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Genetic variants of calcium sensing receptor gene and risk of colorectal cancer: A case-control study.

ABSTRACT: Objectives:To determine the role of two genetic variants, (rs3804594) and (rs1801725), in calcium sensing receptor (CASR) gene with colorectal cancer (CRC) risk in patients visited King Abdulaziz University hospital (KAUH) in Jeddah, Saudi Arabia. Methods:Genomic DNA was extracted, by commercial DNA extraction kit, from whole blood of 100 CRC patients and 124 controls who visited KAUH from January 2016 to September 2016. Then genotype and allele distributions of both variants were determined by PCR-RFLP and DNA sequencing techniques. All statistical analyses were performed by unpaired t-test and P-values <0.05 were considered statistically significant. Results:Data obtained from ?2 test showed that intron 4 variant in CASR gene was distributed 100% normally in the 224 participants, however, exon 7 variant showed 100% homozygous distribution in the controls; whereas, in CRC patients it was distributed equally into 50% heterozygous and 50% homozygous with no detection for wild type. Conclusion:Intron 4 variant (rs3804594) in CASR gene is not correlated to CRC risk. However, more investigations are needed to elucidate the role of CASR gene exon 7 (rs1801725) variant in CRC development as the current results are not definitive.

SUBMITTER: Al-Ghafari AB

PROVIDER: S-EPMC6500844 | biostudies-literature | 2019 Mar-Apr

REPOSITORIES: biostudies-literature

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Calcium intake and genetic variants in the calcium sensing receptor in relation to colorectal cancer mortality: an international consortium study of 18,952 patients.

Project description:Research on calcium intake as well as variants in the calcium sensor receptor (CaSR) gene and their interaction in relation to CRC survival is still limited. Data from 18,952 CRC patients, were included. Associations between primarily pre-diagnostic dietary (n = 13.085), supplemental (n = 11,837), total calcium intake (n = 5970) as well as 325 single nucleotide polymorphisms (SNPs) of the CaSR gene (n = 15,734) in relation to CRC-specific and all-cause mortality were assessed using Cox proportional hazard models. Also interactions between calcium intake and variants in the CaSR gene were assessed. During a median follow-up of 4.8 years (IQR 2.4-8.4), 6801 deaths occurred, of which 4194 related to CRC. For all-cause mortality, no associations were observed for the highest compared to the lowest sex- and study-specific quartile of dietary (HR 1.00, 95%CI 0.92-1.09), supplemental (HR 0.97, 95%CI 0.89-1.06) and total calcium intake (HR 0.99, 95%CI 0.88-1.11). No associations with CRC-specific mortality were observed either. Interactions were observed between supplemental calcium intake and several SNPs of the CaSR gene. Calcium intake was not associated with all-cause or CRC-specific mortality in CRC patients. The association between supplemental calcium intake and all-cause and CRC-specific mortality may be modified by genetic variants in the CaSR gene.

| S-EPMC11368808 | biostudies-literature

Genetic variation in calcium-sensing receptor and risk for colon cancer.

Project description:Experimental and epidemiologic studies have suggested that high calcium intake is associated with decreased colon cancer risk, yet very limited data are available for candidate genes in the calcium-vitamin D pathway and colon cancer risk. To address this, we evaluated whether calcium-sensing receptor (CASR) single-nucleotide polymorphisms are associated with colon cancer risk. We also examined interactions among CASR, calcium, and vitamin D intake and previously genotyped vitamin D-related genes.We conducted a large multicenter population-based case-control study of 1,600 cases and 1,949 controls. Seventeen tagging single-nucleotide polymorphisms for CASR were selected from common single-nucleotide polymorphisms (minor allele frequency, >or=5%) based on resequencing data. Haplotypes were estimated and evaluated using HaploStats.We did not observe an association between any CASR genotypes or haplotypes and colon cancer risk overall. However, when stratified by anatomic site, statistically significant associations were seen with risk for proximal colon cancer [rs10934578 TT: odds ratio, 1.35; 95% confidence interval (95% CI), 1.01-1.81; rs12485716 AG/AA: odds ratio, 0.84; 95% CI, 0.71-1.00; rs4678174 CT/CC: odds ratio, 0.83; 95% CI, 0.70-0.98; rs2270916 CC: odds ratio, 0.43; 95% CI, 0.19-0.97]. Concordantly, we observed a suggested association for a CASR haplotype (rs4678174, rs2270916) with risk for proximal colon cancer (global P=0.08). We did not observe any meaningful gene-environment (calcium and vitamin D) or gene-gene (CYP24A1, CYP27B1, and VDR) interactions with CASR genotypes and colon cancer risk.Our study does not provide evidence for an overall association between CASR single-nucleotide polymorphisms and colon cancer; however, results suggest a possible role of CASR on proximal colon cancer, and subsite differences are consistent with known calcium biology. Nonetheless, these findings require confirmation.

| S-EPMC2633716 | biostudies-literature

Common variants in the calcium-sensing receptor gene are associated with total serum calcium levels.

Project description:Serum calcium levels are tightly regulated. We performed genome-wide association studies (GWAS) in population-based studies participating in the CHARGE Consortium to uncover common genetic variations associated with total serum calcium levels. GWAS of serum calcium concentrations was performed in 20 611 individuals of European ancestry for ?2.5 million genotyped and imputed single-nucleotide polymorphisms (SNPs). The SNP with the lowest P-value was rs17251221 (P = 2.4 * 10(-22), minor allele frequency 14%) in the calcium-sensing receptor gene (CASR). This lead SNP was associated with higher serum calcium levels [0.06 mg/dl (0.015 mmol/l) per copy of the minor G allele] and accounted for 0.54% of the variance in serum calcium concentrations. The identification of variation in CASR that influences serum calcium concentration confirms the results of earlier candidate gene studies. The G allele of rs17251221 was also associated with higher serum magnesium levels (P = 1.2 * 10(-3)), lower serum phosphate levels (P = 2.8 * 10(-7)) and lower bone mineral density at the lumbar spine (P = 0.038), but not the femoral neck. No additional genomic loci contained SNPs associated at genome-wide significance (P < 5 * 10(-8)). These associations resemble clinical characteristics of patients with familial hypocalciuric hypercalcemia, an autosomal-dominant disease arising from rare inactivating mutations in the CASR gene. We conclude that common genetic variation in the CASR gene is associated with similar but milder features in the general population.

| S-EPMC2951868 | biostudies-literature

Calcium intake and risk of colorectal cancer according to expression status of calcium-sensing receptor (CASR).

Project description:ObjectiveAlthough evidence suggests an inverse association between calcium intake and the risk of colorectal cancer, the mechanisms remain unclear. The calcium-sensing receptor (CASR) is expressed abundantly in normal colonic epithelium and may influence carcinogenesis. We hypothesized that calcium intake might be associated with lower risk of CASR-positive, but not CASR-negative, colorectal cancer.DesignWe assessed tumour CASR protein expression using immunohistochemistry in 779 incident colon and rectal cancer cases that developed among 136 249 individuals in the Nurses' Health Study and Health Professionals Follow-Up Study. Duplication method Cox proportional hazards regression analysis was used to assess associations of calcium intake with incidence of colorectal adenocarcinoma subtypes by CASR status.ResultsTotal calcium intake was inversely associated with the risk of developing colorectal cancer (ptrend=0.01, comparing ≥1200 vs <600 mg/day: multivariable HR=0.75, 95% CI 0.60 to 0.95). For the same comparison, higher total calcium intake was associated with a lower risk of CASR-positive tumours (ptrend=0.003, multivariable HR=0.67, 95% CI 0.51 to 0.86) but not with CASR-negative tumours (ptrend=0.67, multivariable HR=1.15, 95% CI 0.75 to 1.78; pheterogeneity=0.06 between the CASR subtypes). The stronger inverse associations of calcium intake with CASR-positive but not CASR-negative tumours generally appeared consistent regardless of sex, tumour location and source of calcium.ConclusionsOur molecular pathological epidemiology data suggest a causal relationship between higher calcium intake and lower colorectal cancer risk, and a potential role of CASR in mediating antineoplastic effect of calcium.

| S-EPMC5754263 | biostudies-literature

Genetic association of deleted in colorectal carcinoma variants with breast cancer risk: A case-control study.

Project description:Deleted in colorectal carcinoma (DCC), a netrin-1 dependence receptor, is correlated with cell progression, migration, and adhesion. Evidence indicated that DCC was frequently down-regulated in many cancers. However, the association of DCC with breast cancer remains uncertain. We conducted a case-control study to investigate the impact of three DCC gene variants (rs2229080, rs7504990, and rs4078288) on breast cancer susceptibility in Chinese women. This study included 560 breast cancer patients and 583 age-matched healthy controls from Northwest China. The three gene variants were genotyped via Sequenom MassARRAY. Odds ratios (ORs) and 95% confidence intervals (CIs) were utilized to evaluate the associations. We found that individuals with the rs2229080 C/G, C/C, and C/G-CC genotypes had a higher breast cancer risk, and the minor allele C was associated with increased breast cancer risk in an allele model. We observed a significantly decreased breast cancer risk with the rs7504990 C/T, T/T, and C/T-T/T genotypes, and the minor allele T was protective against breast cancer in an allele model. In addition, rs2229080 was associated with the axillary lymph node (LN) metastasis status. An age-stratified analysis revealed an association between rs2229080 and reduced breast cancer risk among older patients (≥ 49 years). Furthermore, the haplotype analysis showed that the Crs2229080Crs7504990Ars4078288 haplotype was associated with a decreased breast cancer risk. However, the results indicated a lack of association between rs4078288 and breast cancer risk. These findings affirmed that rs2229080 and rs7504990 polymorphisms in DCC might be related with breast cancer susceptibility in Chinese women.

| S-EPMC5078049 | biostudies-literature

Common calcium-sensing receptor (CASR) gene variants do not modify risk for chronic pancreatitis in a Hungarian cohort.

Project description:The calcium-sensing receptor (CASR) is expressed in the pancreas where it might regulate calcium concentrations in pancreatic secretions. Two independent studies reported conflicting results claiming that commonly occurring missense variants of the CASR gene are risk factors for chronic pancreatitis (CP). Here, we attempted to replicate the association between CASR variants and CP. We analyzed 337 patients and 840 controls from the Hungarian National Pancreas Registry either by direct sequencing of exon 7 and the flanking noncoding regions or by TaqMan SNP genotyping assays. We identified two common missense variants, c.2956G>T (p.A986S), and c.2968A>G (p.R990G), three low-frequency variants, c.3031C>G (p.Q1011E), c.2610G>A (p.E870=) and c.∗60T>A, and 8 rare variants including the novel variant c.1895G>A (p.G632D). When allelic or genotype distributions were considered, none of the CASR variants associated with CP. Subgroup analysis of nonalcoholic versus alcoholic patients revealed no disease association either. Our results demonstrate that common CASR variants do not modify the risk for CP and should not be considered as genetic risk factors in the clinical setting.

| S-EPMC8663126 | biostudies-literature

Genetic variation in the retinoid X receptor and calcium-sensing receptor and risk of colorectal cancer in the Colon Cancer Family Registry.

Project description:Genetic variants in the calcium/vitamin D metabolic pathway may be related to risk for colorectal cancer. While several investigations of vitamin D receptor (VDR) polymorphisms and colorectal cancer have been conducted, no studies to date have evaluated the association of genetic variation in the heterodimer partner for VDR, the retinoid X receptor (RXR). Another important gene in this pathway is the calcium-sensing receptor (CASR). Employing a discordant-sibship case-control design, we examined the association between single nucleotide polymorphisms (SNPs) in RXRA and CASR and risk for colorectal cancer overall and by colorectal subsite and microsatellite instability (MSI) status using data from the Colon Cancer Family Registry. No gene-level relationships between RXRA or CASR and colorectal cancer overall were observed. However, for RXRA SNP rs7861779, a high-interest SNP selected for study a priori, there was a statistically significantly increased risk for proximal colorectal cancer among those with at least one A allele [odds ratio (OR) = 1.42; 95% confidence interval (CI) = 1.03-1.97]. Another selected RXRA SNP, rs12004589, was significantly associated with risk of MSI-high cancers (OR = 2.27; 95% CI = 1.13-4.56). Additionally, CASR SNP rs1801726 was significantly associated with a reduced risk for rectal cancer (OR = 0.53; 95% CI = 0.29-0.96). These results provide support that RXRA SNPs rs7861779 and rs12004589 and CASR SNP rs1801726 may be important markers for colorectal neoplasia. Further work is needed to elucidate their role in the carcinogenic pathway.

| S-EPMC2915636 | biostudies-literature

The role of the Calcium-Sensing receptor in colorectal cancer

Project description:The Calcium-Sensing receptor (CaSR) is a G proteins-coupled receptor involved in calcium homeostasis. The CaSR regulates cell proliferation and apoptosis and has been suggested to play an antitumor role in colorectal cancer. However it is down-regulated during carcinogenesis and in more malignant tumors its expression is lost.

2019-11-26 | GSE140984 | GEO

Common genetic variation of the calcium-sensing receptor and lethal prostate cancer risk.

Project description:Bony metastases cause substantial morbidity and mortality from prostate cancer (PCa). The calcium-sensing receptor (CaSR) is expressed on prostate tumors and may participate in bone metastases development. We assessed whether (i) common genetic variation in CaSR was associated with PCa risk and (ii) these associations varied by calcium intake or plasma 25-hydroxyvitamin D [25(OH)D] levels.We included 1,193 PCa cases and 1,244 controls nested in the prospective Health Professionals Follow-up Study (1993-2004). We genotyped 18 CaSR single-nucleotide polymorphism (SNPs) to capture common variation. The main outcome was risk of lethal PCa (n = 113); secondary outcomes were overall (n = 1,193) and high-grade PCa (n = 225). We used the kernel machine approach to conduct a gene-level multimarker analysis and unconditional logistic regression to compute per-allele ORs and 95% confidence intervals (CI) for individual SNPs.The joint association of SNPs in CaSR was significant for lethal PCa (P = 0.04); this association was stronger in those with low 25(OH)D (P = 0.009). No individual SNPs were associated after considering multiple testing; three SNPs were nominally associated (P < 0.05) with lethal PCa with ORs (95% CI) of 0.65(0.42-0.99): rs6438705; 0.65(0.47-0.89): rs13083990; and 1.55(1.09-2.20): rs2270916. The three nonsynonymous SNPs (rs1801725, rs1042636, and rs1801726) were not significantly associated; however, the association for rs1801725 was stronger in men with low 25(OH)D [OR(95%CI): 0.54(0.31-0.95)]. There were no significant associations with overall or high-grade PCa.Our findings indicate that CaSR may be involved in PCa progression.Further studies investigating potential mechanisms for CaSR and PCa, including bone remodeling and metastases are warranted.

| S-EPMC3538912 | biostudies-literature

Alanine to Serine Variant at Position 986 of Calcium Sensing Receptor and Colorectal Cancer Risk.

Project description:BACKGROUND:With regard to the effect of calcium against colorectal cancer (CRC) and considering the key role of calcium sensing receptor (CaSR) in calcium homeostasis, this study investigated whether CaSR gene rs1801725 or A986S variant was associated with susceptibility to CRC risk. METHODS:This study was conducted as a case-control study and 303 cases with CRC and 354 controls were enrolled. All 657 subjects were genotyped for CaSR gene A986S variant using PCR-RFLP method. RESULTS:No significant difference was observed for the A986S variant of CaSR gene in either genotype or allele frequencies between the cases and the controls and this lack of difference remained non-significant even after adjustment for age, BMI, sex, smoking status, and family history of CRC. No evidence for the effect modification of the association A986S variant and CRC by BMI, sex, or tumor site was also observed. Furthermore, the risk of obesity in relation to the A986S variant in the controls and the cases was separately analyzed and we observed no significant difference between normal weight (BMI < 25kg/m2) and overweight/obese (BMI ? 25kg/m2) subjects. CONCLUSIONS:Our findings do not support a role for effect of the CaSR gene A986S variant on CRC risk; nevertheless, this finding requires confirmation and the role of the gene variant in carcinogenesis needs to be further investigated.

| S-EPMC5056015 | biostudies-literature

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