Users Online: 660
Home Print this page Email this page
Home About us Editorial board Search Browse articles Submit article Ahead of Print Instructions Subscribe Contacts Login 

Previous article Browse articles Next article 
Adv Biomed Res 2018,  7:37

A Rare Missense Mutation and a Polymorphism with High Frequency in LDLR Gene among Iranian Patients with Familial Hypercholesterolemia

1 Department of Genetics, Faculty of Medicine; Medical Genetics Research Center, Yazd, Iran
2 Yazd Clinical and Research Center for Infertility, Yazd, Iran
3 Department of Genetics and Molecular Biology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
4 Yazd Cardiovascular Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
5 Department of Genetics, Faculty of Medicine; Yazd Clinical and Research Center for Infertility, Yazd, Iran

Date of Web Publication22-Jan-2018

Correspondence Address:
Dr. Ehsan Farashahi Yazd
Department of Genetics, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences Campus, Shohadaye Gomnam Blvd., 8915173143, Yazd
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2277-9175.225927

Rights and Permissions

Background: Familial hypercholesterolemia (FH) is a disorder that is inherited by autosomal dominant pattern. The main cause of FH disease is the occurrence of mutations in low-density lipoprotein receptor (LDLR) gene sequence, as well as apolipoprotein B and proprotein convertase subtilisin/kexin type 9 genes, located in the next ranks, respectively. Materials and Methods: Forty-five unrelated Iranian patients with FH were screened using a high-resolution melting (HRM) method for exon 9 along with intron/exon boundaries of LDLR gene. Samples with shift in resultant HRM curves were compared to normal ones, sequenced, and analyzed. Results: Our findings revealed a missense mutation c. 1246C>T and a known variant IVS9-30C>T (rs1003723) that was recognized in 71% of the patients (22%: homozygous and 49%: heterozygous genotypes). In silico analysis, predicted the pathological effect of the c. 1246C>T mutation in LDLR protein structure, but IVS9-30C>T variant had no predicted effect on splice site and branch point function. Conclusion: FH is a hereditary type of hypercholesterolemia that leads to premature cardiovascular disease and atherosclerosis, and early diagnosis is needed. We detected a rare missense mutation (1246C>T) and a common single nucleotide polymorphism (SNP) in the Iranian population. These reports could help in the genetic diagnosis and counseling of FH patients.

Keywords: Familial hypercholesterolemia, high-resolution melting, Iran, low-density lipoprotein receptor, missense mutation

How to cite this article:
Tajamolian M, Kolahdouz P, Nikpour P, Forouzannia SK, Sheikhha MH, Yazd EF. A Rare Missense Mutation and a Polymorphism with High Frequency in LDLR Gene among Iranian Patients with Familial Hypercholesterolemia. Adv Biomed Res 2018;7:37

How to cite this URL:
Tajamolian M, Kolahdouz P, Nikpour P, Forouzannia SK, Sheikhha MH, Yazd EF. A Rare Missense Mutation and a Polymorphism with High Frequency in LDLR Gene among Iranian Patients with Familial Hypercholesterolemia. Adv Biomed Res [serial online] 2018 [cited 2020 Sep 24];7:37. Available from:

  Introduction Top

The level of the cholesterol is affected by many factors, including lifestyle, diet, and heredity factors.[1] Familial Hypercholesterolemia (FH) (OMIM 143890) is a hereditary type of hypercholesterolemia that is generally transmitted in an autosomal dominant pattern.[1],[2] FH is categorized as a lipoprotein metabolism disorder with a frequency of 1:500 in the heterozygote form in most population; but its homozygote form is infrequent (1:1000000 in a live born), extremely severe and usually causes death in the early decades of life.[3]

The main pathophysiology of FH is generally the mutation in low-density lipoprotein receptor (LDLR) gene,[4] and less frequently in apolipoprotein B (APOB) and proprotein convertase subtilisin/kexin type 9 genes.[5]LDLR gene is located on chromosome 19 and has 18 exons with length 45 kbps. Up to now, over 1288 unique mutations and allelic variants have been identified in LDLR gene.[6] The mutation distribution and frequency in LDLR gene are not balanced through the gene sequence. According to the study of Palacios et al.,[7] some exons such as four and nine have the highest frequency through the LDLR exons among different populations worldwide.

In physiological conditions, LDLRs regulate cholesterol metabolism by up taking LDL-cholesterol (LDL-C) from blood circulation [8] and this process is mediated by ApoB protein; which is a fundamental part of the LDL particle. Mutations in LDLR gene result in lack of functional LDLR on the surface of hepatocytes that subsequently increases the plasma LDL level.[9] The raised levels of LDL-C and total cholesterol (TC) in plasma are the most important biochemical characteristics of FH.[10] The deposited cholesterol in peripheral tissues causes xanthomas, xanthelasma, arcus senilis, and increases the risk of premature atherosclerosis, coronary heart disease, and eventually myocardial infarction (MI).[11] Early diagnosis and clinical management of the elevated cholesterol will decrease the risk of atherosclerosis, premature cardiovascular condition and improve the prognosis in patients with FH.[12] The genetic mutation screening in FH patients has been found to be cost-effective and could help early diagnosis and management.[13] Genetic studies of patients with FH around the world were mostly performed in non-Iranian population, and there are few studies have investigated Iranian population.[14],[15],[16] In these limited studies, mainly, the genetic alteration profiles of exon four of LDLR gene were investigated and to the best of our knowledge, there is only one study exploring the exon 9 of LDLR in the Iranian FH population.[17] Thus, according to high frequency of mutation that has been reported in this exon among many population around the world and the limited studies on it in Iran, we screened this part of LDLR gene in 45 unrelated Iranian patients suspected to FH.

  Materials and Methods Top

Sample collection

Dutch Lipid Clinic Network (DLCN) criteria were used for screening FH patients among people with hypercholesterolemia.[18] Finally, 45 unrelated patients of 500 suspected FH patients were selected from hospitals/clinics Shahid Sadoughi University of Medical Sciences (Yazd, Iran). The sampling protocol was reviewed and accepted by Shahid Sadoughi University of Medical Sciences Ethics Committee.

Lipid profile

Lipid profile containing TC, LDL-C, high-density-lipoprotein-cholesterol (HDL-C) and triglyceride (TG) of all the subjects were obtained with BT3000 PLUS automated system by using commercial kits cholesterol-L (CHOD-PAP) Cat. No. 135 L, cholesterol-LDL direct-L Cat. No. 145 L, cholesterol-HDL direct-L Cat. No. 143 L and TGs-L (GPO-PAP) Cat. No. 315 L (Biotecnica Instruments, Rome, Italy).

Primer designing

Polymerase chain reaction (PCR) primers for amplifying exon 9 and the exon-intron boundaries of it were designed using the GenRunner software ( and Oligo7.5 ( NCBI primer blast [19] was used to check the primers for specificity against LDLR gene.

DNA extraction and measurement

Genomic DNA (gDNA) was extracted from whole blood by AccuPrep ® gDNA Extraction Kit (Bioneer, Daejeon, Korea) according to the manufacturer's instruction. The purity and quality of DNA samples were measured by Thermo Scientific™ NanoDrop 2000 (Thermo Scientific, Waltham, MA, USA).

Polymerase chain reaction and high-resolution melting

PCR and high-resolution melting (HRM) were accomplished by Rotor-Gene Q 2plx HRM (Qiagen, Hilden, Germany) using Type-it HRM PCR Kit (Qiagen, Hilden, Germany) with 60 ng of gDNA and 13 pmol of each primer in a final volume of 25 μl, in accordance with manufacturer's instruction. The amplified segment of exon 9, including coding region and exon-intron boundaries of LDLR, was screened by HRM as described in Whittall et al. procedure [20] and the samples with a shift in HRM and melting temperature curves were then sequenced.


The amplified products were purified using the ExoSAP-ITzreg Purification Kit from Affymetrix/USB and sequenced by ABI3730XL (Applied Biosciences, ABI) sequence system in the MacroGen company (Macrogen, Seoul, Korea).

In-silico analysis

For predicting the mutation effects on the function of LDLR protein in-silico, web-based tools including PolyPhen 2 ( 2/) sift ( and Mutation-t@ster ( were used. These software programs predict the possible impacts of an amino acid substitution on the structure and function of a human protein by considering evaluating its physical and molecular characteristics in compared to the database.[21],[22],[23] Furthermore, HOPE tool (homotopy optimization using perturbations and ensembles)[24] was employed to determine the mutation effects on the three-dimensional (3D) structure of protein. T-coffee tool was also used for evaluating and manipulating multiple alignments of protein sequences and structures.[25] The possible effects of nucleotide changes (in intronic conserved site) on splicing process were investigated using Splice Port, NetGene2 Server and Human Splicing Finder software programs.[26],[27],[28] These programs provide predictive scores for splicing site and branch point sequence for wild and modified sequence types.

  Results Top

Clinical characteristics of the patients

The medical history and clinical examination of 45 possible FH subjects that they gained DLCN diagnostic criteria revealed that 82.2% of them had family history of coronary artery disease and MI, 46.6% had combined xanthelasmata with corneal arcus, 24.4% had combined xanthomata and corneal arcus, 13.3% had corneal arcus alone, 8.8% had corneal arcus with xanthelasmata, and 4.4% had xanthelasmata alone [Table 1].
Table 1: Lipid profile of the studied patients

Click here to view

A rare missense mutation was found in low-density lipoprotein receptor gene among Iranian patients

PCR-HRM technique was employed for nucleotide alteration screening in exon 9 (coding region and exon-intron boundaries) of the LDLR gene. The missense mutation, c. 1246C>T; p.(R416W) was detected in exon 9 in one patient after DNA sequencing of modified HRM profile in comparison to normal ones [Figure 1].
Figure 1: High-resolution melting and sequencing of low-density lipoprotein receptor exon 9 showing c.1246C>T; p.(R416W) in a patient. (a) High-resolution melting. The wild type profile and shift in patient are shown. (b) Sequencing. The homozygous sequence of the variant in patient is shown in the upper panel and the wild type sequence in the bottom panel. The relevant bases are arrowed

Click here to view

The arginine (Arg), amino acid in this site in different species, is extremely conserved [Figure 2] and moreover, our prediction by polyPhen-2 (“Sift” and “Mutation Taster” were also used, and their results are shown in [Table 2]) also showed that this change could be “Probably Damaging” (score 0.998). The change in ionic charge, hydrophobicity, and size of the amino acid side chain when Arg to tryptophan substitution happens is expected to bring about an alteration in the protein conformation. This expectancy was also illustrated by protein modeling in [Figure 3].
Figure 2: Amino acid conservation in different species. The low-density lipoprotein receptor protein of the species indicated was aligned using ClustalW (T-Coffee Server). The relevant amino acid, p.R416W, is arrowed showing that the amino acid is highly conserved across species

Click here to view
Table 2: In-silico analysis of nucleotide changes and the predicted impacts

Click here to view
Figure 3: The three-dimensional structural effect of the low-density lipoprotein receptor mutation. (a) Three-dimensional structure of the protein with purple area representing the site of mutation. (b) Close-up of the mutation. The protein is Gray, the side chains of both the wild-type and the mutant residue are shown in green and red respectively. (c) The wild-type structure with the arginine side chain. (d) The substitution of Tryptophan results in the change of the side chain thereby affecting the charge, hydrophobicity, and size of the amino acid. (e) The structural representation of arginine and tryptophan

Click here to view

High frequency of rs1003723 polymorphism among Iranian patients

The PCR-HRM analysis and DNA sequencing of the patients showed 32 (CT: 22 and TT: 10) of them has a polymorphism that has not been previously reported in Iran [Figure 4], and its allele frequency was about 71.1% among investigated patients. This polymorphism, IVS9-30C>T (rs1003723), was detected in intron 9 of LDLR gene. As for, the site of this polymorphism were analyzed by different programs, including “NetGene2,” “Splice port,” and “Human splicing finder” to predict the potential effect(s) of it on splicing procedure of LDLR transcript (produced results has been shown in [Table 2]). All of them predicted that rs1003723 has no effect on splice sites, branch point, or alternative splice sites.
Figure 4: High-resolution melting and sequencing of low-density lipoprotein receptor intron 9 showing IVS9-30C>T (rs1003723) in patients. (a) High-resolution melting. The wild type profile and shifts in patients are shown. The heterozygous and homozygous patients are distinguishable in their curve. (b) Sequencing. The homozygous sequence of the variant in a patient is shown in the upper panel; the heterozygous sequence is shown in the middle panel and the wild type sequence in the bottom panel. The relevant bases are arrowed

Click here to view

  Discussion Top

LDLR protein has different domains and any modification in their function can result in a spectrum of hypercholesterolemia with various severities. The epidermal growth factor (EGF) precursor homology domain which is encoded by exons 7–14 of LDLR gene is located near the ligand binding domain and includes two EGF-like motifs, a series of six YWTD repeats and again EGF-like motif. Second and third EGF-like motifs accompanied by YWTD repeats create six bladed β-propeller that is responsible for the release of LDL particle at low pH of endosome and recycling of the receptor to the cell membrane.[29] Mutations in these repeats and C-terminal of the third EGF-like motif can cause defects in releasing of the receptors from the LDL particle in the endosome by interruption of the β-propeller configuration.[29],[30] The recently recognized mutation, c.1246C>T; p.(R416W), is close to the YWDT repeats. Therefore, the defective recycling of the receptor by this change may finally decrease the number of cell surface LDLR, and increases TC and LDL-C levels.

Chiou and Charng [31] have previously reported two nucleotide substitutions in this amino acid; c.1246C>T; p.(R416W), similar to our result, and c.1247G>T; p.(R416 L) among the Taiwanese population. The evaluation of R416 conservation reveals that this amino acid residue in this site is highly conserved among different species of vertebrates [Figure 3]. Furthermore, our predicted effects of the p.(R416W) on protein structure revealed that these changes, i.e., R416W and R416 L can have different effects on LDLR protein. The R416W is potentially able to result in the loss of hydrogen bonds and/or disturbing correct folding, while R416 L causes the loss of interactions with other molecules.

Etxebarria et al. have recently acclaimed that this mutation does not affect expression levels of LDLR but can significantly reduce the presence of receptors on the mutant cell surfaces. He ascertains that this phenomenon is related to defects in the returning procedure of receptors in the cell surfaces and locates this mutation in class IV of LDLR pathogenic variants.[32] Hence, the c.1246C>T variant in exon 9 in this study is supposed to be the causal variant involved in elevated serum cholesterol levels in the patients and the other mutation c.1247G>T; p.(R416 L) seems to have a benign effect on 3D structure of LDLR protein.

We also identified an SNP, IVS9-30C>T (rs1003723), with high frequency among investigated patients. The minor allele frequency of rs1003723 in 1000 genome project was reported t = 28.2%. However, the frequency of this allele in investigating patients with FH was 71.1%. Andreotti et al. have previously studied this allele in a Chinese population.[33],[34] Their results showed that this allele is associated with high TC and LDL.[33] They also claimed that this polymorphism can be associated with a 1.5-fold increased risk of bile duct cancer [34] but its mechanism is not clear. Our in-silico analysis did not predict any effect from IVS9-30C>T on splice sites, branch point or alternative splice sites. However, recent In-silico investigation for finding mirtrons in human genome has predicted that the sequence of intron 9 consists of mirtron (miR6886)[35] and rs1003723 SNP is exactly placed in the loop on this predicted mirtron.

  Conclusion Top

FH is a hereditary type of hypercholesterolemia that leads to premature cardiovascular disease and atherosclerosis, and early diagnosis is needed. We detected a rare missense mutation (1246C>T) and a common SNP in Iranian population. These reports will help in the genetic diagnosis and counseling of FH patients.

In the future, investigation of other regions of LDLR sequence and different related genes involved in cholesterol metabolism in the patient that has missense homozygous 1246C>T would be able to make us more sure about clinical effect(s) of this mutation on LDLR function. Moreover, further study about the frequency of rs1003723 SNP (T-allele) in normal Iranian population in comparison to population with FH, and determining the effects of it on miR6886 function are other aims that we will follow them. Finally seems to be elucidating the role of miR6886 in the regulation of TC concentration in blood could be explained the susceptibility to bile duct cancer and would be able to open a new perspective regarding the effects of noncoding RNA (ncRNA) on LDL level in blood and related resultant diseases.


We greatly appreciate the family members who participated in this project. We are grateful to Mahmood Akhavan Tafti, Lab Manager for Central Laboratory Shahid Sadoughi University of Medical Sciences, Yazd, Iran, for help during the sample collection. We wish to thank Ebrahim M. Kolahdouz and Ali Atabaki for their useful comments on the grammatical structure and reviews of this manuscript.

Financial support and sponsorship

This study was funded by Shahid Sadoughi University of Medical Sciences, Yazd, Iran.

Conflicts of interest

There are no conflicts of interest.

  References Top

Chahil JK, Lye SH, Bagali PG, Alex L. A novel pathogenic variant of the LDLR gene in the Asian population and its clinical correlation with familial hypercholesterolemia. Mol Biol Rep 2012;39:7831-8.  Back to cited text no. 1
Goldstein JL, Hobbs HH, Brown MS. Familial hypercholesterolemia. In: The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York: McGraw-Hill Book Co.; 2001. p. 2863-913.  Back to cited text no. 2
Goldstein JL, Hobbs HH, Brown MS. Familial hypercholester-olemia. In: Scriver CR, Beaudet AL, Sly WS, Valle D, editors. The Metabolic Basis of Inherited Disease. New York, NY: McGraw-Hill Book Co; 1995. p. 1981-2030.  Back to cited text no. 3
Varret M, Abifadel M, Rabès JP, Boileau C. Genetic heterogeneity of autosomal dominant hypercholesterolemia. Clin Genet 2008;73:1-13.  Back to cited text no. 4
Brown MS, Goldstein JL. A receptor-mediated pathway for cholesterol homeostasis. Science 1986;232:34-47.  Back to cited text no. 5
Usifo E, Leigh SE, Whittall RA, Lench N, Taylor A, Yeats C, et al. Low-density lipoprotein receptor gene familial hypercholesterolemia variant database: Update and pathological assessment. Ann Hum Genet 2012;76:387-401.  Back to cited text no. 6
Palacios L, Grandoso L, Cuevas N, Olano-Martín E, Martinez A, Tejedor D, et al. Molecular characterization of familial hypercholesterolemia in Spain. Atherosclerosis 2012;221:137-42.  Back to cited text no. 7
Austin MA, Hutter CM, Zimmern RL, Humphries SE. Genetic causes of monogenic heterozygous familial hypercholesterolemia: A HuGE prevalence review. Am J Epidemiol 2004;160:407-20.  Back to cited text no. 8
Anderson RG. Joe Goldstein and Mike Brown: From cholesterol homeostasis to new paradigms in membrane biology. Trends Cell Biol 2003;13:534-9.  Back to cited text no. 9
Lye SH, Chahil JK, Bagali P, Alex L, Vadivelu J, Ahmad WA, et al. Genetic polymorphisms in LDLR, APOB, PCSK9 and other lipid related genes associated with familial hypercholesterolemia in Malaysia. PLoS One 2013;8:e60729.  Back to cited text no. 10
Ahmed W, Ajmal M, Sadeque A, Whittall RA, Rafiq S, Putt W, et al. Novel and recurrent LDLR gene mutations in Pakistani hypercholesterolemia patients. Mol Biol Rep 2012;39:7365-72.  Back to cited text no. 11
Al-Allaf FA, Coutelle C, Waddington SN, David AL, Harbottle R, Themis M. LDLR-Gene therapy for familial hypercholesterolaemia: Problems, progress, and perspectives. Int Arch Med 2010;3:36.  Back to cited text no. 12
Jarvik GP, Brunzell JD, Motulsky AG. Frequent detection of familial hypercholesterolemia mutations in familial combined hyperlipidemia. J Am Coll Cardiol 2008;52:1554-6.  Back to cited text no. 13
Farrokhi E, Shayesteh F, Asadi Mobarakeh S, Roghani Dehkordi F, Ghatreh Samani K, Hashemzadeh Chaleshtori M. Molecular characterization of Iranian patients with possible familial hypercholesterolemia. Indian J Clin Biochem 2011;26:244-8.  Back to cited text no. 14
Fard-Esfahani P, Khatami S. Familial hypercholesterolemia in Iran: A novel frameshift mutation in low density lipoprotein receptor (LDLR) gene. Iran J Pathol 2010;5:22-6.  Back to cited text no. 15
Fard-Esfahani P, Zeinali C, Rouhi-Dehboneh S, Taghikhani M, Khatami S.A novel mutation in exon 4 of the low density lipoprotein (LDL) receptor gene in an Iranian familial hypercholesterolemia patient. Iran Biomed J 2005;9:139-42.  Back to cited text no. 16
Shayesteh F, Farrokhi E, Shirani M, Modarresi M, Roghani F, Hashemzadeh M. The study of mutations of the 9 exons of LDLR gene in patients with familial hypercholesterolemia in Cheharmahal Bakhtiari province. Arak Univ Med Sci J 2011;13:30-7.  Back to cited text no. 17
Yuan G, Wang J, Hegele RA. Heterozygous familial hypercholesterolemia: An underrecognized cause of early cardiovascular disease. CMAJ 2006;174:1124-9.  Back to cited text no. 18
Ye J, Coulouris G, Zaretskaya I, Cutcutache I, Rozen S, Madden TL. Primer-BLAST: A tool to design target-specific primers for polymerase chain reaction. BMC Bioinformatics 2012;13:134.  Back to cited text no. 19
Whittall RA, Scartezini M, Li K, Hubbart C, Reiner Z, Abraha A, et al. Development of a high-resolution melting method for mutation detection in familial hypercholesterolaemia patients. Ann Clin Biochem 2010;47(Pt 1):44-55.  Back to cited text no. 20
Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, et al. Amethod and server for predicting damaging missense mutations. Nat Methods 2010;7:248-9.  Back to cited text no. 21
Schwarz JM, Cooper DN, Schuelke M, Seelow D. MutationTaster2: Mutation prediction for the deep-sequencing age. Nat Methods 2014;11:361-2.  Back to cited text no. 22
Kumar P, Henikoff S, Ng PC. Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc 2009;4:1073-81.  Back to cited text no. 23
Venselaar H, Te Beek TA, Kuipers RK, Hekkelman ML, Vriend G. Protein structure analysis of mutations causing inheritable diseases. An e-Science approach with life scientist friendly interfaces. BMC Bioinformatics 2010;11:548.  Back to cited text no. 24
Di Tommaso P, Moretti S, Xenarios I, Orobitg M, Montanyola A, Chang JM, et al. T-Coffee: A web server for the multiple sequence alignment of protein and RNA sequences using structural information and homology extension. Nucleic Acids Res 2011;39:W13-7.  Back to cited text no. 25
Hebsgaard SM, Korning PG, Tolstrup N, Engelbrecht J, Rouzé P, Brunak S. Splice site prediction in Arabidopsis thaliana pre-mRNA by combining local and global sequence information. Nucleic Acids Res 1996;24:3439-52.  Back to cited text no. 26
Desmet FO, Hamroun D, Lalande M, Collod-Béroud G, Claustres M, Béroud C. Human splicing finder: An online bioinformatics tool to predict splicing signals. Nucleic Acids Res 2009;37:e67.  Back to cited text no. 27
Dogan RI, Getoor L, Wilbur WJ, Mount SM. SplicePort – An interactive splice-site analysis tool. Nucleic Acids Res 2007;35:W285-91.  Back to cited text no. 28
Jeon H, Meng W, Takagi J, Eck MJ, Springer TA, Blacklow SC. Implications for familial hypercholesterolemia from the structure of the LDL receptor YWTD-EGF domain pair. Nat Struct Biol 2001;8:499-504.  Back to cited text no. 29
Springer TA. An extracellular beta-propeller module predicted in lipoprotein and scavenger receptors, tyrosine kinases, epidermal growth factor precursor, and extracellular matrix components. J Mol Biol 1998;283:837-62.  Back to cited text no. 30
Chiou KR, Charng MJ. Detection of mutations and large rearrangements of the low-density lipoprotein receptor gene in Taiwanese patients with familial hypercholesterolemia. Am J Cardiol 2010;105:1752-8.  Back to cited text no. 31
Etxebarria A, Benito-Vicente A, Palacios L, Stef M, Cenarro A, Civeira F, et al. Functional characterization and classification of frequent low-density lipoprotein receptor variants. Hum Mutat 2015;36:129-41.  Back to cited text no. 32
Andreotti G, Menashe I, Chen J, Chang SC, Rashid A, Gao YT, et al. Genetic determinants of serum lipid levels in Chinese subjects: A population-based study in Shanghai, China. Eur J Epidemiol 2009;24:763-74.  Back to cited text no. 33
Andreotti G, Chen J, Gao YT, Rashid A, Chen BE, Rosenberg P, et al. Polymorphisms of genes in the lipid metabolism pathway and risk of biliary tract cancers and stones: A population-based case-control study in Shanghai, China. Cancer Epidemiol Biomarkers Prev 2008;17:525-34.  Back to cited text no. 34
Ladewig E, Okamura K, Flynt AS, Westholm JO, Lai EC. Discovery of hundreds of mirtrons in mouse and human small RNA data. Genome Res 2012;22:1634-45.  Back to cited text no. 35


  [Figure 1], [Figure 2], [Figure 3], [Figure 4]

  [Table 1], [Table 2]


Previous article  Next article
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

  In this article
Materials and Me...
Article Figures
Article Tables

 Article Access Statistics
    PDF Downloaded135    
    Comments [Add]    

Recommend this journal