Long‐term course of oxaliplatin‐induced polyneuropathy: a prospective 2‐year follow‐up study

This prospective study sought to identify the potential reversibility of oxaliplatin‐induced peripheral neuropathy (OXAIPN) by following‐up its long‐term course 2 years after discontinuation of oxaliplatin (OXA)‐based chemotherapy. Participants were 91 colorectal cancer patients treated with OXA‐based chemotherapy. Neurological assessment, clinical Total Neuropathy Score© (TNSc©) and nerve conduction studies were performed at baseline (T0), the end of chemotherapy (T1) and 2 years (T2) after discontinuation of chemotherapy. A total of 73 of 91 (80%) patients experienced OXAIPN at T1. At a median follow‐up of 25 months, persistence of chronic OXAIPN was present in 61 of 73 patients (84%) and complete resolution was present in 12 patients (17%). Longitudinal comparison of TNSc© values between T1 and T2 revealed that the overall severity of OXAIPN in those 61 patients significantly decreased over time. Median TNSc© values were nine (range: 2–15) at T1 vs. four (range: 2–12) at T2 (P < 0.001). Likewise, sensory nerve conduction measures at T2 significantly improved in all sensory nerves tested, compared with T1. Severity of OXAIPN at T2 was significantly associated (P < 0.001) with high severity of OXAIPN at T1. In conclusion, persistence of OXAIPN beyond 2 years after finishing chemotherapy is common. Clinical and neurophysiological improvement is observed, although recovery is often incomplete.     

Rasch‐Transformed Total Neuropathy Score clinical version (RT‐TNSc©) in patients with chemotherapy‐induced peripheral neuropathy

Composite scales such as the Total Neuropathy Score clinical version (TNSc^©) have been widely used to measure neurological impairment in a standardized manner but they have been criticized due to their ordinal setting having no fixed unit. This study aims to improve impairment assessment in patients with chemotherapy‐induced peripheral neuropathy (CIPN) by subjecting TNSc^© records to Rasch analyses. In particular, we wanted to investigate the influence of factors affecting the use of the TNSc^© in clinical practice. TNSc^© has 7 domains (sensory, motor, autonomic, pin‐prick, vibration, strength, and deep tendon reflexes [DTR]) each being scored 0–4. Data obtained in 281 patients with stable CIPN were subjected to Rasch analyses to determine the fit to the model. The TNSc^© did not meet Rasch model's expectations primarily because of misfit statistics in autonomic and DTR domains. Removing these two, acceptable model fit and uni‐dimensionality were obtained. However, disordered thresholds (vibration and strength) and item bias (mainly cultural) were still seen, but these findings were kept to balance the assessment range of the Rasch‐Transformed TNSc^© (RT‐TNSc^©). Acceptable reliability findings were also obtained. A 5‐domains RT‐TNSc^© may be a more proper assessment tool in patients with CIPN. Future studies are needed to examine its responsive properties.     

Oxaliplatin rechallenge in metastatic colorectal cancer patients with clinically significant oxaliplatin‐induced peripheral neurotoxicity

We investigated whether rechallenge with oxaliplatin (OXA) can worsen the pre‐existing oxaliplatin‐induced peripheral neurotoxicity (OXAIPN) in metastatic colorectal cancer (mCRC) patients. Patients previously treated with OXA, having clinically significant grade 1 or 2 OXAIPN were assessed, after receiving rechallenge with OXA, using the clinical version of the Total Neuropathy Score (TNSc). Peripheral neuropathy was assessed at the end of first OXA exposure and at completion of OXA rechallenge. The first line OXA‐based chemotherapy was completed at least 9 months earlier (OXA‐free interval). We studied 25 mCRC patients, 14 males and 11 females, with a median age of 63 (35‐77) years. After their first exposure to OXA‐based chemotherapy, 9 (36%) patients developed grade 1 OXAIPN and 16 patients grade 2 (64%) neurotoxicity. OXA reintroduction with a median of 10 (8‐14) cycles led to grade 1 OXAIPN in two patients (8%), grade 2 in 19 patients (76%), and grade 3 neuropathy in 4 (16%) patients Worsening of pre‐existing OXAIPN was documented in seven (28%) patients and was significantly associated with higher OXA delivered cumulative dose (P < .001). Median TNSc scores following treatment (10; range 4‐18) were significantly increased (P < .001), when compared to the scores recorded at the end of first line treatment (8; range 2‐12). Rechallenging OXA appears to relatively worsen the severity of existing OXAIPN. However, the majority of rechallenged patients developed a clinically significant (grade 2) OXAIPN, rather than treatment‐emergent grade 3. As such, OXA rechallenge might be a feasible option in patients previously having OXAIPN.     

Association between Parkinson's disease and the HLA‐DRB1 locus

Two genome‐wide association studies (GWASs) recently highlighted the HLA‐DRA and HLA‐DRB5 genes as associated with Parkinson disease (PD). However, because HLA‐DRA displays a low level of polymorphisms and HLA‐DRB5 is only present in approximately 20% of the population, these findings are difficult to interpret. Our aims were: (1) to replicate and investigate in greater detail the association between PD and the HLA‐DR region; (2) to identify PD‐associated HLA alleles; and (3) to perform a meta‐analysis of our top finding. As part of 2 French population‐based case–control studies of PD including highly ethnically homogeneous participants, we investigated the association between PD and 51 Single‐nucleotide polymorphisms (SNPs) in the HLA‐DR region. HLA‐DRB1 alleles were imputed using the HLA^*IMP software. HLA typing was performed in a subsample of the participants. We performed a meta‐analysis of our top finding based on 4 GWAS data sets. Among 499 cases and 1123 controls, after correction for multiple testing, we found an association with rs660895 (OR/minor allele, 0.70; 95% CI, 0.57–0.87) within the HLA‐DRB1 gene, which encodes the most polymorphic HLA‐DR chain (DRβ). A meta‐analysis (7996 cases, 36455 controls) confirmed this association (OR, 0.86; 95% CI, 0.82–0.91; P < .0001). SNP‐based imputation of HLA alleles showed an inverse association between PD and the HLA‐DRB1^*04 allele. We replicated an association between PD and the HLA‐DR region and provided further insight into the loci and alleles involved. The highly polymorphic HLA‐DRB1 locus contains rs660895, which represents a more legitimate candidate than previous ones. Our finding is in agreement with the hypothesis of an immune component in PD pathophysiology. © 2012 Movement Disorder Society     

Liability of the voltage‐gated potassium channel KCNN3 repeat polymorphism to acute oxaliplatin‐induced peripheral neurotoxicity

Thus far, there are conflicting results on the causal role of K+ channels in the pathogenesis of acute oxaliplatin‐induced peripheral neurotoxicity (OXAIPN). As such, we tested the hypothesis that the voltage‐gated K+ channel KCNN3 repeat polymorphism confers liability to acute OXAIPN. DNA from 151 oxaliplatin‐treated patients for colorectal cancer was extracted and genotyped. The incidence of acute OXIPN was measured by the OXA‐neuropathy questionnaire, while the severity of acute OXAIPN was scored basing on the number of symptoms reported by the patients at each clinical assessment. The increased number of acute symptoms was considered as being suggestive of an increased severity of acute OXAIPN. A total of 130/151 (86.1%) patients developed any grade of acute OXAIPN. Grade I acute neurotoxicity was revealed in 43 (28.5%) patients; grade II in 34 (22.5%); and grade III in 53 (53.1%) patients. Genotyping revealed alleles carrying 11 to 20 CAG repeats. The majority of patients were heterozygous (131; 89.4%). The most common numbers of CAG repeats were 15 (n = 46), 16 (n = 53), and 17 (n = 95). Patients carrying alleles with either 15 to 17 CAG repeats (P = .601) did not experience a higher incidence of grade III (treatment‐emergent) acute OXAIPN. Likewise, no increased incidence of acute treatment‐emergent OXAIPN was noted in heterozygous patients carrying either two short alleles (<19 CAG repeats) or one short and one long (≥19 CAG repeats) allele (P = .701). Our results do not support a causal relationship between the KCNN3CAG repeat polymorphism and acute OXΑIPN.     

Evidence for cis‐acting regulation of ANK3 and CACNA1C gene expression

Quinn EM, Hill M, Anney R, Gill M, Corvin AP, Morris DW. Evidence for cis‐acting regulation of ANK3 and CACNA1C gene expression.
Bipolar Disord 2010: 12: 440–445. © 2010 The Authors. Journal compilation © 2010 John Wiley & Sons A/S. Objectives: Genome‐wide association studies (GWAS) have identified Ankyrin‐G (ANK3) and the α‐1C subunit of the L‐type voltage‐gated calcium channel (CACNA1C) as susceptibility genes for bipolar disorder. Available biological information on these genes suggests a potential molecular mechanism involving ion channel dysfunction. The associated single nucleotide polymorphisms (SNPs) at ANK3 (rs10994336) and CACNA1C (rs1006737) are both intronic with no obvious impact on gene function. We investigated whether, instead of affecting protein function, these risk variants might impact on gene regulation affecting expression. Methods: We have done this by testing for allelic expression imbalance (AEI) to identify cis‐acting regulatory polymorphisms. Results: We identified evidence of cis‐acting variation at both loci in HapMap Caucasian Europeans from Utah (CEU) lymphoblastoid cell lines. There was considerable evidence of AEI at ANK3 with more than half of all heterozygous samples (21 out of 34) for marker SNP rs3750800 showing AEI and a small number of samples showing near monoallelic expression. The AEI at either gene could not be attributed to the GWAS‐associated SNPs. Conclusions: These data indicate that there is genetic variation local to both genes affecting their expression, but that this variation is not responsible for increasing risk of bipolar disorder.     

Real world,open label experience with lacosamide against acute painful oxaliplatin‐induced peripheral neurotoxicity

We report the outcome of a pilot, open‐label study that tested the potential of lacosamide (200 mg/bi.d) as an effective and safe symptomatic treatment against acute painful oxaliplatin‐induced peripheral neurotoxicity (OXAIPN). Lacosamide was introduced in 18 colorectal cancer patients with evidence of clinically significant acute, painful OXAIPN after infusion of the third course (T1) of oxaliplatin‐based chemotherapy (FOLFOX4) and was maintained until completion of all 12 courses (T4). The OXA‐Neuropathy Questionnaire (OXA‐NQ) was used to record the severity of acute OXAIPN; the PI‐NRS estimated the severity of neuropathic pain, while the chronic OXAIPN was graded with TNSc. The EuroQOL ( EQ‐5D) instrument was also applied. The Patient Global Impression of Change (PGIC) scale measured the lacosamide‐attributed perception of change. LCM‐responders were considered those with ≥50% reduction in PI‐NRS and OXA‐NQ scores at T4, compared to T1. Patients experienced on T1 a median number of acute OXAIPN symptoms of 4 and had a median neuropathic pain severity score of 6, which was strongly related to lower quality of life, according to EQ‐VAS (P < .001). At T4, 12 patients (66.7%) were classified as responders. A significant clinical improvement was documented in the severity of acute OXAIPN and neuropathic pain in relation to lacosamide (P < .001) at T4 compared to T1, which was associated with improved EQ‐VAS scores (P < .001). Twelve patients scored PGIC ≥5 (lacosamide‐attributed) at T4. There were no incidences of early drop‐outs for safety reasons. Lacosamide appears to be an effective and well‐tolerated symptomatic treatment against acute, painful OXAIPN.     

Fever is associated with doubling of odds of short‐term mortality in ischemic stroke: an updated meta‐analysis

Prasad K, Krishnan PR. Fever is associated with doubling of odds of short‐term mortality in ischemic stroke: an updated meta‐analysis.
Acta Neurol Scand: 2010: 122: 404–408.
© 2010 The Authors Journal compilation © 2010 Blackwell Munksgaard. Objective – Association between fever and ischemic stroke mortality is known, but the magnitude and independence of the association is controversial. This paper aims to determine the size of independent effect of fever on short term mortality in acute ischemic stroke. Methods – We searched the Medline and Cochrane library databases for papers studying the relationship between fever in acute ischemic stroke and short term mortality from January, 1990 to November, 2008. Two authors independently selected the studies for inclusion in the review using explicit criteria. Data was entered into software Revman 4.2.8. Heterogeneity was assessed using I² and chi‐square statistics. Odds ratios (OR) from logistic regression were combined. Magnitude of association was determined using meta‐analysis of the adjusted odds ratio using fixed effects model. Results – Six cohort studies involving 2986 patients were included. There was no significant heterogeneity among studies reporting short‐term mortality (I² = 21.2%, P = 0.28). Meta‐analysis yielded a combined OR of 2.20 (95% CI 1.59–3.03, P < 0.00001). Conclusions – This meta‐analysis suggests that fever within first 24 h of hospitalization in patients with ischemic stroke is associated with doubling of odds of mortality within one month of the onset of stroke.     

Genetic predisposition in anti‐LGI1 and anti‐NMDA receptor encephalitis

We performed a genome‐wide association study in 1,194 controls and 150 patients with anti‐N‐methyl‐D‐aspartate receptor (anti‐NMDAR, n = 96) or anti‐leucine‐rich glioma‐inactivated1 (anti‐LGI1, n = 54) autoimmune encephalitis. Anti‐LGI1 encephalitis was highly associated with 27 single‐nucleotide polymorphisms (SNPs) in the HLA‐II region (leading SNP rs2858870 p = 1.22 × 10^?17, OR = 13.66 [7.50–24.87]). Potential associations, below genome‐wide significance, were found with rs72961463 close to the doublecortin‐like kinase 2 gene (DCLK2) and rs62110161 in a cluster of zinc‐finger genes. HLA allele imputation identified association of anti‐LGI1 encephalitis with HLA‐II haplotypes encompassing DRB1*07:01, DQA1*02:01 and DQB1*02:02 (p < 2.2 × 10^?16) and anti‐NMDAR encephalitis with HLA‐I allele B*07:02 (p = 0.039). No shared genetic risk factors between encephalitides were identified. Ann Neurol 2018;83:863–869     

The interleukin‐1 cluster gene region is associated with multiple sclerosis in an Italian Caucasian population

Background: Polymorphisms of the interleukin‐1 (IL‐1) gene family have been proposed as potential variants for different diseases including multiple sclerosis (MS). With respect to MS, IL‐1 beta (?511 C/T; rs16944), IL‐1 beta (+3954 C/T; rs1143634), IL‐1 alpha (?889 C/T; rs1800587), IL‐1 alpha (+4845 G/T; rs17561), and the variable number of tandem repeats in intron 2 of the IL‐1 receptor antagonist (IL‐1RN) gene polymorphisms have been studied in different ethnic groups, leading to conflicting results. Methods: This study investigates the association between IL‐1 genes and MS by means of 70 markers spanning the 1.1 Mb region where the IL‐1 genes map and exploring both the linkage disequilibrium (LD) and the haplotype structure in a case–control design including 410 subjects (160 patients and 250 controls). Results: From allelic/genotypic tests, significant association was found for several polymorphisms including the IL‐1 beta (?511 C/T) variant (P‐adjusted = 4.5 × 10^?4) and some polymorphisms around the IL‐1RN gene. The ‘block‐step’ pattern obtained from both the LD map and pairwise analysis identifies four LD regions. Region 1 showed a significant association with MS for the global test (P < 0.0001) and haplotypes containing the IL‐1 beta (?511 C/T) variant still demonstrate highly significant association with disease (P‐value range: 9.9 × 10^?5 to 0.02). Conclusions: Our findings support the existence of a causative variant for MS within this candidate region in a representative Italian Caucasian population and, in particular, the role of the IL‐1 beta (?511 C/T) variant warrants further investigation.     

Association studies of 19 candidate SNPs with sporadic Alzheimer’s disease in the North Chinese Han population

Genome-wide association studies (GWAS) identified multiple single-nucleotide polymorphisms (SNPs) that are associated with the pathogenesis of Alzheimer's disease (AD). As replication in independent studies remains the only way to validate proposed GWAS signals, we detect SNPs reported in the GWAS, in order to explore their association with sporadic AD (SAD) in the Chinese population. We analyzed genotype and allele distributions of 19 SNPs reported in GWAS in 191 SAD patients and 180 healthy controls. We found that higher frequencies of rs10868366 G and rs7019241 C carriers were observed in SAD patients compared with controls (rs10868366 G: P?=?0.026, odds ratio (OR)?=?1.4, 95% confidence intervals (CI) 1.0-1.9; rs7019241 C: P?=?0.019, OR 1.4, 95% CI 1.6-1.9). Furthermore, rs10868366 G/T and rs7019241 C/T in GOLPH2 were in strong linkage disequilibrium and formed a relative protective factor rs10868366 T/rs7019241 T and a relative risk factor rs10868366 G/rs7019241 C. For SNP rs3826656 in near gene 5' region of CD33, the results revealed that in subjects with APOE ε4 alleles, the A allele was associated with a reduced risk of SAD compared with the G allele (OR 0.479; 95% CI 0.263-0.870, P?=?0.015), and AA genotype was associated with a reduced risk of SAD compared with the genotype AG?+?GG (OR 0.395; 95% CI 0.158-0.659, P?=?0.008). Our results support the view that rs10868366 and rs7019241 in GOLPH2 and rs3826656 in near gene 5' region of CD33 are significantly associated with SAD in the north Chinese Han population.     

Variants in estrogen‐related genes and risk of Parkinson's disease

Incidence rates of Parkinson's disease are higher in men than in women at all ages, and these differences may be a result of the neuroprotective effects of estrogen on the nigrostriatal pathway. We investigated the association of common variants in 4 estrogen‐related genes with Parkinson's disease. Tagging single‐nucleotide polymorphisms in the CYP19A1, ESR1, ESR2, and PRDM2 genes were selected from the International Haplotype Map and genotyped in 1103 Parkinson's disease cases from the upper Midwest of the United States and in 1103 individually matched controls (654 unaffected siblings, and 449 unrelated controls from the same region). Of 137 informative single‐nucleotide polymorphisms, 2 PRDM2 single‐nucleotide polymorphisms were significantly associated with an increased risk of Parkinson's disease at the Bonferroni‐corrected significance level of 0.0004 (rs2744690: OR, 1.54; SE(logOR), .109; 99.96% CI, 1.05–2.26; uncorrected P = .0001; rs2744687: OR, 1.53; SE(logOR), .113; 99.96% CI, 1.03–2.29, uncorrected P = .0002); the association was significant in the women‐only stratum but not in the men‐only stratum. An additional 6 single‐nucleotide polymorphisms in PRDM2, 2 in ESR1, 1 in ESR2, and 1 in CYP19A1 had significant P values in the overall sample before Bonferroni correction. None of the single‐nucleotide polymorphisms were significantly associated with age at onset of Parkinson's disease after Bonferroni correction. Our results confirm the association of PRDM2 variants with Parkinson's disease susceptibility, especially in women. © 2011 Movement Disorder Society     

Suggestive evidence for association between L‐type voltage‐gated calcium channel (CACNA1C) gene haplotypes and bipolar disorder in Latinos: a family‐based association study

Objectives: Through recent genome‐wide association studies (GWASs), several groups have reported significant association between variants in the calcium channel, voltage‐dependent, L‐type, alpha 1C subunit (CACNA1C) and bipolar disorder (BP) in European and European‐American cohorts. We performed a family‐based association study to determine whether CACNA1C is associated with BP in the Latino population. Methods: This study included 913 individuals from 215 Latino pedigrees recruited from the USA, Mexico, Guatemala, and Costa Rica. The Illumina GoldenGate Genotyping Assay was used to genotype 58 single‐nucleotide polymorphisms (SNPs) that spanned a 602.9‐kb region encompassing the CACNA1C gene including two SNPs (rs7297582 and rs1006737) previously shown to associate with BP. Individual SNP and haplotype association analyses were performed using Family‐Based Association Test (version 2.0.3) and Haploview (version 4.2) software. Results: An eight‐locus haplotype block that included these two markers showed significant association with BP (global marker permuted p = 0.0018) in the Latino population. For individual SNPs, this sample had insufficient power (10%) to detect associations with SNPs with minor effect (odds ratio = 1.15). Conclusions: Although we were not able to replicate findings of association between individual CACNA1C SNPs rs7297582 and rs1006737 and BP, we were able to replicate the GWAS signal reported for CACNA1C through a haplotype analysis that encompassed these previously reported significant SNPs. These results provide additional evidence that CACNA1C is associated with BP and provides the first evidence that variations in this gene might play a role in the pathogenesis of this disorder in the Latino population.     

Re‐sequencing of ankyrin 3 exon 48 and case‐control association analysis of rare variants in bipolar disorder type I

Doyle GA, Lai AT, Chou AD, Wang M‐J, Gai X, Rappaport EF, Berrettini WH. Re‐sequencing of ankyrin 3 exon 48 and case‐control association analysis of rare variants in bipolar disorder type I. Bipolar Disord 2012: 14: 809–821. © 2012 The Authors. Journal compilation © 2012 John Wiley & Sons A/S. Objectives: Genome‐wide association studies (GWAS) recently identified ankyrin 3 (ANK3) as a candidate gene for bipolar disorder type I (BPD‐I). Because the GWAS suggested multiple common haplotypes associated with BPD‐I (with odds ratio ～1.3), we hypothesized that rare variants within these common haplotypes might increase risk for BPD‐I. Methods: We undertook a project in which the serine‐rich domain–tail domain (SRD‐TD)‐encoding exon of ANK3 was amplified from genomic DNA (gDNA) of 384 BPD‐I patients and re‐sequenced by next generation sequencing (NGS; SOLiD?). Results: We confirmed 18 novel mis‐sense rare variants and one novel insertion/deletion variant within the SRD‐TD exon, many of which change amino acid residues with extremely high evolutionary conservation. We genotyped most of these mis‐sense variants in ≥ 1000 BPD‐I and ≥ 1000 control individuals. We found no statistically significant association of any of the rare variants detected with BPD‐I. Conclusions: Thus, we conclude that rare variants within the re‐sequenced structural domains of ANK3 exon 48 do not contribute to BPD‐I.     

Integrin beta‐3 L33P: a new insight into the pathogenesis of chronic oxaliplatin‐induced peripheral neuropathy?

Aim: To assess the significance of the ITGB3 polymorphism at residue 33 (ITGB3 L33P) in the development of chronic oxaliplatin‐induced peripheral neuropathy (OXLIPN). Methods: Fifty‐five patients with advanced colorectal cancer were genotyped, using allele‐specific primers and sybr green in real‐time PCR. Patients had received adjuvant oxaliplatin‐based chemotherapy. The severity of the OXLIPN was defined by means of the clinical total neuropathy score (TNSc). Following the discontinuation of treatment, 34/55 patients (61.8%) developed OXLIPN. Grade I neurotoxicity was revealed in 13 (38.2%) patients and grade II neurotoxicity in 21 (61.8%) patients. Results: Patients without OXLIPN (n = 21) were 19% homozygous for C, 33.3% were heterozygous, and 47.7% were homozygous for T. The corresponding percentages for patients developing any grade of OXLIPN (n = 34) were similar. About half of patients (46.1%) with grade I OXLIPN were heterozygotes (CT), 23.1% were CC, and 30.8% were TT. The majority of patients with grade II OXLIPN were TT (66.7%) with the remaining 33.3% being CT. The TT genotype was associated with increased severity of OXLIPN compared to the genotypes containing the C allele (P = 0.044). Conclusion: The ITGB3 L33P seems to be unrelated to the development of OXLIPN, but it appears to be related to its severity.     

Replication of MAPT and SNCA,but not PARK16‐18, as susceptibility genes for Parkinson's disease

Recent genome‐wide association studies of Parkinson's disease have nominated 3 new susceptibility loci (PARK16‐18) and confirmed 2 known risk genes (MAPT and SNCA) in populations of European ancestry. We sought to replicate these findings. We genotyped single‐nucleotide polymorphisms in each of these genes/loci in 1445 Parkinson's disease patients and 1161 controls from northern Spain. Logistic regression was used to test for association between genotype and Parkinson's disease under an additive model, adjusting for sex, age, and site. We also performed analyses stratified by age at onset. Single‐nucleotide polymorphisms in MAPT (rs1800547; P = 3.1 × 10^?4) and SNCA (rs356219; P = 5.5 × 10^?4) were significantly associated with Parkinson's disease. However, none of the markers in PARK16‐18 associated with Parkinson's disease in the overall sample, or in any age stratum, with P values ranging from .09 to .88. Although our data further validate MAPT and SNCA as Parkinson's disease susceptibility genes, we failed to replicate PARK16, PARK17, and PARK18. Potential reasons for the discordance between our study and previous genome‐wide association studies include effects of population structure, power, and population‐specific environmental interactions. Our findings suggest that additional studies of PARK16‐18 are necessary to establish the role of these loci in modifying risk for Parkinson's disease in European‐derived populations. © 2011 Movement Disorder Society     

HLA‐B*15:02 association with carbamazepine‐induced Stevens‐Johnson syndrome and toxic epidermal necrolysis in an Indian population: a pooled‐data analysis and meta‐analysis

This study aimed to investigate the prevalence and association of HLA‐B*15:02 with carbamazepine‐induced Stevens‐Johnson syndrome and toxic epidermal necrolysis (CBZ‐SJS/TEN) in the Indian population in Malaysia, which mostly originated from Southern India. HLA‐B alleles in five Indian case patients with CBZ‐SJS/TEN and 52 CBZ‐tolerant controls, and followed by a pooled sample of seven cases from two centers in Malaysia were analyzed. Positive association for HLA‐B*15:02 with CBZ‐SJS/TEN was detected in Indians (40% [2/5] vs. 3.8% [2/52], odds ratio [OR] 16.7, p = 0.0349), of which 80% (4/5) of the Indian patients originated from Southern India. A pooled sample of seven cases showed stronger association between HLA‐B*15:02 and CBZ‐SJS/TEN (57.1% [4/7] vs. 3.8% [2/52], OR 33.3, 95% confidence interval [CI] 4.25–162.21, p = 1.05 × 10^?3). Subsequent meta‐analysis on Indians from Malaysia and India further demonstrated a significant and strong association between HLA‐B*15:02 and CBZ‐SJS/TEN (OR 38.54; 95% CI 6.83–217.34, p < 1.0 × 10^?4). Our study is the first on Indians predominantly from Southern India that demonstrated HLA‐B*15:02 as a strong risk factor for CBZ‐SJS/TEN despite a low population allele frequency. This stressed the importance of testing for HLA‐B*15:02, irrespective of the ancestral background, including populations with low allele frequency.     

Leukoaraiosis is associated with genes regulating blood–brain barrier homeostasis in ischaemic stroke patients

Background: The biologic agents causing leukoaraiosis are unknown. Our aim was to study the genetic basis of leukoaraiosis. Methods: We analyzed 212 single nucleotide polymorphisms (SNPs) in 142 patients with ischaemic stroke, generating a total of 30 104 genotypes. Seventy‐nine subjects (55.6%) presented leukoaraiosis measured by the Fazekas scale and 69 (48.6%) by ARWMC scale. We analyzed the presence of synergic associations between SNPs using the hfcc software. Finally, functional studies were performed in 56 subjects. The Ingenuity Pathways software (ipa ) was used to examine the role of the identified genes. Results: Six SNPs were associated with leukoaraiosis using both measuring scales. After logistic regression adjusted for leukoaraiosis risk factors, the rs2252070 of MMP13 (OR = 4.9, 95%CI: 1.34–17.9, P = 0.016), rs662 of PON1 (OR = 0.37, 95%CI: 0.15–0.87, P = 0.024) and rs1800779 of NOS3 (OR = 3.9, 95%CI: 1.38–11.38, P = 0.01) were independently associated with leukoaraiosis under a dominant/recessive model and the rs2290608 of IL5RA (OR = 0.46, 95%CI: 0.25–0.85, P = 0.013) and rs669 of A2M (OR = 2.5, 95%CI: 1.36–4.83, P = 0.004) under an additive model. Computational analysis showed a synergic association of rs10497212‐AA of ITGB6 and rs2290608‐GG of IL5RA with leukoaraiosis using both scales. (i) ARWMC (P = 1.3 × 10⁻⁴) and (ii) Fazekas (P = 4.5 × 10⁻⁵). Functional studies showed that the rs669 SNP was associated with plasma levels of A2M (P = 0.012) and A2M levels with leukoaraiosis in Fazekas scale (P = 0.02). ipa analysis revealed that the genes associated with leukoaraiosis were involved in blood–brain barrier (BBB) homeostasis. Conclusions: Amongst patients with ischaemic stroke, several genes associated with BBB homeostasis could be involved with a higher risk of leukoaraiosis.     

COMT polymorphisms as predictors of cognitive dysfunction during manic and mixed episodes in bipolar I disorder

Soeiro‐de‐Souza MG, Machado‐Vieira R, Soares Bio D, Do Prado CM, Moreno RA. COMT polymorphisms as predictors of cognitive dysfunction during manic and mixed episodes in bipolar I disorder. Bipolar Disord 2012: 14: 554–564. © 2012 The Authors.
Journal compilation © 2012 John Wiley & Sons A/S. Objective: The dopaminergic system plays an important role in the prefrontal cortex (PFC) and is believed to mediate cognitive dysfunction (CD) in bipolar disorder (BD). The enzyme catechol‐O‐methyltransferase (COMT) is involved in the catabolism of dopamine in the PFC, and an association between COMT single nucleotide polymorphisms (SNPs) and BD has been reported. COMT SNPs have also been associated with executive and working memory performance in healthy subjects, patients with schizophrenia, and euthymic BD patients. The objective of this study was to investigate the association between COMT SNPs and acute CD during BD mood episodes. Methods: Seventy‐two symptomatic, medication‐free subjects with bipolar I disorder (BD‐I) and 76 healthy controls were evaluated using neuropsychological tests, and genotyped for COMT SNPs rs4680 and rs165599. Results: Patients undergoing mania and mixed episodes carrying the COMT allele G had better performance on executive function, memory, verbal fluency, and intelligence tests. Moreover, an interaction was detected between the COMT allele G and the Young Mania Rating Scale in BD CD. Conclusions: Allele G from COMT SNPs rs4680 and rs165599 may represent reliable state‐dependent predictors of global CD during manic and mixed episodes in BD. Further studies in larger samples are necessary to confirm these findings.     

GWAS-Supported <Emphasis Type="Italic">CRP</Emphasis> Gene Polymorphisms and Functional Outcome of Large Artery Atherosclerotic Stroke in Han Chinese

Elevated C-reactive protein (CRP) levels increase the risk of poor functional disability in patients with ischemic stroke (IS). This study aimed to investigate the association between CRP gene polymorphisms and 3-month functional disability of large artery atherosclerotic (LAA) stroke in Han Chinese. Patients with first-ever LAA IS were prospectively enrolled in Nanjing Stroke Registry Program between August 2013 and October 2015. Five single-nucleotide polymorphisms (SNPs) (rs876537, rs2794520, rs3093059, rs7553007 and rs11265260) in CRP gene related to CRP levels in Asian by genome-wide association study were genotyped. The functional outcome at 3 months after the index stroke was assessed by the modified Rankin scale. Associations between genotypes and functional outcome of LAA IS were analyzed with logistic regression model. A total of 690 eligible patients (507 males) were evaluated. SNPs rs11265260 (multivariate-adjusted, p?=?0.022), rs2794520 (multivariate-adjusted, p?=?0.036) and rs3093059 (multivariate-adjusted, p?=?0.027) were significantly associated with elevated CRP in acute IS. Two SNPs, rs3093059 (dominant model: adjusted OR 2.49; 95% CI 1.55–4.00; recessive model: adjusted OR 3.67; 95% CI 1.22–11.03) and rs11265260 (dominant model: adjusted OR 2.51; 95% CI 1.56–4.02; recessive model: adjusted OR 4.70; 95% CI 1.63–13.56) independently predicted 3-month poor outcome of first-ever LAA IS, after adjusting for covariates. In addition, haplotype analysis indicated that haplotype GCTGC (adjusted OR 1.76; 95% CI 1.05–2.95; p?=?0.031) increased the poor outcome risk. SNPs rs3093059 and rs11265260 in CRP gene may influence the 3-month functional outcome of first-ever LAA IS in Han Chinese.