Two four-marker haplotypes on 7q36.1 region indicate that the potassium channel gene HERG1 (KCNH2, Kv11.1) is related to schizophrenia: a case control study

<p>Abstract</p> <p>Background</p> <p>The pathobiology of schizophrenia is still unclear. Its current treatment mainly depends on antipsychotic drugs. A leading adverse effect of these medications is the acquired long QT syndrome, which results from the blockade of cardiac HERG1 channels (human ether-a-go-go-related gene potassium channels 1) by antipsychotic agents. The HERG1 channel is encoded by <it>HERG1 </it>(<it>KCNH2</it>, <it>Kv11.1</it>) gene and is most highly expressed in heart and brain. Genetic variations in <it>HERG1 </it>predispose to acquired long QT syndrome. We hypothesized that the blockade of HERG1 channels by antipsychotics might also be significant for their therapeutic mode of action, indicating a novel mechanism in the pathogenesis of schizophrenia.</p> <p>Methods</p> <p>We genotyped four single nucleotide polymorphisms (SNPs) in 7q36.1 region (two SNPs, rs1805123 and rs3800779, located on <it>HERG1</it>, and two SNPs, rs885684 and rs956642, at the 3'-downstream intergenic region) and then performed single SNP and haplotype association analyses in 84 patients with schizophrenia and 74 healthy controls after the exclusion of individuals having prolonged or shortened QT interval on electrocardiogram.</p> <p>Results</p> <p>Our analyses revealed that both genotype and allele frequencies of rs3800779 (c.307+585G>T) were significantly different between populations (<it>P </it>= 0.023 and <it>P </it>= 0.018, respectively). We also identified that two previously undescribed four-marker haplotypes which are nearly allelic opposite of each other and located in chr7:150225599-150302147bp position encompassing <it>HERG1 </it>were either overrepresented (A-A-A-T, the at-risk haplotype, <it>P </it>= 0.0007) or underrepresented (C-A-C-G, the protective haplotype, <it>P </it>= 0.005) in patients compared to controls.</p> <p>Conclusions</p> <p>Our results indicate that the potassium channel gene <it>HERG1 </it>is related to schizophrenia. Our findings may also implicate the whole family of HERG channels (HERG1, HERG2 and HERG3) in the pathogenesis of psychosis and its treatment.</p

Intronic variants in the long non-coding RNA CDKN2B-AS1 are strongly associated with the risk of coronary artery disease in the Northern Tribes of Tanzania

Introduction: Sub-Saharan Africa (SSA) is facing a rising epidemic of non-communicable diseases including the coronary artery disease (CAD) ranking at the top of the list. Chromosome locus 9p21.3 containing CDKN2B antisense RNA 1 (CDKN2B-AS1), identified in many genome-wide association studies for coronary artery disease (CAD), encompasses multiple single nucleotide polymorphisms (SNPs). This study aimed to conduct the first genetic study evaluating the common polymorphisms in 9p21.3 locus in Tanzanian CAD patients from different regions of Tanzania and their associations with CAD risk factors. Material and Methods: A total of 90 patients from Northern region (N-CAD) of Tanzania and 65 patients from other regions (South, East, West and Central) (R-CAD) were included in the study. Further the biochemical analysis the genotyping of common variants was performed with the LightSNiP typing assay using qRT-PCR method.&nbsp; Results: Our analyses revealed that both genotype and allele frequencies of rs10757274, rs10757278 and rs10811656 were significantly different between the groups (p&lt;0.05, respectively). We identified that one previously undescribed three-marker haplotype (rs1333049, rs10757274 and rs10757278) encompassing CDKN2B-AS1 was overrepresented (G-G-G, the risk haplotype, p&lt;0.05) in N-CAD group compared to R-CAD group. The AUC of a risk model based on non-genetic factors was 0.730 (0.654-0.797) and the combination with genetic risk factors improved the AUC to 0.784 (95%CI=0.713-0.844, p&lt;0.0001). Conclusion: Our results identified the presence of a novel three-marker haplotype having a significant association with CAD in Northern Tanzania. Moreover, combination of the nongenetic and genetic risk models were demonstrated to indicate good diagnostic accuracy for CAD in Northern Tanzania

Absence of Germline BRCA1 c.68_69delAG and c.5266dupC Mutations among Hormone Receptor-negative Breast Cancer Patients: A First Impression at a Tertiary Cancer-care Facility in Tanzania

The germline BRCA1 c.68_69delAG (185delAG) and c.5266dupC (5382insC) mutations are associated with hormone receptor-negative breast cancer (BC).&nbsp; Limited studies have examined their contribution to alarming BC incidence in Sub Saharan Africa (SSA). Our study aimed to examine the contribution of &nbsp;germline BRCA1 c.68_69delAG and c.5266dupC mutations to BC incidence among hormone receptor-negative BC patients admitted to Ocean Road Cancer Institute in Tanzania. Face-to-face interviews were conducted to capture socio-demographic characteristics, anthropometric measurements, family history of cancer and reproductive information from each patient. Their &nbsp;histopathological data were extracted from the hospital medical records. The germline BRCA1 founder mutations were analyzed on blood samples using Sanger sequencing technology. The patients mean age at diagnosis was 47.05 ± 12.82 years. A family history of cancer was observed in 13.6% of patients. The germline BRCA1 c.68_69delAG and c.5266dupC mutations were not detected in the study group. Our findings indicate that the germline BRCA1 c.68_69delAG and c.5266dupC mutations do not contribute to BC manifestation in hormone receptor-negative BC patients in Tanzania. Thus, screening BC patients for these mutations has no clinical relevance. Our data further suggest that the c.68_69delAG and the c.5266dupC mutations should not be considered when developing genetic testing guidelines in Tanzania. Keywords: Breast cancer, germline BRCA1 mutation, c.68_69delAG (185delAG), c.5266dupC (5382insC), Tanzani

CYP21A2 Gene Mutations in Congenital Adrenal Hyperplasia: Genotype−phenotype correlation in Turkish children

Background: Congenital adrenal hyperplasia (CAH) due 21−hydroxylase deficiency (21−OHD) is a common autosomal recessive disorder. It is caused by defects in the CYP21A2 gene

The distribution of reproductive risk factors disclosed the heterogeneity of receptor-defined breast cancer subtypes among Tanzanian women

BACKGROUND: Recent epidemiological studies suggest that reproductive factors are associated with breast cancer (BC) molecular subtypes. However, these associations have not been thoroughly studied in the African populations. The present study aimed to investigate the prevalence of BC molecular subtypes and assess their association with reproductive factors in Tanzanian BC patients. METHODS: This hospital-based case-only cross-sectional study consisted of 263 histologically confirmed BC patients in Tanzania. Clinico-pathological data, socio-demographic characteristics, anthropometric measurements, and reproductive risk factors were examined using the Chi-square test and one-way ANOVA. The association among reproductive factors and BC molecular subtypes was analyzed using multinomial logistic regression. The heterogeneity of the associations was assessed using the Wald test. RESULTS: We found evident subtype heterogeneity for reproductive factors. We observed that post-menopausal status was more prevalent in luminal-A subtype, while compared to luminal-A subtype, luminal-B and HER-2 enriched subtypes were less likely to be found in post-menopausal women (OR: 0.21, 95%CI 0.10–0.41, p = 0.001; OR: 0.39, 95%CI 0.17–0.89, p = 0.026, respectively). Also, the luminal-B subtype was more likely to be diagnosed in patients aged ≤ 40 years than the luminal-A subtype (OR: 2.80, 95%CI 1.46–5.32, p = 0.002). Women who had their first full-term pregnancy at < 30 years were more likely to be of luminal-B (OR: 2.71, 95%CI 1.18–4.17, p = 0.018), and triple-negative (OR: 2.28, 95%CI 1.02–4.07, p = 0.044) subtypes relative to luminal-A subtype. Furthermore, we observed that breastfeeding might have reduced odds of developing luminal-A, luminal-B and triple-negative subtypes. Women who never breastfed were more likely to be diagnosed with luminal-B and triple-negative subtypes when compared to luminal-A subtype (OR: 0.46, 95%CI 0.22–0.95, p = 0.035; OR: 0.41, 95%CI 0.20–0.85, p = 0.017, respectively). . CONCLUSION: Our results are the first data reporting reproductive factors heterogeneity among BC molecular subtypes in Tanzania. Our findings suggest that breast-feeding may reduce the likelihood of developing luminal-A, luminal-B, and triple-negative subtypes. Meanwhile, the first full-term pregnancy after 30 years of age could increase the chance of developing luminal-A subtype, a highly prevalent subtype in Tanzania. More interventions to promote modifiable risk factors across multiple levels may most successfully reduce BC incidence in Africa. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12905-021-01536-6