Whole-Exome Sequencing for Identification of Genetic Variants Involved in Vitamin D Metabolic Pathways in Families With Vitamin D Deficiency in Saudi Arabia

Alharazy, Shatha; Naseer, Muhammad Imran; Alissa, Eman M.; Robertson, M. Denise; Lanham-New, Susan; Chaudhary, Adeel G.

doi:10.3389/fgene.2021.677780

Cited by 4 publications

(3 citation statements)

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“…It also adds more evidence to our recent published finding that reported this SNP in six affected families diagnosed with Vitamin-D deficiency. 28 Regarding rs2228171, there is still no report in the literature associating this SNP with Vitamin-D deficiency (according to our knowledge). However, this SNP has been reported in a recent study suggesting its association with gestational weeks and risk of preterm birth.…”

Section: Discussionmentioning

confidence: 86%

Use of whole exome sequencing for identification of genetic variants related to Growth Hormone Deficiency and Short Stature: A Family-Based Study

Alharazy

Naseer²

2023

Pak J Med Sci

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Objective: Genetic polymorphisms in genes involved in growth process and Vitamin-D metabolism form a significant etiology behind growth hormone deficiency and short stature. The aim of this study was to explore for known and unknown genes and variants related to growth hormone and short stature in a family based study using whole exome sequencing (WES). Method: This family-based study included a family with members diagnosed with growth hormone deficiency, short stature and Vitamin-D deficiency (four boys affected and four boys non-affected). The participants were recruited from King Abdulaziz University Hospital (Jeddah, Saudi Arabia) and referred to King Fahad Centre for Medical Research (Jeddah, Saudi Arabia from April 2022 to June 2022. The consanguineous parents and one of the affected boys (aged 16 years old) underwent WES. Results: Several variants in RNPC3, ACAN, GC, VDR and LRP2 were identified in index cases but not in controls. Novel frameshift and splice region variants in RNPC3 (c.358dupA, p.Arg120fs) were detected. Other missense variants were also observed including variants in ACAN (c.2591C>T, c.2789G>T, c.2815T>A, c.4207A>G, c.4523A>C and c.7119C>G), GC (rs4588 and rs7041) and LRP2 (rs2075252 and rs1991517). A start loss variant in VDR (rs2228570) with high impact was also observed. Conclusions: Our findings suggest a potential association of these variants with growth hormone deficiency and short stature. In this study, novel pathogenic variants in RNPC3 were revealed as well as other variants in ACAN and in genes related to Vitamin-D metabolism (GC, VDR and LRP2) that some or all might be associated with growth hormone deficiency. Further large-scale studies are required to address the association of these variants with growth hormone deficiency and its subsequent short stature. doi: https://doi.org/10.12669/pjms.39.5.7601 How to cite this: Alharazy S, Naseer MI. Use of whole exome sequencing for identification of genetic variants related to Growth Hormone Deficiency and Short Stature: A Family-Based Study. Pak J Med Sci. 2023;39(5):---------. doi: https://doi.org/10.12669/pjms.39.5.7601 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Section: Discussionmentioning

confidence: 86%

Use of whole exome sequencing for identification of genetic variants related to Growth Hormone Deficiency and Short Stature: A Family-Based Study

Alharazy

Naseer²

2023

Pak J Med Sci

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“…More specifically, LRP2 rs2673170 and rs10210408 and CUBN rs4525114 polymorphisms have been associated with season-adjusted 25(OH)D concentration among controls or pregnant women [ 25 , 27 ]. Additionally, LRP2 rs2075252 variant has been associated with vitamin D deficiency [ 24 ], while CUBN rs41301097 has been strongly correlated with higher 25(OH)D levels [ 19 ]. LRP2 rs2228171 and CUBN rs1801222 polymorphisms, that were genotyped in our study, have been previously associated with variable vitamin D levels [ 21 ]; our results in total population did not show such an association.…”

Section: Discussionmentioning

confidence: 99%

Polymorphisms in LRP2 and CUBN genes and their association with serum vitamin D levels and sleep apnea

Anatolou,

Steiropoulos,

Zissimopoulos

et al. 2023

Sleep Breath

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Purpose Vitamin D deficiency has been associated with the occurrence of obstructive sleep apnea syndrome (OSAS). Megalin (LRP2) and cubilin (CUBN) are implicated in vitamin D metabolism, whereas LRP2 and CUBN polymorphisms have been previously associated with variable serum vitamin D levels. The present study aimed to evaluate the role of LRP2 rs2228171 c.8614C > T and CUBN rs1801222 c.758A > G polymorphisms in OSAS susceptibility, independently or in synergy with vitamin D levels. Methods Vitamin D serum concentration of consecutive individuals was measured. PCR–RFLP was used for LRP2 rs2228171 and CUBN rs1801222 genotyping. Results A total of 176 individuals was enrolled, including 144 patients with OSAS and 32 controls. Frequency of LRP2 rs2228171 c.8614 T and CUBN rs1801222 c.758G alleles was estimated at 22.4% and 79.8%, respectively. LRP2 and CUBN polymorphisms were not associated with OSAS occurrence (rs2228171Τ allele: 22.9% in OSAS group vs. 20.3% in controls, p = 0.651; rs1801222A allele 19.4% in OSAS group vs. 23.4% in controls, p = 0.471). Frequency of CUBN rs1801222A allele carriers was increased in patients with moderate or severe OSAS compared to mild OSAS (p = 0.028). Patients with OSAS homozygous for LRP2 CC and CUBN GG genotypes had lower vitamin D serum concentration compared to controls carrying the same genotype (18.0 vs 27.0 ng/mL, p = 0.006 and 19.0 vs 27.5 ng/mL, p = 0.007, respectively). Conclusion CUBN rs1801222 polymorphism may affect OSAS severity. Among other factors, low vitamin D concentration is associated with OSAS occurrence, irrespectively of LRP2 and CUBN polymorphisms.

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“…Recently, accumulating evidence have reported a family cluster to VitD deficiency, which suggest the importance of genetic factors ( Wang et al, 2010 ; Bahrami et al, 2018 ). This is mainly due to genetic variants involved in VitD metabolic pathways identified by whole-exome sequencing analysis ( Alharazy et al, 2021 ). Therefore, it is proposed that mutation or loss of VitD metabolism-related genes may lead to VitD deficiency and subsequently promote the development of ULs.…”

Section: Introductionmentioning

confidence: 99%

Association of Vitamin D Anabolism-Related Gene Polymorphisms and Susceptibility to Uterine Leiomyomas

et al. 2022

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Background: Uterine leiomyomas (ULs) is the most common gynecological benign tumor in women. Our previous study showed that the phenomenon of vitamin D deficiency existed in patients with ULs. However, the association of vitamin D anabolism-related gene polymorphisms and susceptibility to ULs was unclear.Methods: Vitamin D anabolism-related gene polymorphisms in 110 patients with ULs and 110 healthy controls were detected by sequencing and the differences of the 92 SNPs were analyzed in the two groups via chi-square test. To verify the association between the significantly different SNPs and the risk of ULs, the SNPs were genotyped in another 340 patients and 340 healthy controls. Additionally, an unconditional logistic regression model was conducted to calculate the odds ratio (OR) of ULs occurrence and the 95% confidence interval (CI), adjusting for age and BMI.Findings: In sequencing samples, there were differences in DHCR7 rs1044482 C > T (p = 0.008) and NADSYN1 rs2276360 G > C (p = 0.025) between patients with ULs and healthy controls. DHCR7 rs1044482 was related to the susceptibility to ULs in validation samples (heterogeneous: adjusted OR = 1.967, p = 0.002; homogenous: adjusted OR = 2.494, p = 0.002; additive: adjusted OR = 1.485, p < 0.041; and dominant: adjusted OR = 2.084, p < 0.001). Stratified analysis further showed that the DHCR7 rs1044482 polymorphisms were associated with ULs risks in women over 40 and with 18.5–25.0 BMI. In contrast to the wild-type CG haplotype vectors, individuals with TC haplotypes had a higher risk of developing ULs.Interpretation: The vitamin D anabolism-related gene DHCR7 rs1044482 C > T polymorphism was a risk factor of ULs, especially in patients over 40 with 18.5–25.0 BMI, while the relationship between NADSYN1 rs2276360 and ULs risk was not clear.

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Whole-Exome Sequencing for Identification of Genetic Variants Involved in Vitamin D Metabolic Pathways in Families With Vitamin D Deficiency in Saudi Arabia

Cited by 4 publications

References 29 publications

Use of whole exome sequencing for identification of genetic variants related to Growth Hormone Deficiency and Short Stature: A Family-Based Study

Use of whole exome sequencing for identification of genetic variants related to Growth Hormone Deficiency and Short Stature: A Family-Based Study

Polymorphisms in LRP2 and CUBN genes and their association with serum vitamin D levels and sleep apnea

Association of Vitamin D Anabolism-Related Gene Polymorphisms and Susceptibility to Uterine Leiomyomas

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