants by TaqMan assays. The untreated group comprised 248 men, in which the FSHB −211G>T allele was significantly associated with the reduced serum follicle-stimulating hormone levels (−6.5 U/l per T allele, P=1.3 × 10⁻³). Testosterone treatment (n=150) abolished the observed association. When analysing patients before and under testosterone treatment (n=89), gonadotropin levels were similarly suppressed independently of the FSHB genotype. The FSHR polymorphisms did not exhibit any significant influence in any group, neither on the endocrine nor reproductive parameters. In conclusion, a hypergonadotropic setting such as Klinefelter syndrome does not mask the FSHB −211G>T genotype effects on the follicle-stimulating hormone serum levels. The impact was indeed more pronounced compared with normal or infertile men, whereas gonadotropin suppression under testosterone treatment seems to be independent of the genotype. Thus, the FSHB −211G>T genotype is a key determinant in the regulation of gonadotropins in different reproductive-endocrine pathopyhsiologies.     

IL10 polymorphisms associated with Behçet’s disease in Chinese Han

Objective

IL-10 is a potent anti-inflammatory cytokine that plays important roles in the pathogenesis of Behçet’s disease (BD). Two genome-wide association studies have identified IL10 as a potential risk factor for BD. Here, we investigated the association between IL10 polymorphisms and BD in Chinese Han.

Methods

407 BD patients and 679 healthy controls were enrolled, and genotyped by Sequenom MassArray system (Sequenom iPLEX assay, San Diego, CA).

Results

The frequency of risk allele of rs1800871 was notably higher in BD patients than in controls (71.9% vs. 66.2%, OR: 1.30, 95%CI: 1.08–1.58, p_c = 0.024). Similarly, rs1518111, which showed strong linkage disequilibrium (r² = 1) with allele rs1800871, was also associated with BD (p_c = 0.026). Rs3021094 was in association with BD in a dominant model (p_c = 0.035), and the haplotype (GACC) formed by rs1518111, rs3021094, rs3790622, and rs1800871 was associated with BD (p_c = 0.023). Results obtained from meta-analysis combined with our data showed that rs1800871 and rs1518111 were associated with BD.

Conclusion

IL10 may be the susceptibility gene for BD in Chinese Han population.