Natural selection at the RASGEF1C (GGC) repeat in human and divergent genotypes in late-onset neurocognitive disorder

Expression dysregulation of the neuron-specific gene, RASGEF1C (RasGEF Domain Family Member 1C), occurs in late-onset neurocognitive disorders (NCDs), such as Alzheimer’s disease. This gene contains a (GGC)13, spanning its core promoter and 5′ untranslated region (RASGEF1C-201 ENST00000361132.9). Here we sequenced the (GGC)-repeat in a sample of human subjects (N = 269), consisting of late-onset NCDs (N = 115) and controls (N = 154). We also studied the status of this STR across various primate and non-primate species based on Ensembl 103. The 6-repeat allele was the predominant allele in the controls (frequency = 0.85) and NCD patients (frequency = 0.78). The NCD genotype compartment consisted of an excess of genotypes that lacked the 6-repeat (divergent genotypes) (Mid-P exact = 0.004). A number of those genotypes were not detected in the control group (Mid-P exact = 0.007). The RASGEF1C (GGC)-repeat expanded beyond 2-repeats specifically in primates, and was at maximum length in human. We conclude that there is natural selection for the 6-repeat allele of the RASGEF1C (GGC)-repeat in human, and significant divergence from that allele in late-onset NCDs. STR alleles that are predominantly abundant and genotypes that deviate from those alleles are underappreciated features, which may have deep evolutionary and pathological consequences.

Natural selection at the RASGEF1C (GGC) repeat in human and divergent genotypes in late-onset neurocognitive disorder.

Expression dysregulation of the neuron-specific gene, RASGEF1C (RasGEF Domain Family Member 1C), occurs in late-onset neurocognitive disorders (NCDs), such as Alzheimer’s disease. This gene contains a (GGC)13, spanning its core promoter and 5′ untranslated region (RASGEF1C-201 ENST00000361132.9). Here we sequenced the (GGC)-repeat in a sample of human subjects (N = 269), consisting of late-onset NCDs (N = 115) and controls (N = 154). We also studied the status of this STR across various primate and non-primate species based on Ensembl 103. The 6-repeat allele was the predominant allele in the controls (frequency = 0.85) and NCD patients (frequency = 0.78). The NCD genotype compartment consisted of an excess of genotypes that lacked the 6-repeat (divergent genotypes) (Mid-P exact = 0.004). A number of those genotypes were not detected in the control group (Mid-P exact = 0.007). The RASGEF1C (GGC)-repeat expanded beyond 2-repeats specifically in primates, and was at maximum length in human. We conclude that there is natural selection for the 6-repeat allele of the RASGEF1C (GGC)-repeat in human, and significant divergence from that allele in late-onset NCDs. STR alleles that are predominantly abundant and genotypes that deviate from those alleles are underappreciated features, which may have deep evolutionary and pathological consequences.

Natural selection at the RASGEF1C (GGC) repeat in human and divergent genotypes in late-onset neurocognitive disorder.

Expression dysregulation of the neuron-specific gene, RASGEF1C (RasGEF Domain Family Member 1C), occurs in late-onset neurocognitive disorders (NCDs), such as Alzheimer’s disease. This gene contains a (GGC)13, spanning its core promoter and 5′ untranslated region (RASGEF1C-201 ENST00000361132.9). Here we sequenced the (GGC)-repeat in a sample of human subjects (N=269), consisting of late-onset NCDs (N=115) and controls (N=154). We also studied the status of this STR across various primate and non-primate species based on Ensembl 103. The 6-repeat allele was the predominant allele in the controls (frequency=0.85) and NCD patients (frequency=0.78). The NCD genotype compartment consisted of an excess of genotypes that lacked the 6-repeat (divergent genotypes) (Mid-P exact=0.004). A number of those genotypes were not detected in the control group (Mid-P exact=0.007). The RASGEF1C (GGC)-repeat expanded beyond 2-repeats specifically in primates, and was at maximum length in human. We conclude that there is natural selection for the 6-repeat allele of the RASGEF1C (GGC)-repeat in human, and significant divergence from that allele in late-onset NCDs. STR alleles that are predominantly abundant in human and genotypes that deviate from those alleles are underappreciated features, which may have deep evolutionary and pathological consequences in human.

Natural Selection at an Exceptionally Long GGC Repeat in the Human RASGEF1C and Divergent Genotypes in Late-onset Neurocognitive Disorder

Across the human protein-coding genes, the neuron-specific gene, RASGEF1C, contains the longest (GGC)-repeat, spanning its core promoter and 5′ untranslated region (RASGEF1C-201 ENST00000361132.9). RASGEF1C expression dysregulation occurs in late-onset neurocognitive disorders (NCDs), such as Alzheimer’s disease. Here we sequenced the GGC-repeat in a sample of human subjects (N = 269), consisting of late-onset NCDs (N = 115) and controls (N = 154). We also studied the status of this STR across vertebrates. The 6-repeat allele of this repeat was the predominant allele in the controls (frequency = 0.85) and NCD patients (frequency = 0.78). The NCD genotype compartment consisted of an excess of genotypes that lacked the 6-repeat (Mid-P exact = 0.004). We also detected divergent genotypes that were present in five NCD patients and not in the controls (Mid-P exact = 0.007). This STR expanded beyond 2-repeats specifically in primates, and was at maximum length in human. We conclude that there is natural selection for the 6-repeat allele of the RASGEF1C (GGC)-repeat in human, and significant divergence from that allele in late-onset NCDs. Indication of natural selection for predominantly abundant STR alleles and divergent genotypes enhance the perspective of evolutionary biology and disease pathogenesis in human complex disorders.

The CYP19A1 (TTTA)n Repeat Polymorphism May Affect the Prostate Cancer Risk: Evidence from a Meta-Analysis

Abnormal aromatase (CYP19A1) expression may participate in prostate cancer (PCa) carcinogenesis. However, the results of studies on the CYP19A1 gene polymorphisms and PCa are conflicting. This meta-analysis aimed to systematically evaluate the associations between the CYP19A1 Arg264Cys polymorphism and the (TTTA)n repeat polymorphism and PCa. Electronic databases (PubMed, EmBase, ScienceDirect, and Cochrane Library) were comprehensively searched to identify eligible studies. The strength of the association between the Arg264Cys polymorphism and PCa was assessed by pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) in allelic, dominant, recessive, homozygous, and heterozygous genetic models. To analyze the impact of the (TTTA)n repeat polymorphism, we sequentially took the N-repeat allele (where N equals 7,8,10,11,12, and 13) as the minor allele and the sum of all the other alleles as the major allele. The ORs and 95% CIs were calculated in the allelic model; this analysis was performed individually for each repeat number. Pooled estimates of nine studies addressing the Arg264Cys polymorphism indicated that this polymorphism was not associated with PCa risk in the overall population or in the Caucasian or Asian subgroups. The 8-repeat allele in the (TTTA)n repeat polymorphism increased PCa risk in the overall population (OR = 1.34, 95% CI = 1.14–1.58, p = .001) and in the subgroup with population-based (PB) controls (OR = 1.41, 95% CI = 1.13–1.74, p = .002) as well as in the subgroup using capillary electrophoresis to identify this polymorphism (OR = 1.34, 95% CI = 1.09–1.65, p = .006).The meta-analysis indicated that the CYP19A1 (TTTA)n repeat polymorphism, but not the Arg264Cys polymorphism, may affect PCa risk.

The CYP19A1 (TTTA)n repeat polymorphism, but not Arg264Cys polymorphism, may affect the risk of prostate cancer: evidence from a meta-analysis

Background: Abnormal aromatase (CYP19A1) expression may participate in prostate cancer (PCa) carcinogenesis. However, results of studies on the CYP19A1 gene polymorphisms and PCa are conflicting.This meta-analysis aimed to systematically evaluate the association between the CYP19A1 Arg264Cys polymorphism and (TTTA)n repeat polymorphism and PCa.Methods: Electronic databases (PubMed, EmBase, ScienceDirect, and Cochrane Library) were comprehensively searched to identify eligible studies. The strength of association between the Arg264Cys polymorphism and PCa was assessed by pooled odds ratio (OR) and 95% confidence interval (95% CI) in allelic, dominant, recessive, homozygous, and heterozygous genetic models. To analyze the impact of the (TTTA)n repeat polymorphism, we took sequentially the N-repeat allele (where N equals 7,8,10,11,12, and 13) as the minor allele and the sum of all the other alleles as the major allele. The ORs and 95%CIs were calculated in the allelic model; this analysis was performed individually for each repeat number. Results: Pooled estimates of nine studies addressing the Arg264Cys polymorphism indicated that this polymorphism was not associated with PCa risk in the overall population and in the Caucasian and Asian subgroups. The 8-repeat allele in the (TTTA)n repeat polymorphism increased PCa risk in the overall population (OR=1.34, 95% CI=1.14–1.58, P=0.001) and in the subgroup with population-based (PB) controls (OR=1.41, 95% CI=1.13–1.74, P=0.002) as well as in the subgroup of studies using capillary electrophoresis to identify this polymorphism (OR=1.34, 95%CI=1.09-1.65, P=0.006). Conclusions: The meta-analysis indicated that the CYP19A1 (TTTA)n repeat polymorphism, but not Arg264Cys polymorphism may affect PCa risk.

The CYP19A1 (TTTA)n repeat polymorphism, but not Arg264Cys polymorphism, may affect the risk of prostate cancer: evidence from a meta-analysis

Background: Abnormal aromatase (CYP19A1) expression has been proposed to take part in the carcinogenesis of prostate cancer (PCa).However, results of studies on the CYP19A1 gene polymorphisms and PCa are conflicting.This meta-analysis aimed to systematically evaluate the association between the CYP19A1 Arg264Cys polymorphism and (TTTA)n repeat polymorphism and PCa.Methods: Electronic databases (PubMed, EmBase, ScienceDirect, and Cochrane Library) were comprehensively searched to identify eligible studies. The strength of association between the CYP19A1 Arg264Cys polymorphism and PCa was assessed by pooled odds ratio (OR) and 95% confidence interval (95% CI) in allelic, dominant, recessive, homozygous, and heterozygous genetic models. To analyze the impact of the (TTTA)n repeat polymorphism, we took sequentially the N-repeat allele (where N equals 7,8,10,11,12, and 13) as the minor allele and the sum of all the other alleles as the major allele. The ORs and 95%CIs were calculated in the allelic model; this analysis was performed individually for each repeat number.Results: Pooled estimates of nine eligible studies addressing the Arg264Cys polymorphism indicated that this polymorphism was not associated with the risk of PCa in the overall population and in the Caucasian and Asian subgroups. A meta-analysis of six studies addressing the (TTTA)n repeat polymorphism revealed that the 8-repeat allele increased PCa risk in the overall population (OR=1.34, 95% CI=1.14–1.58, P=0.001) and in the subgroup with population-based (PB) controls (OR=1.41, 95% CI=1.13–1.74, P=0.002). Conclusions: The meta-analysis indicated that the CYP19A1 (TTTA)n repeat polymorphism, but not Arg264Cys polymorphism may affect PCa risk.

Influence of MIF polymorphisms on CpG island hyper-methylation of CDKN2A in the patients with ulcerative colitis

Background CDKN2A hypermethylation is among the major events associated with carcinogenesis and is also observed in non-neoplastic colonic mucosa in patients with ulcerative colitis (UC). Macrophage migration inhibitory factor (MIF) plays a crucial role in promoting gastrointestinal inflammation characteristic of UC. The aim of this study is to explore associations between CDKN2A methylation status and MIF polymorphisms (rs755622 and rs5844572). Methods One hundred and fifty-nine patients diagnosed with UC were enrolled in this study. The methylation status of p14ARF and p16INK4a was determined by MSP; MIF genotypes were identified by PCR-SSCP. Results We found no differences with respect to mean age, gender, clinical type (chronic continuous or relapse/remitting), or extent of disease among the patients with methylated and unmethylated p14ARF or p16INK4a. Carrying the rs755622 C allele indicated a significantly higher risk for p14ARF methylation (odds ratio (OR), 2.16; 95% confidence interval (CI), 1.08–4.32; p = 0.030); similarly, carrying the rs5844572 7-repeat allele indicated a significantly higher risk for p16INK4a methylation (OR, 2.57; 95% CI, 1.26–5.24; p = 0.0094) after an adjusted regression analysis. The carriers of the rs755662 C allele or the rs5844572 7-repeat allele were both at a significantly higher risk for methylation of both p14ARF and p16INK4a when compared to the cohort in which neither of the genes were methylated (OR, 2.70; 95% CI, 1.22–6.01; p = 0.015 and OR, 2.87; 95% CI, 1.25–6.62; p = 0.013, respectively). Additionally, carrying rs755622 C allele was significantly associated with CIHM in chronic continuous of clinical type and total colitis (OR, 25.9; 95% CI, 2.55–262.6; p = 0.0059 and OR, 4.38; 95% CI, 1.12–17.2; p = 0.034, respectively), and carrying 7-repeat allele of rs5844572 was significantly associated in chronic continuous type (OR, 14.5; 95%CI, 1.46–144.3; p = 0.022). Conclusions Taken together, our findings suggest that MIF genotypes associated with inflammation may also be involved in promoting carcinogenesis via CDKN2A hypermethylation in patients diagnosed with UC.

Influence of MIF polymorphisms on CpG island hyper-methylation of CDKN2A in the patients with ulcerative colitis

Background: CDKN2A hypermethylation is among the major events associated with carcinogenesis and is also observed in non-neoplastic colonic mucosa in patients with ulcerative colitis (UC). Macrophage migration inhibitory factor (MIF) plays a crucial role in promoting gastrointestinal inflammation characteristic of UC. The aim of this study is to explore associations between CDKN2A methylation status and MIF polymorphisms (rs755622 and rs5844572). Methods: One hundred and fifty-nine patients diagnosed with UC were enrolled in this study. The methylation status of p14ARF and p16INK4a was determined by MSP; MIF genotypes were identified by PCR-SSCP. Results: We found no differences with respect to mean age, gender, clinical type (chronic continuous or relapse/remitting), or extent of disease among the patients with methylated and unmethylated p14ARF or p16INK4a. Carrying the rs755622 C allele indicated a significantly higher risk for p14ARF methylation (odds ratio (OR), 2.16; 95% confidence interval (CI), 1.08-4.32; p=0.030); similarly, carrying the rs5844572 7-repeat allele indicated a significantly higher risk for p16INK4a methylation (OR, 2.57; 95% CI, 1.26–5.24; p=0.0094) after an adjusted regression analysis. The carriers of the rs755662 C allele or the rs5844572 7-repeat allele were both at a significantly higher risk for methylation of both p14ARF and p16INK4a when compared to the cohort in which neither of the genes were methylated (OR, 2.70; 95% CI, 1.22–6.01; p=0.015 and OR, 2.87; 95% CI, 1.25–6.62; p=0.013, respectively). Additionally, carrying rs755622 C allele was significantly associated with CIHM in chronic continuous of clinical type and total colitis (OR, 25.9; 95% CI, 2.55-262.6; p=0.0059 and OR, 4.38; 95% CI, 1.12-17.2; p=0.034, respectively), and carrying 7-repeat allele of rs5844572 was significantly associated in chronic continuous type (OR, 14.5; 95%CI, 1.46-144.3; p=0.022).Conclusions: Taken together, our findings suggest that MIF genotypes associated with inflammation may also be involved in promoting carcinogenesis via CDKN2A hypermethylation in patients diagnosed with UC.

Influence of MIF polymorphisms on CpG island hyper-methylation of CDKN2A in the patients with ulcerative colitis

Background: CDKN2A hypermethylation is among the major events associated with carcinogenesis and is also observed in non-neoplastic colonic mucosa in patients with ulcerative colitis (UC). Macrophage migration inhibitory factor (MIF) plays a crucial role in promoting gastrointestinal inflammation characteristic of UC. The aim of this study is to explore associations between CDKN2A methylation status and MIF polymorphisms (rs755622 and rs5844572).Methods: One hundred and fifty-nine patients diagnosed with UC were enrolled in this study. The methylation status of p14ARF and p16INK4a was determined by MSP; MIF genotypes were identified by PCR-SSCP.Results: We found no differences with respect to mean age, gender, clinical type (chronic continuous or relapse/remitting), or extent of disease among the patients with methylated and unmethylated p14ARF or p16INK4a. Carrying the rs755622 C allele indicated a significantly higher risk for p14ARF methylation (odds ratio (OR), 2.16; 95% confidence interval (CI), 1.08-4.32; p=0.030); similarly, carrying the rs5844572 7-repeat allele indicated a significantly higher risk for p16INK4a methylation (OR, 2.57; 95% CI, 1.26–5.24; p=0.0094) after an adjusted regression analysis. The carriers of the rs755662 C allele or the rs5844572 7-repeat allele were both at a significantly higher risk for methylation of both p14ARF and p16INK4a when compared to the cohort in which neither of the genes were methylated (OR, 2.70; 95% CI, 1.22–6.01; p=0.015 and OR, 2.87; 95% CI, 1.25–6.62; p=0.013, respectively). Additionally, carrying rs755622 C allele was significantly associated with CIHM in chronic continuous of clinical type and total colitis (OR, 25.9; 95% CI, 2.55-262.6; p=0.0059 and OR, 4.38; 95% CI, 1.12-17.2; p=0.034, respectively), and carrying 7-repeat allele of rs5844572 was significantly associated in chronic continuous type (OR, 14.5; 95%CI, 1.46-144.3; p=0.022).Conclusions: Taken together, our findings suggest that MIF genotypes associated with inflammation may also be involved in promoting carcinogenesis via CDKN2A hypermethylation in patients diagnosed with UC.