Chromosome 15q21-22 related polymorphisms and haplotypes are associated with susceptibility to type-2 diabetic non-proliferative retinopathy
Yao-Yuan, Hsieh, M.D., Ph.D.a,b, Yu-Chuen Huang, Ph.D.a,c,d,e, Chi-Chen Chang, M.D.b,
Yu-Kuo Wang, Ph.D.f, Wen-Hsin Lin, Ph.D.g, Fuu-Jen Tsai, M.D., Ph.D.c,d,e
a School of Chinese Medicine, College of Chinese Medicine, China Medical University,
Taichung, Taiwan.
b Division of Infertility Clinic, Hsieh Yao-Yuan Womens' Hospital, Taichung, Taiwan. c Department of Medical Research, China Medical University Hospital, Taichung, Taiwan.. d Department of Medical Genetics, China Medical University Hospital, Taichung, Taiwan. e School of Post-Baccalaureate Chinese Medicine, College of Chinese Medicine, China
Medical University, Taichung, Taiwan
f Department of Biological Science and Technology, National Chiao Tung University,
Hsinchu, Taiwan
g School of Pharmacy Undergraduate Program Department of Medicine,
China Medical University, No. 91, Hsueh Shih Road., Taichung, Taiwan
Reprints and correspondence to: Fuu-Jen Tsai, M.D., Ph.D.,
Department of Medical Genetics, China Medical University Hospital, No.2 Yuh-Der Road, Taichung, Taiwan
Telephone: 886-4-22052121 ex 2041,
Fax: 886-4-22033295, E-mail: d0704@ mail .cmuh.org.tw
*Yao-Yuan, Hsieh and Yu-Chuen Huang have equal contributions for this survey.
Running title: Chromosome 15q21 SNPs in diabetic retinopathy
Capsule: Chromosome 15q21 related polymorphisms might be associated with diabetic
ABSTRACT
Objective: Diabetic retinopathy (DR) is a microvascular complication of diabetes with a
complex multifactorial pathogenesis. We aimed to investigate if chromosome 15q21-22 related gene polymorphisms could be used as markers of DR susceptibility in type 2 diabetic (T2D) individuals.
Methods: Individuals were divided into three groups: (1) T2D with non-proliferative DR
(NPDR, n=102); (2) T2D with proliferative DR (PDR, n=72); (3) T2D without DR (n=573). Six SNPs (rs7174997, rs3751624, rs8025011, rs17818837, rs2922220, rs2414520) lying within chromosome 15q21-22 region were genotyped by using Illumina HumanHap550-Duo BeadChips. Genotypes/allelic frequencies and haplotypes for these polymorphisms in each group were compared.
Results: The MYO5C related SNP (rs3751624)*A related genotype and allele are associated
with higher susceptibilities to DR, including PDR and NPDR. The rs3751624*GG/AA+AG percentages in each group are: (1) 75.5/24.5%; (2) 73.6/26.4%; (3) 82.5/17.5%. In contrast, the other 5 SNPs in each group were not significantly different. One haplotype (G-A-G-G-T-G) appears significantly different between T2D individuals with and without DR. Other haplotype distributions were not significantly different between each group.
Conclusion: The MYO5C related SNP (rs3751624)*A related genotype/allele and haplotype
(G-A-G-G-T-G) might be associated with susceptibility for retinopathy in T2D individuals. Some chromosome 15q21-22*related genetic variations might contribute to the pathogenesis of DR.
Introduction
Type 2 diabetes (T2D) affects at least 6% of the world population [Zimmet et al., 2001]. T2D is a complex trait characterized by hyperglycemia that results from impaired pancreatic -cell function, decreased insulin action at target tissues and increased glucose output by the liver [Stumvoll et al., 2005]. T2D is considered as a polygenic disorder in which numerous genetic variances confer partial and additive effects. Only 5-10% of T2D are monogenic disorders with single gene defects. Both genetic components and environmental factors might contribute to the pathogenesis of T2D.
Diabetic retinopathy (DR), a microvascular complication of diabetes, remains the commonest cause of visual loss in adults in the developed countries [Caldwell et al., 2003]. The prevalence of retinopathy in T2D patients has been steadily increasing [Mohamed and Wong, 2008]. The pathogenesis of DR is believed to be a complex and multifactorial process. Poor metabolic control, hemodynamic factors and long duration of diabetes might predispose to the development of DR [Stratton et al., 2000]. A recent hypothesis suggested that genetic factors might play certain roles in the pathogenesis of DR. Independent of glycemic control and diabeteic duration, genetic factors play essential roles in the susceptibility to DR [Hallman et al., 2005]. Although many genome screens have been conducted for T2D, there is limited information regarding genetic variation in DR development.
Genetic studies of these multifactorial diseases such as T2D and retinopathy are difficult to approach due to the uncertainty of a polygenic trait. Single nucleotide polymorphisms (SNPs) are the most abundant types of DNA sequence variation in the human genome [Kwok and Gu, 1999]. The SNP markers provide a new way for the identification of complex gene-associated diseases such as T2D and retinopathy. The aim of this study was to assess whether the chromosome 15q21-22 region-related SNPs are associated with T2D and retinopathy. A
total of 6 genetic variations and related haplotypes within chromosome 15q21-22 were evaluated, including rs7174997, rs3751624, rs8025011, rs17818837, rs2922220, and rs2414520. The nearest genes for these SNPs within chromosome 15q21-22 include
CYP19A1, MYO5C, and CGNL1. We tried to search for the roles of these genetic variations in the susceptibility to retinopathy in T2D Taiwanese. To the best of our knowledge, this is the first such survey.
Materials and methods Subjectives
A total of 747 Taiwanese with T2D were recruited and divided: (1) T2D with non-proliferative DR (NPDR) (n=102); (2) T2D with non-proliferative DR (PDR) (n=72); (3) T2D without DR (n=573). All individuals with T2D or retinopathy were evaluated at China Medical University Hospital. All T2D cases were diagnosed using American Diabetic Association Criteria. Subjects with type 1 diabetes, gestational diabetes and MODY
(Maturity-onset diabetes of the young) were excluded from this study. All individuals allowed peripheral blood samplings for genotype analyses.
All T2D subjects permitted complete ophthalmologic examination, including corrected visual acuity, fundoscopic examination, and fundus photography. An expert ophthalmologist graded severity of DR according to international scales of the American Academy of
Ophthalmology. Demographic and clinical data for each group were collected and recorded. This series was approved by the ethical committee and institutional review board of China Medical University Hospital. Informed consent was obtained from all study participants. A questionnaire was designed for collecting information regarding gender, age, age at diagnosis of diabetes, and ocular history.
Genotyping
For the genome-wide association study, genomic DNA was extracted from peripheral blood mononuclear cells using a PUREGENE DNA isolation kit (Gentra Systems,
Minneapolis, MN). SNP discovery and genotyping for rs7174997, rs3751624, rs8025011, rs17818837, rs2922220, and rs2414520 lying near the chromosome 15q21-22 (49409420-55864327) region were obtained from dbSNP (http://ncbi.nih.gov/SNP/) and Applied
variations were suerveyed as previous described [Huang et al., 2011]. In brief, the genotyping using Illumina HumanHap550-Duo BeadChips was performed by deCODE genetics, Inc. (Reykjavík, Iceland). Genotype calling was performed using the standard procedure
implemented in BeadStudio, with default parameters suggested by the platform manufacturer. Quality control of the genotype data was performed by examining several summary statistics. The ratio of loci with heterozygous calls on the X chromosome was calculated to double check the subject gender. Total successful call rate and the minor allele frequency of the cases were also calculated for each single nucleotide polymorphism (SNP). The SNPs were
excluded if they showed one of the following: (1) no polymorphism, (2) a total call rate of <95%, or (3) a minor allele frequency <5%, or a total call rate <99%.
Statistical analyses
Genotype frequencies of each SNP were determined by direct counting. The resulting spectra were processed with SpectroTyper (Sequenom) software. The genotype frequency and allelic frequency distributions in each group were analyzed. Haplotype analysis was
performed using Haploview. The SAS system with 2 test was utilized for statistical analyses.
Allelic frequencies were expressed as a percentage of the total number of alleles. Odds ratios (OR) were calculated from genotype frequencies and allelic frequencies with 95% confidence interval (95% CI) and were adjusted for diabetes duration and HbA1C level. A p-value <0.05
Results
The personal data between each group revealed statistical differences in illness duration, HbA1c levels, systolic blood pressure (BP), and fovel thickness (Table 1). Longer illness duration, higher HbA1c levels, higher systolic BP and larger oveal thickness are associated with T2D with retinopathy. Among these 6 SNPs, only rs3751624 appeared statistically different between each group.
The rs3751624*A related genotype and allele are associated with higher susceptibilities of DR, PDR and NPDR. The rs3751624*GG/AA+AG percentages in each group are: (1) 75.5/24.5%; (2) 73.6/26.4%; (3) 82.5/17.5%, respectively (Table 2). In contrast, the other 5 SNPs in each group were not significantly different. The rs7174997*GG/GT+TT percentages in each group are: (1) 85.3/14.7%; (2) 84.7/15.3%; (3) 87.6/12.4%, respectively (Table 2). The rs8025011*GG/GT+TT percentages in each group are: (1) 96.1/3.9%; (2) 90.3/9.7%; (3) 96.7/3.3%, respectively. The rs17818837*GG/AG+AA percentages in each group are: (1) 18.6/81.4%; (2) 26.4/73.6%; (3) 23.9/76.1%, respectively. The rs2922220*CT+CC/TT percentages in each group are: (1) 96.1/3.9%; (2) 90.3/9.7%; (3) 96.7/3.3%, respectively
(Table 2). The rs2414520*GG/ AA+AG percentages in each group are: (1) 89.2/10.8%; (2)
81.9/18.1%; (3) 90.2/9.8%, respectively.
A total of 6 haplotypes with estimated frequencies 1% are detected.
The haplotypes for these 6 SNPs (G-G-G-G-T-G, G-G-G-G-C-G, G-A-G-G-T-G, T-G-G-G-T-G, G-G-G-G-T-A, G-G-T-A-T-G) in both groups were: 64.1, 8.8, 9.9, 6.2, 4.8, 1.7% and 68.8, 11.2, 6.8, 5.2, 4.4, 0.9%, respectively (Table 3). One haplotype (G-A-G-G-T-G) appeared significantly different between T2D with and without DR. Other haplotypes distributions were not significantly different between each group.
Discussion
T2D, an endocrine illness caused by the malfunction of insulin-dependent glucose and lipid metabolism, is a complex disorder with heterogeneous genetic and environmental background. Whole-genome linkage scans have identified some chromosomal regions linked to T2D. Some T2D-related loci have been identified, including
non-insulin-dependent-diabetes 2 (NIDDM2) loci on chromosome12q24.2 [Gragnoli, 2010], angiotensin-I converting enzyme (ACE) gene on chromosome 17q23 [Chmaisse et al., 2009], etc. Candidate-gene studies provide strong evidence for common variants in peroxisome proliferator-activated receptor-r gene (PPARG) [Altshuler et al., 2000], potassium inwardly-rectifying channel J11 (KCNJ11) [Florez et al., 2004], transcription factor 2 isoform b (TCF2) [Gudmundsson et al., 2007], melatonin receptor 1B (MTNR1B) [Bouatia-Naji et al., 2009], transcription factor 7-like 2 (TCF7L2) [Sladek et al., 2007], juxtaposed with another zinc finger gene 1 (JAZF1) [Zeggini et al., 2008], insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) [Saxena et al., 2007], ADAM metallopeptidase with thrombospondin type 1 motif, 9
(ADAMTS9) [Zeggini et al., 2008], etc. However, few reports studied the role of chromosome 15q21-22 upon T2D and DR.
Chromosome 15q21-22 has been demonstrated to be associated with numerous disorders and pathogenesis, including Marfan syndrome [Hilhorst-Hofstee et al., 2010], keloid
[Nakashima et al., 2010], leukemia [Crowther-Swanepoel et al., 2010], hereditary spastic paraplegia [Kim et al., 2009], reading disabilities [Wigg et al., 2008], mental retardation [Tempesta et al., 2008], lens dislocation and glaucoma [Deng et al., 2008], dyslexia
[Poelmans et al., 2009], psoriatic arthritis [Liu et al., 2008], atopic dermatitis [Enomoto et al., 2007], osteoarthritis [Lee et al., 2006], congenital heart disease [Lalani et al., 2006], myotonic dystrophy [Huang et al., 2005], etc. Loss of heterozygosity (LOH) of 15q21 might have a strong impact upon tumor immunogenicity and the efficiency of cancer immunotherapy
[Maleno et al., 2011]. Deng et al. [Deng et al., 2008] demonstrated that glycosylation of the fibrillin-1 (FBN1) gene located on 15q21.1 might be associated with late-onset bilateral lens dislocation and glaucoma. Deletions or LOH on chromosome 15q21 has been found in numerous human tumors, including cancers of the head, neck, colorectum, breast, lung, prostate, and bladder [Poetsch et al., 2006; Ma et al., 2007]. It suggests the presence of potential tumor suppressor gene(s) in this particular region of chromosome 15q21.
Complications of T2D include retinopathy, nephropathy, neuropathy, and cardiovascular disease. Genetic susceptibility plays an important role in the pathogenesis of DR. Some literature demonstrated the association of DR with genetic variations, including intracellular adhesion molecule (ICAM)-1 gene (K469E, G241A) [Petrovic et al., 2008], vascular
endothelial growth factor [Petrovic et et al., 2008], basic fibroblast growth factor (-834 T/A, 754C/G) [Petrovic et al., 2008; Beranek et al., 2008], matrix metalloproteinases (MMPs) [Beránek et al., 2008], aldose reductase (ALR2) gene (-106C/T) [Olmos et al., 2006], angiotensin-converting enzyme (ACE I/D) [Degirmenci et al., 2005], aldose reductase
(ALR2, (AC)23, (AC)24 allele) [Olmos et al., 1999; 2000], sickle cell trait and gender [Ajayi et al., 2004], etc. In contrast, some non-associated genetic variations with DR have also been demonstrated, including adiponectin (94T/G) [Rudofsky et al., 2005], Von Willebrand factor (1793G/C and Thr789Ala) [Beránek et al., 2002], and methylene-tetrahydro-folate-reductase (MTHFR 677C/T) [Lauszus et al., 2001]. However, no investigator demonstrated the
association of the T2D or DR with the genetic variations within chromosome 15q21.
Myosin Vc (MYO5C) is a novel member of the class V myosins. MYO5C is the product of one of the three genes of the class V myosin found in vertebrates [Takagi et al., 2008]. MYO5C is expressed chiefly in non-neuronal tissues [Rodriguez et al., 2002]. MYO5C is abundant in epithelial and glandular tissues, including pancreas, prostate, mammary, stomach, colon and lung. MYO5C influences actin-based membrane trafficking in many
physiologically crucial tissues [Rodriguez and Cheney, 2002; Jacobs et al., 2009]. MYO5C is a molecular signature marker for endothelial cells [Wada et al., 2011]. MYO5C is associated with function of airway epithelial cells [Lin et al., 2010]. MYO5C associated with Rab8 is involved in the pathogenesis of dengue virus [Xu et al., 2009].
MYO5C is associated with organelle transport [Rodriguez et al., 2002]. MYO5C functions as a cargo transporter by different mechanisms from other myosin V isoforms [Watanabe et al., 2008]. Rab proteins influence vesicle trafficking pathways through the assembly of regulatory protein complexes. Rab GTPases regulate diverse endocytic trafficking pathways through recruitment of MYO5C [Roland et al., 2009]. MYO5C has a role in restraining Na(+)/K(+)-ATPase-containing vesicles within intracellular pools [Lecuona et al., 2009]. MYO5C is associated with the stimulation of cAMP, the recruitment of the Na(+)/K(+)-ATPase to the plasma membrane, and increased activity [Lecuona et al., 2009]. However, the function of MYO5C upon T2D or RD at a molecular level remains obscure.
In this survey, we surveyed the correlation between T2D and some genetic loci on chromosome 15q21-22. We observed MYO5C-region genetic variation (rs3751624) might be associated with retinopathy in T2D individuals. The genotype distributions for rs3751624 in T2D with retinopathy and T2D without retinopathy patients were statistically different. The percentages of rs3751624*A-related genotype (AA,AG) were higher in the individuals with PDR or NPDR. These differences exist in the T2D individuals with DR (including PDR or NPDR) compared to T2D without DR. In contrast, the other 5 SNPs (rs7174997, rs8025011, rs17818837, rs2922220, and rs2414520) on chromosome 15q21-22 region are not associated with DR susceptibility. These findings suggested that MYO5C-related SNPs, such as
rs3751624 polymorphisms within chromosome 15q21-22, might be useful genetic markers in the prediction of prognosis of retinopathy in T2D individuals. The related genetic variations might compromise the progression and pathogenesis of DR.
Our findings also suggest that some MYO5C 1 genetic variations might be involved in DR susceptibility and progression. These novel T2D and RD risk loci might be involved genes implicated in insulin sensitivity, cell function, and control of glucagon and insulin secretion. These MYO5C-related factors might influence the production of chromatin-associated proteins, isopeptidase, proteasome, or signalosome, which further affect the progression of retinopathy. They might also participate in regulation of insulin action on its target cells. These genetic variants might alter glucose signaling in the pancreas, which implicate its role in the regulation of insulin and/or glucagon secretion. It is well known that glucose controls are major susceptibility factors for DR. In this survey, we also observed the different characteristics and the clinical profiles between each group. The age, duration of diabetes, HbA1c, and blood pressure are associated with the RD susceptibility.
In conclusion, we identified one novel locus that predisposed to T2D and DR in Taiwanese. Chromosome 15q21-22 region SNP*rs3751624, might be associated with
susceptibility for retinopathy in T2D patients. The related genetic variations might contribute to the pathogenesis of retinopathy in T2D individuals. Some MYO5C-related genes might be useful markers for the prediction of DR susceptibility. This could provide the database for a further survey of genetic polymorphisms within MYO5C or chromosome 15q21-22 regions. However, the real roles of MYO5C polymorphism upon the T2D and retinopathy remain to be clarified. Other MYO5C gene polymorphisms upon T2D and retinopathy development merits further surveys. Furthermore, future studies of the candidate genes at this locus will identify a specific gene influencing the T2D and retinopathy, which will provide insights into novel regulatory mechanisms of T2D metabolism as well as development of retinopathy. The related surveys might be also important for the development of preventive therapies for T2D and DR.
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Acknowledge: We gratefully acknowledge the National Research Program for Genomic
Medicine from National Science Council, Taiwan, and the National Clinical Core for Genomic Medicine at Academia Sinica (grand number:NSC96-3112-B-001-010) for
providing supports (services) of the statistical analysis, data coordination, subject recruitment, and project management.
