1p13 Locus Research Articles

Impact of rs599839 Polymorphism on Coronary Artery Disease Risk in Saudi Diabetic Patients.

Coronary artery diseases may be affected by several genetic and nongenetic factors. Single-nucleotide polymorphism (SNP) rs599839 and type 2 diabetes mellitus (T2DM) can affect the occurrence and severity of coronary artery disease (CAD). Our aim was to investigate how T2DM and the rs599839 variant affected serum lipid levels and the degree of CAD patients' coronary artery stenosis. rs599839 polymorphism genotyping was done on Saudi patients with coronary angiography performed previously. Patients enrolled were divided into group A (360 DM patients), group B (225 DM patients with CAD), and group C (190 healthy volunteers as control). Individuals with diabetes and CAD who possessed the GG genotype in rs599839 exhibited markedly reduced means of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG; 224.5, 116.2, and 221.4 versus 251.6, 131.3, and 261.7 mg/dl, p=0.003, 0.007, and 0.025, respectively) than AA genotype. The odds ratio and the confidence interval of 95% for G allele carriers of rs599839 were OR = 0.62, 95% CI: 0.41-0.82, and p=0.003, among diabetic patients with CAD. In patients with diabetic CAD, the locus 1p13.3 polymorphism rs599839 was found to be substantially correlated with serum lipid levels. Furthermore, among Saudi patients with diabetes, the G allele of rs599839 variant lowers the CAD risk.

PSRC1 rs599839 G allele may promote protection from coronary artery disease in a Madeira Island population

Abstract Previous research associates the PSRC1 gene on the chromosomal locus 1p13.3 with coronary artery disease (CAD). Specifically, the A wild allele of the PSRC1 rs599539 A>G was identified as a risk allele for CAD, and the mutated G minor allele with a reduced risk of CAD. However, the underlying genetic mechanism is not yet fully understood and is controversial in other populations. Aim To investigate the association of rs599839 A>G variant with CAD risk and lipid profile in a Portuguese population from Madeira Island. Materials and Methods We performed a case-control study including 3161 participants, 1724 patients with CAD (78.7% male) and 1437 controls (76.3% male). Coronary patients were recruited from the Madeira Central Hospital, and controls were from the normal population. PSRC1 was genotyped by TaqMan allelic discrimination assay (Applied Biosystems, 7300 Real-Time PCR). Pearson´s Chi-squared test evaluated the association between CAD-genotypes and the t Student test for genotypes-lipid levels. Results PSRC1 rs599839 A>G variant was within Hardy -Weinberg equilibrium. The wild dominant model (AA+AG) conferred a trend for CAD risk (OR=1.16; p=0.414), and the mutated dominant model (GG+GA) presented slight protection for CAD susceptibility. However, the minor G (protector) allele was associated with low levels of total cholesterol (p=0.003) and LDL-cholesterol (p=0.004). Conclusions This finding is consistent with previous reports indicating a decrease in LDL-C and total cholesterol levels in carriers of the minor allele G of rs599839. Recent research refers that this allele could affect PSRC1 expression, resulting in lower levels of LDL cholesterol and reduced risk of CAD. In contrast, the A wild allele is associated with high LDL levels. PSRC1, lipid, and CAD risk is a complex topic involving genetic, epigenetic and environmental factors.

Concomitant deletion of the short arm (del(1p13.3)) and amplification or gain (1q21) of chromosome 1 by fluorescence in situ hybridization are associated with a poor clinical outcome in multiple myeloma.

Chromosome 1 abnormalities in multiple myeloma (MM) are increasingly recognized as high risk-defining features. The authors report the prognostic value of del(1p13.3) by fluorescence in situ hybridization (FISH) at enrollment in subjects treated on total therapy clinical trials 2-6. FISH probes were generated from specific BAC DNA clones for the AHCYL1 gene locus (1p13.3) and the CKS1B locus (1q21). A total of 1133 patients were included in this analysis. Although del(1p13.3) was detected in 220 (19.4%) patients, 1q21gain or 1q21amp were observed in 300 (26.5%) and 150 (13.2%) patients, respectively. Concomitant del(1p13.3) with 1q21 gain or amp was observed in 65 (5.7%) and 29 (2.5%) patients, respectively. There was enrichment of high-risk features such as International Staging System (ISS) stage 3 disease and gene expression profiling (GEP)70 high risk (HR) in the group with del(1p13.3). Presence of del(1p13.3) confers inferior progression-free survival (PFS) and overall survival (OS). On multivariate analysis, the presence of ISS stage 3 disease, GEP70 HR, 1q21gain, and 1q21amp were independent predictors of PFS or OS. The PFS and OS of patients with combined abnormalities of del (1p13.3)/1q21gain or amp was significantly worse compared to del(1p13.3) alone and 1q21gain or 1q21 amp alone, which identifies a subset of patients with poor clinical outcomes.

Concomitant Deletion of Short Arm (del 1p) and Amplification or Gain (1q21) of Chromosome 1 By Fluorescence in Situ Hybridization (FISH) Is Associated with Poor Clinical Outcome

Introduction- Chromosome 1 abnormalities in multiple myeloma (MM) are increasingly recognized as high risk defined features. While there is robust data on 1q21 gain and amplification (amp), the clinical characteristics and outcome of patients with del 1p is less defined. Novel agents are incorporated into a backbone of multi-agent chemotherapy and tandem autologous stem cell transplantation (ASCT) in successive Total Therapy (TT) protocols for MM patients. We hereby report the prognostic value of del 1p by FISH at enrollment in subjects treated on TT protocols.Methods: (FISH was performed on bone marrow obtained at the time of first visit to our institution or initial diagnosis. FISH probes were generated from specific BAC DNA clones for AHCYL1 gene locus (1p13.3) and CKS1B locus (1q21). MM cells were identified post-hybridization using isotype specific antibody conjugated with 7-amino-4-methylcoumarin-3-acetic acid (AMCA) to stain Ig-Kappa or Ig-Lambda light chain in cytoplasm (cIg) of myeloma tumor cells. The FISH signals in 100 myeloma cells were recorded. For this analysis, 3 copies of 1q21 are considered as 1q21 gain and ≥ 4 copies as 1q21 amp. A 20% cutoff point was used for detection of significant abnormalities, i.e. del 1p and 1q21 gain and amp. A multivariable logistic regression model was used to examine the combined effects of clinical variables on progression free (PFS) and overall survival (OS).Results- A total of 1133 patients were included in this analysis. The median age was 60 (range 30.2-75), 434 (38.3%) patients were female and 106 (9.4%) were African Americans. ISS stage III disease accounted for 287 (25.3%). GEP70 high-risk was noted in 160/1133 (14.1%) of all patients. Of all patients, 1084 (95.7%) had at least one ASCT and 812 (71.7%) had tandem upfront ASCT. Metaphase cytogenetic abnormalities were noted in 548 (48.4%). While del 1p was detected in 220 (19.4%) patients, 1q21 gain or amplification were observed in 300 (26.5%) and 150 (13.2%) patients, respectively. Isolated 1q21 gain and amplification without del 1p were seen in 235 (20.7%) and 121 (10.7%) patients. Overall, there was enrichment of high-risk features such as ISS stage III disease (5.7% vs 10.9% p=0.049), GEP70 high-risk (8.4% vs 36.8%), GEP 70 subtypes such as MF (4.6% vs 8.2%), MS (10.5% vs 13.6%) and PR (11.3% vs 22.7%) and abnormal cytogenetic abnormalities (45.7% vs 59.5% p=<0.01) in the group with del 1p . The median progression free survival (57 vs 39m; p= <0.0004) and overall survival (131 vs 89 m; p=<0.0013) were inferior in the subgroup with del 1p. On multivariate analysis, presence of ISS stage III disease, GEP high-risk, 1q21 gain and amplification were significant while presence of del 1p did not emerge as independent predictors of PFS or OS. Next, we looked at concomitant 1q21 gain and amp in the context of del 1p. del 1p with 1q21 gain or amp was observed in 65 (5.7%) and 29 (2.5%) patients, respectively. The PFS of the group with combined del 1p/1q21 gain and del 1p/1q21 amp were 25m and 35m respectively compared to 44 m with 1q21 gain and 37m with 1q21 amp alone. The OS of the group with both 1 del 1p/1q21 gain and del 1p/1q21 amp were dismal at 59m and 84 m respectively compared to 108 m with 1q21 gain and 76 m with 1q21 amp alone (Fig 1).Conclusion: Deletion of short arm of chromosome 1p was observed in 19% of MM patients. Concomitant del 1p with 1q21 gain and /or amp was present in 8% of patients. The PFS and OS of patients with combined del1p/1q21gain abnormalities was significantly worse compared to del 1p alone and 1q21 gain alone and thus identifies a subset of patients with poor clinical outcome. [Display omitted] DisclosuresMohan: Medical College of Wisconsin: Current Employment.

Identification of Novel Pleiotropic SNPs Associated with Osteoporosis and Rheumatoid Arthritis.

Genome-wide association studies (GWASs) have identified hundreds of genetic loci for osteoporosis (OP) and rheumatoid arthritis (RA), individually, however, a large proportion of the total trait heritability remains unexplained. Previous studies demonstrated that these two diseases may share some common genetic determination and risk factors, but they were generally focused on individual trait and failed to identify the common variants that play key functional roles in the etiology of these two diseases. Here, we performed a conditional false discovery rate (cFDR) analysis to identify novel pleiotropic variants shared between them by integrating two independent GWASs with summary statistics for total body bone mineral density (TB-BMD, a major risk factor for osteoporosis) (n = 66,628) and RA (n = 58,284). A fine-mapping approach was also applied to identify the most probable causal variants with biological effects on both TB-BMD and RA. As a result, we found 47 independent pleiotropic SNPs shared between TB-BMD and RA, and 40 of them were validated in heel ultrasound estimated BMD (eBMD), femoral neck BMD (FN-BMD) or lumbar spine (LS-BMD). We detected one SNP (rs13299616) was novel and not identified by previous BMD or RA-related studies. Combined with fine-mapping and GWAS-eQTL colocalization analyses, our results suggested that locus 1p13.2 (including PTPN22, MAGI3, PHTF1, and RSBN1) was an important region to regulate TB-BMD and RA simultaneously. These findings provide new insights into the shared biological mechanisms and functional genetic determinants between OP and RA, and novel potential targets for treatment development.

Neural crest-derived tumor neuroblastoma and melanoma share 1p13.2 as susceptibility locus that shows a long-range interaction with the SLC16A1 gene.

Neuroblastoma (NB) and malignant cutaneous melanoma (CMM) are neural crest cells (NCC)-derived tumors and may have a shared genetic basis, but this has not been investigated systematically by genome-wide association studies (GWAS). We took a three-staged approach to conduct cross-disease meta-analysis of GWAS for NB and CMM (2101 NB cases and 4202 controls; 12 874 CMM cases and 23 203 controls) to identify shared loci. Findings were replicated in 1403 NB cases and 1403 controls of European ancestry and in 636 NB, 508 CMM cases and 2066 controls of Italian origin. We found a cross-association at locus 1p13.2 (rs2153977, odds ratio = 0.91, P = 5.36 × 10-8). We also detected a suggestive (P < 10-7) NB-CMM cross-association at 2q37.1 with opposite effect on cancer risk. Pathway analysis of 110 NB-CMM risk loci with P < 10-4 demonstrated enrichment of biological processes such as cell migration, cell cycle, metabolism and immune response, which are essential of human NCC development, underlying both tumors. In vitro and in silico analyses indicated that the rs2153977-T protective allele, located in an NB and CMM enhancer, decreased expression of SLC16A1 via long-range loop formation and altered a T-box protein binding site. Upon depletion of SLC16A1, we observed a decrease of cellular proliferation and invasion in both NB and CMM cell lines, suggesting its role as oncogene. This is the largest study to date examining pleiotropy across two NC cell-derived tumors identifying 1p13.2 as common susceptibility locus for NB and CMM risk. We demonstrate that combining genome-wide association studies results across cancers with same origins can identify new loci common to neuroblastoma and melanoma arising from tissues which originate from neural crest cells. Our results also show 1p13.2 confer risk to neuroblastoma and melanoma by regulating SLC16A1.

Relation of locus 1p13 rs646776 polymorphism with the risk of preeclampsia

ABSTRACTObjective: This study aimed to assess the relation of locus 1p13 rs646776 (T/C) polymorphism with preeclampsia in Egyptian women. Methods: The study included 100 healthy pregnant female subjects and 100 preeclampsia patients. The genotypes of the polymorphisms were assessed. Endothelin-1 level was determined in plasma. Results: The major T allele of the 1p13.3 genomic region rs646776 polymorphism had a higher frequency in preeclampsia patients. Carriers of C allele had significantly lower endothelin-1 levels, lower systolic and diastolic blood pressure, decreased proteinuria, and increased HDL-C in the patients. Conclusion: The rare C allele of rs646776 polymorphism in chromosomal locus 1p13.3 is associated with decreased risk of preeclampsia.

Sortilin and Its Multiple Roles in Cardiovascular and Metabolic Diseases.

Cardiovascular disease is a leading cause of morbidity and mortality in the Western world. Studies of sortilin's influence on cardiovascular and metabolic diseases goes far beyond the genome-wide association studies that have revealed an association between cardiovascular diseases and the 1p13 locus that encodes sortilin. Emerging evidence suggests a significant role of sortilin in the pathogenesis of vascular and metabolic diseases; this includes type II diabetes mellitus via regulation of insulin resistance, atherosclerosis through arterial wall inflammation and calcification, and dysregulated lipoprotein metabolism. Sortilin is also known for its functional role in neurological disorders. It serves as a key receptor for cytokines, lipids, and enzymes and participates in pathological cargo loading to and trafficking of extracellular vesicles. This article provides a comprehensive review of sortilin's contributions to cardiovascular and metabolic diseases but focuses particularly on atherosclerosis. We summarize recent clinical findings that suggest that sortilin may be a cardiovascular risk biomarker and also discuss sortilin as a potential drug target.

Fine mapping of the chromosome 1p13 locus for susceptibility to Paget's disease of bone

Searchable abstracts of presentations at key conferences on calcified tissues ISSN 2052-1219 (online)

Targeting sortilin in immune cells reduces proinflammatory cytokines and atherosclerosis.

Genome-wide association studies have identified a link between genetic variation at the human chromosomal locus 1p13.3 and coronary artery disease. The gene encoding sortilin (SORT1) has been implicated as the causative gene within the locus, as sortilin regulates hepatic lipoprotein metabolism. Here we demonstrated that sortilin also directly affects atherogenesis, independent of its regulatory role in lipoprotein metabolism. In a mouse model of atherosclerosis, deletion of Sort1 did not alter plasma cholesterol levels, but reduced the development of both early and late atherosclerotic lesions. We determined that sortilin is a high-affinity receptor for the proinflammatory cytokines IL-6 and IFN-γ. Moreover, macrophages and Th1 cells (both of which mediate atherosclerotic plaque formation) lacking sortilin had reduced secretion of IL-6 and IFN-γ, but not of other measured cytokines. Transfer of sortilin-deficient BM into irradiated atherosclerotic mice reduced atherosclerosis and systemic markers of inflammation. Together, these data demonstrate that sortilin influences cytokine secretion and that targeting sortilin in immune cells attenuates inflammation and reduces atherosclerosis.

SORT1 protective allele is associated with attenuated postprandial: lipaemia in young adults.

Elevated levels of lipids and lipoproteins have strong genetic determinants and are recognized as key risk factors for atherogenesis and cardiovascular disease, particularly in the postprandial state. The aim of the study to determine whether young adults, when stratified by genotype at the rs646776 variant of the 1p13 locus, displayed differential postprandial responses to an oral fat tolerance test. Participants (n=30) received a high-fat mixed meal (91 g; 55% kcal from fat) after an overnight fast and a fat-exclusion meal (3.9 g; 6% kcal from fat) at 8 hours postprandially. Blood samples were obtained at t=0, 2, 4, 6, 8, and 24 hours for lipoprotein analyses via nuclear magnetic resonance profiling. Carriers of the minor, protective allele (TC/CC) displayed lower fasting (TC/CC, 30.1±3.0 nmol/L versus TT, 48.8±5.1 nmol/L; P<0.01) and mean postprandial (TC/CC, 44.2±3.1 nmol/L versus TT, 57.0±4.5 nmol/L; P=0.03) very low-density lipoprotein and chylomicron particle number in addition to triglyceride content when compared with individuals homozygous for the major, risk allele (TT). We report a novel association between the SORT1 1p13 locus and extent of postprandial lipaemia. These results provide evidence of decreased exposure to atherogenic particles in carriers of the minor SORT1 allele, suggesting relative protection against cardiovascular disease when compared with TT homozygotes.

214 Generation of Isogenic Cell Lines to Study a Single Disease Associated Variant at the 1P13 Cad Risk Locus

Coronary artery disease (CAD) is a leading cause of mortality worldwide and has a significant heritable component. In the last few years genome-wide association studies (GWAS) have identified 46 genome-wide...

Genetic variants in loci 1p13 and 9p21 and fatal coronary heart disease in a Norwegian case-cohort study.

Single nucleotide polymorphisms (SNPs) in loci 1p13 and 9p21 have previously been found to be associated with incident coronary heart disease (CHD). This study aimed to investigate whether these SNPs show associations with fatal CHD in a population-based cohort study after adjustment for socioeconomic- and lifestyle-related CHD risk factors not commonly included in genetic association studies. Using the population-based Cohort of Norway (CONOR), a nested case-cohort study was set up and DNA from 2,953 subjects (829 cases and 2,124 non-cases) were genotyped. The association with fatal CHD was estimated for four SNPs, three from locus 1p13 and one from locus 9p21. Multivariable Cox regression was used to estimate unstratified and gender-stratified hazard ratios while adjusting for major CHD risk factors. The associations between three SNPs from locus 1p13 and non-HDL cholesterol levels were also estimated. Men homozygous for the risk alleles on rs1333049 (9p21) and rs14000 (1p13) were found to have significantly increased hazard ratios in crude and adjusted models, and the hazard ratios remained statistically significant when both genders were analyzed together. Adjustment for additional socioeconomic- and lifestyle-related CHD risk factors influenced the association estimates only slightly. No significant associations were observed between the other two SNPs in loci 1p13 (rs599839 and rs646776) and CHD mortality in either gender. Both rs599839 and rs646776 showed significant, gradual increases in non-HDL cholesterol levels with increasing number of risk alleles. This study confirms the association between 9p21 (rs1333049) and fatal CHD in a Norwegian population-based cohort. The effect was not influenced by several socioeconomic- and lifestyle-related risk factors. Our results show that 1p13 (rs14000) may also be associated with fatal CHD. SNPs at 1p13 (rs599839 and rs646776) were associated with non-HDL cholesterol levels.

The SORT1 risk allele is associated with exaggerated postprandial lipaemia in young adults (383.5)

Elevations in low‐density lipoproteins (LDL), very‐low density lipoproteins (VLDL) and triglycerides (TG) in the postprandial state have a strong genetic component and recognized atherogenic potential. We sought to determine if there is a difference in postprandial lipaemia following an oral fat tolerance test when stratified by genotype at the SORT1 1p13 locus, the strongest LDL‐cholesterol associated locus identified to date. Thirty, healthy young adults (age=23.57) received a high fat, mixed meal (91 g, 55% kcal from fat). Blood samples drawn at fasting, 2, 4, 8 and 24 hrs postprandial, underwent comprehensive lipoprotein analyses via nuclear magnetic resonance profiling. At fasting, VLDL particles differed based upon SORT1 genotype (TT: 48.81±5.07 nmol/L versus TC/CC: 30.05±2.99 nmol/L, p=0.004). Major, risk allele homozygotes (TT) had significantly elevated area‐under‐the‐curve and mean concentration for VLDL particles, TG and VLDL‐TG (p&lt;0.05). These results indicate increased fasting and postprandial exposure to atherogenic particles in TT homozygotes. This highlights SORT1 as a valuable target for identifying individuals for early, personalized interventions to prevent atherosclerosis.

Identification of rare genetic variants in novel loci associated with Paget’s disease of bone

In genome-wide association studies, single nucleotide polymorphisms located in five novel loci were associated with PDB. We aimed at identifying rare genetic variants of candidate genes located in these loci and search for genetic association with PDB in the French-Canadian population. Exons, promoter and exon-intron junctions from patients with familial PDB and healthy individuals were sequenced in candidate genes, located within novel loci associated with PDB in our population. Rare variant was defined by a minor allele frequency <0.05 or absent from dbSNP (NCBI). We sequenced seven genes in 1p13 locus, three genes in 7q33, three genes in 8q22, and five genes in 15q24 locus. We identified 126 rare variants in at least one patient with PDB of whom 55 were located in 1p13 locus, 32 in 7q33, 10 in 8q22 and 29 in 15q24 locus. We located 71 of these 126 rare variants in an intron, 30 in an exon and 9 in an untranslated region. 60 % of these variants were located in functionally relevant gene regions. Among the 12 missense rare variants in PDB, two (rs62620995 in TM7SF4; rs62641691 in CD276) were predicted to be damaging by in silico analysis tools. Rs62620995, which altered a conserved amino acid (p.Leu397Phe) in the TM7SF4 gene, encoding the DC-STAMP protein involved in osteoclastogenesis through RANK signaling pathway, was found to have a marginal association with PDB (p = 0.09). Rs35500845, located in the CTHRC1 gene, which encodes a regulator of collagen matrix deposition, was also associated with PDB in the French-Canadian population (p = 0.046).

Sortilin and the risk of cardiovascular disease

Plasma low-density lipoprotein cholesterol (LDL-C) levels are a key determinant of the risk of cardiovascular disease, which is why many studies have attempted to elucidate the pathways that regulate its metabolism. Novel latest-generation sequencing techniques have identified a strong association between the 1p13 locus and the risk of cardiovascular disease caused by changes in plasma LDL-C levels. As expected for a complex phenotype, the effects of variation in this locus are only moderate. Even so, knowledge of the association is of major importance, since it has unveiled a new metabolic pathway regulating plasma cholesterol levels. Crucial to this discovery was the work of three independent teams seeking to clarify the biological basis of this association, who succeeded in proving that SORT1, encoding sortilin, was the gene in the 1p13 locus involved in LDL metabolism. SORT1 was the first gene identified as determining plasma LDL levels to be mechanistically evaluated and, although the three teams used different, though appropriate, experimental methods, their results were in some ways contradictory. Here we review all the experiments that led to the identification of the new pathway connecting sortilin with plasma LDL levels and risk of myocardial infarction. The regulatory mechanism underlying this association remains unclear, but its discovery has paved the way for considering previously unsuspected therapeutic targets and approaches.

Saturated fatty acids activate ERK signaling to downregulate hepatic sortilin 1 in obese and diabetic mice

Hepatic VLDL overproduction is a characteristic feature of diabetes and an important contributor to diabetic dyslipidemia. Hepatic sortilin 1 (Sort1), a cellular trafficking receptor, is a novel regulator of plasma lipid metabolism and reduces plasma cholesterol and triglycerides by inhibiting hepatic apolipoprotein B production. Elevated circulating free fatty acids play key roles in hepatic VLDL overproduction and the development of dyslipidemia. This study investigated the regulation of hepatic Sort1 in obesity and diabetes and the potential implications in diabetic dyslipidemia. Results showed that hepatic Sort1 protein was markedly decreased in mouse models of type I and type II diabetes and in human individuals with obesity and liver steatosis, whereas increasing hepatic Sort1 expression reduced plasma cholesterol and triglycerides in mice. Mechanistic studies showed that the saturated fatty acid palmitate activated extracellular signal-regulated kinase (ERK) and inhibited Sort1 protein by mechanisms involving Sort1 protein ubiquitination and degradation. Consistently, hepatic ERK signaling was activated in diabetic mice, whereas blocking ERK signaling by an ERK inhibitor increased hepatic Sort1 protein in mice. These results suggest that increased saturated fatty acids downregulate liver Sort1 protein, which may contribute to the development of dyslipidemia in obesity and diabetes.

Sortilina e risco de doença cardiovascular

Plasma low-density lipoprotein cholesterol (LDL-C) levels are a key determinant of the risk of cardiovascular disease, which is why many studies have attempted to elucidate the pathways that regulate its metabolism. Novel latest-generation sequencing techniques have identified a strong association between the 1p13 locus and the risk of cardiovascular disease caused by changes in plasma LDL-C levels. As expected for a complex phenotype, the effects of variation in this locus are only moderate. Even so, knowledge of the association is of major importance, since it has unveiled a new metabolic pathway regulating plasma cholesterol levels. Crucial to this discovery was the work of three independent teams seeking to clarify the biological basis of this association, who succeeded in proving that SORT1, encoding sortilin, was the gene in the 1p13 locus involved in LDL metabolism. SORT1 was the first gene identified as determining plasma LDL levels to be mechanistically evaluated and, although the three teams used different, though appropriate, experimental methods, their results were in some ways contradictory. Here we review all the experiments that led to the identification of the new pathway connecting sortilin with plasma LDL levels and risk of myocardial infarction. The regulatory mechanism underlying this association remains unclear, but its discovery has paved the way for considering previously unsuspected therapeutic targets and approaches.

Abstract 5: Sortilin Regulates Hepatic VLDL Secretion and LDL Uptake in a Lysosome-Dependent Manner

Sortilin, the protein product of the SORT1 gene, is a multi-ligand sorting receptor involved in Golgi to lysosome and plasma membrane to lysosome protein trafficking. Genome wide association studies for lipid traits have identified the 1p13 locus harboring the SORT1 gene as strongly associated both with plasma low-density lipoprotein cholesterol (LDL-C) and myocardial infarction (MI) risk in humans. Adeno-associated virus (AAV)-mediated hepatic sortilin overexpression in LDL receptor deficient mice reduced plasma cholesterol by 30% at two weeks ( n = 6 mice per group, P = 0.02), with a concomitant reduction in LDL-C. In vivo VLDL production studies demonstrated a 50% reduction in the VLDL triglyceride secretion rate ( P = 0.007) and a 50% reduction in apoB secretion ( P = 0.02) with sortilin overexpression. In vivo LDL turnover studies demonstrated a 3-fold increase in the LDL fractional catabolic rate (FCR) with sortilin overexpression ( n = 6 mice per group, P = 0.00002). Sortilin deficiency both alone and on an LDL receptor deficient background led to a 40% and 50% reduction in FCR ( n = 6 mice per group, P = 0.002 and P = 0.01). The effect of sortilin on both VLDL secretion and LDL turnover is dependent on the ability of sortilin to traffic to the lysosome, as sortilin mutants that cannot traffic to the lysosome do not affect VLDL secretion or LDL uptake in vivo or in vitro . Surface plasmon reasonance demonstrated a high affinity interaction between sortilin and the apoB in LDL particles at physiological pH with a K d of ∼2 nM, and this affinity virtually disappears at the acidic lysosomal pH. In sum, these data are consistent with a model in which sortilin binds apoB-containing lipoprotein particles in the Golgi apparatus and at the plasma membrane and traffics them to the endolysosomal compartment for degradation, thereby reducing VLDL secretion and facilitating LDL uptake, explaining the strong association of hepatic sortilin overexpression in humans with reduced plasma cholesterol.

The genetic association of polymorphisms rs599839, rs646776 and rs4970834, in chromosomal locus 1p13.3 with coronary artery disease

BackgroundAbnormalities in lipids with increased serum concentration of LDL‐C are risk factors for coronary artery disease (CAD), and atherosclerosis. The aim of this study was to investigate the association between serum LDL‐cholesterol, and significant coronary artery stenosis with well‐known genetic variants in chromosomal locus 1p13.3 among CAD patients with and without significant coronary artery stenosis [case and control groups] respectively.MethodsBlood was drawn from a total of 178 patients. Genotyping for the variants rs599839, rs646776 and rs4970834, were performed by the 5’ nuclease test using TaqMan assay.ResultsThe HDL‐C level of rs599839 was [12.01± 3.9 mM vs. 3.46± 1.45 mM] for GG vs. AA+AG using the recessive genetic model with p value=0.006. Using the additive model, rs64776 variant had a significantly higher triglycerides levels [7.76±2.25 vs. 1.74±0.15 mM] for AA vs. GG respectively with p value=0.031. No significant difference was observed for LDL‐C and cholesterol among genotypes of all variants using different genetic models. The rs599839 variant had a significant association with the severity of coronary stenosis using additive model. The OR was 2.7 times among patients with significant stenosis (p =0.04). Stepwise regression analysis revealed that the following independent variables have a statistically significant effect on LDL‐C level; BMI, diabetes, TC, TG, HDL‐C, and anti‐lipidemic treatment in presence of rs59839 and rs646776 and rs4970834.ConclusionIn summary, polymorphism rs646776 and of rs599839 were significantly associated with HLD‐C and triglycerides levels, but not with LDL‐C. In addition the variant rs599839 had a significant association with atherosclerotic lesion in coronary vessels.