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Objective: To study the telomerase reverse transcriptase (TERT) mutation and the p53 pathway in T1 urinary bladder cancer (UBC). Materials and Methods: This prospectively performed population‐based study included all patients in the Southeast Healthcare Region in Sweden with T1 UBC registered in the period 1992–2001, inclusive. Given that p53 and TERT are important factors for tumour proliferation, although their interrelationships are unknown, we assessed both the TERT and the p53 mutations. Furthermore, we conducted a p53 immunohistochemistry (IHC) analysis using two thresholds for p53 positivity: 10% of tumour cells and 50% of tumour cells (p53 IHC50%). Cox proportional hazards analysis and Kaplan–Meier curves were used to study time to tumour progression. Results: Out of 158 patients, we observed the TERT mutation in 74 (47%), the p53 mutation in 48 (30%), and p53 IHC50% positivity in 72 patients (46%). The TERT mutation was more common in p53 mutation‐positive patients (P = 0.009), and the latter group also had more patients with p53 IHC50%‐positive tumour cells (P = 0.02). In the TERT mutation‐negative tumours a p53‐positive mutation was associated with a shorter time to progression (P = 0.03) compared to patients with p53‐negative mutation. In contrast, in tumours with both TERT mutation positivity and p53 mutation positivity, a longer time to progression was observed in the group with p53 IHC50% positivity compared to the group with p53 IHC50%‐negative tumours. Conclusions: In stage T1 UBC, the combination of the TERT mutation and the p53 mutation was associated with tumour progression. A protective effect of the TERT promotor mutation against tumour progression induced by the p53 mutation and subsequent p53 accumulation in tumour cells might be possible, but further investigations are necessary. [ABSTRACT FROM AUTHOR]

OBJECTIVES:Crohn's disease (CD) is characterized by overproduction of proinflammatory cytokines like interleukin (IL)-1β. Production of mature IL-1β is dependent on a caspase-1-activatingprotein complex called the NALP3 inflammasome, composed of NALP3, ASC, and CARD8. NALP3 shares structural similarities with Nod2, and both of these proteins are required forbacteria-induced IL-1β secretion. The combination of the polymorphisms CARD8 (C10X)and NALP3 (Q705K) was recently shown to be associated with rheumatoid arthritis.Our aim was to investigate whether these combined polymorphisms play a role in the susceptibility to CD.METHODS:The study included 498 CD patients in two cohorts from different regions and 742 control individuals from a Swedish population. DNA was isolated from whole blood. Polymorphisms of (Q705K) NALP3 and (C10X) CARD8, as well as the Nod2 variants, R702W and G908R, were genotyped using the Taqman single nucleotide polymorphism assay. The Nod2 frameshift mutation, L1007fs, was detected by Megabace SNuPe genotyping.RESULTS:Our results show that men who have both the C10X and Q705K alleles in CARD8 and NALP3, and who express wild-type alleles of Nod2 are at an increased risk of developing CD (odds ratio, OR: 3.40 range: 1.32–8.76); P=0.011). No association with these polymorphisms was found in women (OR: 0.89 (range: 0.44–1.77); P=0.74).CONCLUSIONS:We suggest a role for combined polymorphisms in CARD8 and NALP3 in the development of CD in men, with obvious sex differences in the genetic susceptibility pattern. These findings give further support to the importance of innate immune responses in CD.Am J Gastroenterol 2009; 104:1180–1188; doi:10.1038/ajg.2009.29; published online 24 March 2009 [ABSTRACT FROM AUTHOR]

Background: In this study we investigated the association between SNPs in the S100B gene and Parkinson’s disease (PD) in two independent Swedish cohorts. The SNP rs9722 has previously been shown to be associated with higher S100B concentrations in serum and frontal cortex in humans. S100B is widely expressed in the central nervous system and has many functions such as regulating calcium homeostasis, inflammatory processes, cytoskeleton assembly/disassembly, protein phosphorylation and degradation, and cell proliferation and differentiation. Several of these functions have been suggested to be of importance for the pathophysiology of PD. Methods: The SNPs rs9722, rs2239574, rs881827, rs9984765, and rs1051169 of the S100B gene were genotyped using the KASPar® PCR SNP genotyping system in a case-control study of two populations (431 PD patients and 465 controls, 195 PD patients and 378 controls, respectively). The association between the genotype and allelic distributions and PD risk was evaluated using Chi-Square and Cox proportional hazards test, as well as logistic regression. Linear regression and Cox proportional hazards tests were applied to assess the effect of the rs9722 genotypes on age of disease onset. Results: The S100B SNPs tested were not associated with the risk of PD. However, in both cohorts, the T allele of rs9722 was significantly more common in early onset PD patients compared to late onset PD patients. The SNP rs9722 was significantly related to age of onset, and each T allele lowered disease onset with 4.9 years. In addition, allelic variants of rs881827, rs9984765, and rs1051169, were significantly more common in early-onset PD compared to late-onset PD in the pooled population. Conclusions: rs9722, a functional SNP in the 3’-UTR of the S100B gene, was strongly associated with age of onset of PD. [ABSTRACT FROM AUTHOR]

Thiopurines are widely used in the treatment of leukemia and inflammatory bowel diseases. Thiopurine metabolism varies among individuals because of differences in the polymorphic enzyme thiopurine methyltransferase (TPMT, EC 2.1.1.67), and to avoid severe adverse reactions caused by incorrect dosing it is recommended that the patient's TPMT status be determined before the start of thiopurine treatment. This study describes the concordance between genotyping for common TPMT alleles and phenotyping in a Swedish cohort of 12,663 patients sampled before or during thiopurine treatment. The concordance between TPMT genotype and enzyme activity was 94.5%. Compared to the genotype, the first measurement of TPMT enzyme activity was lower than expected for 4.6% of the patients. Sequencing of all coding regions of the TPMT gene in genotype/phenotype discrepant individuals led to the identification of rare and novel TPMT alleles. Fifteen individuals (0.1%) with rare or novel genotypes were identified, and three TPMT alleles (TPMT*42, *43, and *44) are characterized here for the first time. These 15 patients would not have been detected as carrying a deviating TPMT genotype if only genotyping of the most common TPMT variants had been performed. This study highlights the benefit of combining TPMT genotype and phenotype determination in routine testing. More accurate dose recommendations can be made, which might decrease the number of adverse reactions and treatment failures during thiopurine treatment. [ABSTRACT FROM AUTHOR]

• T369M is not associated with PD in Sweden. • T369M was not more common in Swedish patients with early onset. • T369M might be more common in northern/Scandinavian populations. Genetic variants in the Beta-glucocerebrosidase gene (GBA1) is a known risk factor for Parkinson's disease. The GBA1 mutations L444P, N370S and many other have been shown to associate with the disease in populations with diverse background. Some GBA1 polymorphisms have a less pronounced effect, and their pathogenicity has been debated. We have previously found associations with L444P, N370S and E326K and Parkinson's disease in Sweden. In this study we used pyrosequencing to genotype the T369M variant in a large Swedish cohort consisting of 1,131 patients with idiopathic Parkinson's disease, and 1,594 control subjects to evaluate the possibility of this variant conferring an increased risk for Parkinson's disease. The minor allele frequency was 2.15% in patients and 1.76% in controls. Statistical analysis showed that there was no significant difference in allele frequency between patients and control subjects, p-value 0.37, Odds Ratio 1.23 with a 95% confidence interval of 0.82–1.83. Our results suggest that T369M is not a risk factor for Parkinson's disease in the Swedish population. [ABSTRACT FROM AUTHOR]

Several genetic studies have demonstrated an association between mutations in glucocerebrosidase ( GBA ), originally implicated in Gaucher's disease, and an increased risk of Parkinson's disease (PD). We have investigated the possible involvement of genetic GBA variations in PD in the Swedish population. Three GBA variants, E326K, N370S, and L444P were screened in the largest Swedish Parkinson cohort reported to date; 1625 cases and 2025 control individuals. We found a significant association with high effect size of the rare variant L444P with PD (odds ratio 8.17; 95% confidence interval: 2.51–26.23; p -value = 0.0020) and a significant association of the common variant E326K (odds ratio 1.60; 95% confidence interval: 1.16–2.22; p -value = 0.026). The rare variant N370S showed a trend for association. Most L444P carriers (68%) were found to reside in northern Sweden, which is consistent with a higher prevalence of Gaucher's disease in this part of the country. Our findings support the role of GBA mutations as risk factors for PD and point to lysosomal dysfunction as a mechanism contributing to PD etiology. [ABSTRACT FROM AUTHOR]

Objective: Autoantibodies against the adrenal enzyme 21-hydroxylase is a hallmark manifestation in autoimmune Addison's disease (AAD). Steroid 21-hydroxylase is encoded by CYP21A2, which is located in the human leucocyte antigen (HLA) region together with the highly similar pseudogene CYP21A1P. A high level of copy number variation is seen for the 2 genes, and therefore, we asked whether genetic variation of the CYP21 genes is associated with AAD., Design: Case-control study on patients with AAD and healthy controls., Methods: Using next-generation DNA sequencing, we estimated the copy number of CYP21A2 and CYP21A1P, together with HLA alleles, in 479 Swedish patients with AAD and autoantibodies against 21-hydroxylase and in 1393 healthy controls., Results: With 95% of individuals carrying 2 functional 21-hydroxylase genes, no difference in CYP21A2 copy number was found when comparing patients and controls. In contrast, we discovered a lower copy number of the pseudogene CYP21A1P among AAD patients (P = 5 × 10-44), together with associations of additional nucleotide variants, in the CYP21 region. However, the strongest association was found for HLA-DQB1*02:01 (P = 9 × 10-63), which, in combination with the DRB1*04:04-DQB1*03:02 haplotype, imposed the greatest risk of AAD., Conclusions: We identified strong associations between copy number variants in the CYP21 region and risk of AAD, although these associations most likely are due to linkage disequilibrium with disease-associated HLA class II alleles., Competing Interests: Conflict of interest: L.R. has received honorarium for lectures from AstraZeneca and participated in advisory board for UCB. O.K. is a board member of Navinci Diagnostics AB and member of the Scientific Advisory Board for the Leo Foundation Skin Immunology Research Center, University of Copenhagen., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Endocrinology.)

Standard treatment for glioblastoma (GBM) patients is surgery and radiochemotherapy (RCT) with temozolomide (TMZ). TMZ is a substrate for ABCB1, a transmembrane drug transporter. It has been suggested that survival for GBM patients receiving TMZ is influenced by different single-nucleotide variants (SNV) of ABCB1. We therefore examined SNV:s of ABCB1, namely 1199G>A, 1236C>T, 2677G>T/A, and 3435C>T and correlated to survival for GBM patients receiving RCT. In a pilot cohort (97 patients) a significant correlation to survival was found for SNV 1199G>A, with median OS for variant G/G patients being 18.2 months versus 11.5 months for A/G (p = 0.012). We found no correlation to survival for the other SNV:s. We then expanded the cohort to 179 patients (expanded cohort) and also included a confirmatory cohort (49 patients) focusing on SNV 1199G>A. Median OS for G/G versus A/G plus A/A was 15.7 and 11.5 months, respectively (p = 0.085) for the expanded cohort and 13.8 versus 16.8 months (p = 0.19) for the confirmatory. In conclusion, in patients with GBM receiving RCT with TMZ, no correlation with survival was found for the SNV:s 1236C>T, 2677G>T/A, and 3435C>T of ABCB1. Although the SNV 1199G>A might have some impact, a clinically significant role could not be confirmed.

Background: Immunoglobulin G subclass deficiencies (IgGsd) are associated with recurrent respiratory tract infections. Immunoglobulin substitution therapy may be needed to prevent chronic lung tissue damage but tools for identifying the patients that will benefit from this treatment are still insufficient. Some FcγR polymorphisms seem to predispose for an increased risk for infections. In this study we wanted to evaluate if the FcγR-profile differs between individuals with IgGsd and a control population., Methods: Single nucleotide polymorphisms (SNPs) of FcγRIIa, FcγRIIIa and FcγRIIc in 36 IgGsd patients and 192 controls with similar sex and geographical distribution were analyzed by TaqMan allelic discrimination assay or Sanger sequencing., Results: In the IgGsd-group, homozygous frequency for FcγRIIa-R/R131 (low-binding capacity isoform) was higher (p = .03) as well as for non-classical FcγRIIc-ORF (p = .03) and classical FcγRIIc-ORF tended (p = .07) to be more common compared to the controls. There was no difference between the groups regarding FcγRIIIa., Conclusion: The gene for classical FcγRIIc-ORF tended to be more frequent in individuals with immunoglobulin G subclass deficiency and the genes for non-classical FcγRIIc-ORF as well as low-binding capacity receptor FcγRIIa-R/R131 were more frequent. Further studies on the FcγR polymorphisms may pave way for identifying individuals that will benefit from immunoglobulin substitution.

Autoimmune Addison's disease (AAD) is the predominating cause of primary adrenal failure. Despite its high heritability, the rarity of disease has long made candidate-gene studies the only feasible methodology for genetic studies. Here we conducted a comprehensive reinvestigation of suggested AAD risk loci and more than 1800 candidate genes with associated regulatory elements in 479 patients with AAD and 2394 controls. Our analysis enabled us to replicate many risk variants, but several other previously suggested risk variants failed confirmation. By exploring the full set of 1800 candidate genes, we further identified common variation in the autoimmune regulator (AIRE) as a novel risk locus associated to sporadic AAD in our study. Our findings not only confirm that multiple loci are associated with disease risk, but also show to what extent the multiple risk loci jointly associate to AAD. In total, risk loci discovered to date only explain about 7% of variance in liability to AAD in our study population.

Background: The transcription factor Nrf2, encoded by the NFE2L2 gene, is an important regulator of the cellular protection against oxidative stress. Parkinson's disease is a neurodegenerative disease highly associated with oxidative stress. In a previously published study, we reported associations of NFE2L2 haplotypes with risk and age at onset of idiopathic Parkinson's disease in a Swedish discovery material and a Polish replication material. Here, we have extended the replication study and performed meta-analyses including the Polish material and four new independent European patient-control materials. Furthermore, all SNPs included in the haplotype windows were investigated individually for associations with Parkinson's disease in meta-analyses including all six materials., Methods: Totally 1038 patients and 1600 control subjects were studied. Based on previous NFE2L2 haplotype associations with Parkinson's disease, five NFE2L2 tag SNPs were genotyped by allelic discrimination and three functional NFE2L2 promoter SNPs were genotyped by sequencing. The impact of individual SNPs and haplotypes on risk and age at onset of Parkinson's disease were investigated in each material individually and in meta-analyses of the obtained results., Results: Meta-analyses of NFE2L2 haplotypes showed association of haplotype GAGCAAAA, including the fully functional promoter haplotype AGC, with decreased risk (OR = 0.8 per allele, p = 0.012) and delayed onset (+1.1 years per allele, p = 0.048) of Parkinson's disease. These results support the previously observed protective effect of this haplotype in the first study. Further, meta-analyses of the SNPs included in the haplotypes revealed four NFE2L2 SNPs associated with age at onset of Parkinson's disease (rs7557529 G > A, -1.0 years per allele, p = 0.042; rs35652124 A > G, -1.1 years per allele, p = 0.045; rs2886161 A > G, -1.2 years per allele, p = 0.021; rs1806649 G > A, +1.2 years per allele, p = 0.029). One of these (rs35652124) is a functional SNP located in the NFE2L2 promoter. No individual SNP was associated with risk of Parkinson's disease., Conclusion: Our results support the hypothesis that variation in the NFE2L2 gene, encoding a central protein in the cellular protection against oxidative stress, may contribute to the pathogenesis of Parkinson's disease. Functional studies are now needed to explore these results further.

Context: Pheochromocytomas and paragangliomas have a highly diverse genetic background, with a third of the cases carrying a germline mutation in 1 of 14 identified genes., Objective: This study aimed to evaluate next-generation sequencing for more efficient genetic testing of pheochromocytoma and paraganglioma and to establish germline and somatic mutation frequencies for all known susceptibility genes., Design: A targeted next-generation sequencing approach on an Illumina MiSeq instrument was used for a mutation analysis in 86 unselected pheochromocytoma and paraganglioma tumor samples. The study included the genes EGLN1, EPAS1, KIF1Bβ, MAX, MEN1, NF1, RET, SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, and VHL. RESULTS were verified in tumor and constitutional DNA with Sanger sequencing., Results: In all cases with clinical syndromes or known germline mutations, a mutation was detected in the expected gene. Among 68 nonfamilial tumors, 32 mutations were identified in 28 of the samples (41%), including germline mutations in EGLN1, KIF1Bβ, SDHA, SDHB, and TMEM127 and somatic mutations in EPAS1, KIF1Bβ, MAX, NF1, RET, and VHL, including one double monoallelic EPAS1 mutation., Conclusions: Targeted next-generation sequencing proved to be fast and cost effective for the genetic analysis of pheochromocytoma and paraganglioma. More than half of the tumors harbored mutations in the investigated genes. Notably, 7% of the apparently sporadic cases carried germline mutations, highlighting the importance of comprehensive genetic testing. KIF1Bβ, which previously has not been investigated in a large cohort, appears to be an equally important tumor suppressor as MAX and TMEM127 and could be considered for genetic testing of these patients.

Cystinuria is an autosomal recessive disorder characterized by increased urinary excretion of cystine and dibasic amino acids, which cause recurrent stone formation in affected individuals. Three subtypes of cystinuria have been described (type I, II, and III): type I is caused by mutations in the SLC3A1 gene, whereas nontype I (II and III) has been associated with SLC7A9 mutations. Of the 53 patients reported in our previous work, patients that showed SLC7A9 mutations in single-strand conformation polymorphism (SSCP) screening and/or either lacked or showed heterozygosity for SLC3A1 mutations were included in the present study. The entire coding region and the exon/intron boundaries of the SLC7A9 gene were analyzed by means of both SSCP and DNA sequencing in 16 patients, all but one of which were clinically diagnosed as homozygous cystinurics. Three novel SLC7A9 mutations were identified in the patient group: two missense mutations (P261L and V330M), and one single base-pair deletion (1009 delA). We also detected the previously reported A182T and nine novel polymorphisms in the patients. Mutations V330M and 1009delA occurred on different alleles in one individual, and we suggest that these mutations cause cystinuria in this patient. One patient that was homozygously mutated in the SLC3A1 gene carried the third novel mutation (P261L). We conclude that SLC3A1 is still the major disease gene among Swedish cystinuria patients, with only a minor contribution of SLC7A9 mutations as the genetic basis of cystinuria. The absence of SLC3A1 and SLC7A9 mutations in a substantial proportion of the patients implies that mutations in parts of the genes that were not analyzed may be present, as well as large deletions that escape detection by the methods used. However, our results raise the question of whether other, as yet unknown genes, may also be involved in cystinuria.