Identification of a Common Variant for Coronary Heart Disease at PDE1A Contributes to Individualized Treatment Goals and Risk Stratification of Cardiovascular Complications in Chinese Patients With Type 2 Diabetes.

OBJECTIVE: In this study we aim to unravel genetic determinants of coronary heart disease (CHD) in type 2 diabetes (T2D) and explore their applications. RESEARCH DESIGN AND METHODS: We performed a two-stage genome-wide association study for CHD in Chinese patients with T2D (3,596 case and 8,898 control subjects), followed by replications in European patients with T2D (764 case and 4,276 control subjects) and general populations (n = 51,442-547,261). Each identified variant was examined for its association with a wide range of phenotypes and its interactions with glycemic, blood pressure (BP), and lipid controls in incident cardiovascular diseases. RESULTS: We identified a novel variant (rs10171703) for CHD (odds ratio 1.21 [95% CI 1.13-1.30]; P = 2.4 × 10-8) and BP (ß ± SE 0.130 ± 0.017; P = 4.1 × 10-14) at PDE1A in Chinese T2D patients but found only a modest association with CHD in general populations. This variant modulated the effects of BP goal attainment (130/80 mmHg) on CHD (Pinteraction = 0.0155) and myocardial infarction (MI) (Pinteraction = 5.1 × 10-4). Patients with CC genotype of rs10171703 had >40% reduction in either cardiovascular events in response to BP control (2.9 × 10-8 < P < 3.6 × 10-5), those with CT genotype had no difference (0.0726 < P < 0.2614), and those with TT genotype had a threefold increase in MI risk (P = 6.7 × 10-3). CONCLUSIONS: We discovered a novel CHD- and BP-related variant at PDE1A that interacted with BP goal attainment with divergent effects on CHD risk in Chinese patients with T2D. Incorporating this information may facilitate individualized treatment strategies for precision care in diabetes, only when our findings are validated.

Nonsense-Mediated Decay Targeted RNA (ntRNA): Proposal of a ntRNA-miRNA-lncRNA Triple Regulatory Network Usable as Biomarker of Prognostic Risk in Patients with Kidney Cancer.

The most prevalent subtype of renal cell carcinoma (RCC), kidney renal clear cell carcinoma (KIRC) may be associated with a poor prognosis in a high number of cases, with a stage-specific prognostic stratification currently in use. No reliable biomarkers have been utilized so far in clinical practice despite the efforts in biomarker research in the last years. Nonsense-mediated mRNA decay (NMD) is a critical safeguard against erroneous transcripts, particularly mRNA transcripts containing premature termination codons (called nonsense-mediated decay targeted RNA, ntRNA). In this study, we first characterized 296 differentially expressed ntRNAs that were independent of the corresponding gene, 261 differentially expressed miRNAs, and 4653 differentially expressed lncRNAs. Then, we constructed a hub ntRNA-miRNA-lncRNA triple regulatory network associated with the prognosis of KIRC. Moreover, the results of immune infiltration analysis indicated that this network may influence the changes of the tumor immune microenvironment. A prognostic model derived from the genes and immune cells associated with the network was developed to distinguish between high- and low-risk patients, which was a better prognostic than other models, constructed using different biomarkers. Additionally, correlation of methylation and ntRNAs in the network suggested that some ntRNAs were regulated by methylation, which is helpful to further study the causes of abnormal expression of ntRNAs. In conclusion, this study highlighted the possible clinical implications of ntRNA functions in KIRC, proposing potential significant biomarkers that could be utilized to define the prognosis and design personalized treatment plans in kidney cancer management in the next future.

Clinical Predictors and Long-term Impact of Acute Kidney Injury on Progression of Diabetic Kidney Disease in Chinese Patients With Type 2 Diabetes.

We aim to assess the long-term impact of acute kidney injury (AKI) on progression of diabetic kidney disease (DKD) and all-cause mortality and investigate determinants of AKI in Chinese patients with type 2 diabetes (T2D). A consecutive cohort of 9,096 Chinese patients with T2D from the Hong Kong Diabetes Register was followed for 12 years (mean ± SD age 57 ± 13.2 years; 46.9% men; median duration of diabetes 5 years). AKI was defined based on the Kidney Disease: Improving Global Outcomes (KDIGO) criteria using serum creatinine. Estimated glomerular filtration rate measurements were used to identify the first episode with chronic kidney disease (CKD) and end-stage renal disease (ESRD). Polygenic risk score (PRS) composed of 27 single nucleotide polymorphisms (SNPs) known to be associated with serum uric acid (SUA) in European populations was used to examine the role of SUA in pathogenesis of AKI, CKD, and ESRD. Validation was sought in an independent cohort including 6,007 patients (age 61.2 ± 10.9 years; 59.5% men; median duration of diabetes 10 years). Patients with AKI had a higher risk for developing incident CKD (hazard ratio 14.3 [95% CI 12.69-16.11]), for developing ESRD (12.1 [10.74-13.62]), and for all-cause death (7.99 [7.31-8.74]) compared with those without AKI. Incidence rate for ESRD among patients with no episodes of AKI and one, two, and three or more episodes of AKI was 7.1, 24.4, 32.4, and 37.3 per 1,000 person-years, respectively. Baseline SUA was a strong independent predictor for AKI. A PRS composed of 27 SUA-related SNPs was associated with AKI and CKD in both discovery and replication cohorts but not ESRD. Elevated SUA may increase the risk of DKD through increasing AKI. The identification of SUA as a modifiable risk factor and PRS as a nonmodifiable risk factor may facilitate the identification of individuals at high risk to prevent AKI and its long-term impact in T2D.

A Decade in Review after Idiopathic Scoliosis Was First Called a Complex Trait-A Tribute to the Late Dr. Yves Cotrel for His Support in Studies of Etiology of Scoliosis.

Adolescent Idiopathic Scoliosis (AIS) is a prevalent and important spine disorder in the pediatric age group. An increased family tendency was observed for a long time, but the underlying genetic mechanism was uncertain. In 1999, Dr. Yves Cotrel founded the Cotrel Foundation in the Institut de France, which supported collaboration of international researchers to work together to better understand the etiology of AIS. This new concept of AIS as a complex trait evolved in this setting among researchers who joined the annual Cotrel meetings. It is now over a decade since the first proposal of the complex trait genetic model for AIS. Here, we review in detail the vast information about the genetic and environmental factors in AIS pathogenesis gathered to date. More importantly, new insights into AIS etiology were brought to us through new research data under the perspective of a complex trait. Hopefully, future research directions may lead to better management of AIS, which has a tremendous impact on affected adolescents in terms of both physical growth and psychological development.

Direct Measurement of B Lymphocyte Gene Expression Biomarkers in Peripheral Blood Transcriptomics Enables Early Prediction of Vaccine Seroconversion.

Peripheral blood transcriptome is a highly promising area for biomarker development. However, transcript abundances (TA) in these cell mixture samples are confounded by proportions of the component leukocyte subpopulations. This poses a challenge to clinical applications, as the cell of origin of any change in TA is not known without prior cell separation procedure. We developed a framework to develop a cell-type informative TA biomarkers which enable determination of TA of a single cell-type (B lymphocytes) directly in cell mixture samples of peripheral blood (e.g., peripheral blood mononuclear cells, PBMC) without the need for subpopulation separation. It is applicable to a panel of genes called B cell informative genes. Then a ratio of two B cell informative genes (a target gene and a stably expressed reference gene) obtained in PBMC was used as a new biomarker to represent the target gene expression in purified B lymphocytes. This approach, which eliminates the tedious procedure of cell separation and directly determines TA of a leukocyte subpopulation in peripheral blood samples, is called the Direct LS-TA method. This method is applied to gene expression datasets collected in influenza vaccination trials as early predictive biomarkers of seroconversion. By using TNFRSF17 or TXNDC5 as the target genes and TNFRSF13C or FCRLA as the reference genes, the Direct LS-TA B cell biomarkers were determined directly in the PBMC transcriptome data and were highly correlated with TA of the corresponding target genes in purified B lymphocytes. Vaccination responders had almost a 2-fold higher Direct LS-TA biomarker level of TNFRSF17 (log 2 SMD = 0.84, 95% CI = 0.47-1.21) on day 7 after vaccination. The sensitivity of these Direct LS-TA biomarkers in the prediction of seroconversion was greater than 0.7 and area-under curves (AUC) were over 0.8 in many datasets. In this paper, we report a straightforward approach to directly estimate B lymphocyte gene expression in PBMC, which could be used in a routine clinical setting. Moreover, the method enables the practice of precision medicine in the prediction of vaccination response. More importantly, seroconversion could now be predicted as early as day 7. As the acquired immunology pathway is common to vaccination against influenza and COVID-19, these biomarkers could also be useful to predict seroconversion for the new COVID-19 vaccines.

Development of genome-wide polygenic risk scores for lipid traits and clinical applications for dyslipidemia, subclinical atherosclerosis, and diabetes cardiovascular complications among East Asians.

BACKGROUND: The clinical utility of personal genomic information in identifying individuals at increased risks for dyslipidemia and cardiovascular diseases remains unclear. METHODS: We used data from Biobank Japan (n = 70,657-128,305) and developed novel East Asian-specific genome-wide polygenic risk scores (PRSs) for four lipid traits. We validated (n = 4271) and subsequently tested associations of these scores with 3-year lipid changes in adolescents (n = 620), carotid intima-media thickness (cIMT) in adult women (n = 781), dyslipidemia (n = 7723), and coronary heart disease (CHD) (n = 2374 cases and 6246 controls) in type 2 diabetes (T2D) patients. RESULTS: Our PRSs aggregating 84-549 genetic variants (0.251 < correlation coefficients (r) < 0.272) had comparably stronger association with lipid variations than the typical PRSs derived based on the genome-wide significant variants (0.089 < r < 0.240). Our PRSs were robustly associated with their corresponding lipid levels (7.5 × 10- 103 < P < 1.3 × 10- 75) and 3-year lipid changes (1.4 × 10- 6 < P < 0.0130) which started to emerge in childhood and adolescence. With the adjustments for principal components (PCs), sex, age, and body mass index, there was an elevation of 5.3% in TC (ß ± SE = 0.052 ± 0.002), 11.7% in TG (ß ± SE = 0.111 ± 0.006), 5.8% in HDL-C (ß ± SE = 0.057 ± 0.003), and 8.4% in LDL-C (ß ± SE = 0.081 ± 0.004) per one standard deviation increase in the corresponding PRS. However, their predictive power was attenuated in T2D patients (0.183 < r < 0.231). When we included each PRS (for TC, TG, and LDL-C) in addition to the clinical factors and PCs, the AUC for dyslipidemia was significantly increased by 0.032-0.057 in the general population (7.5 × 10- 3 < P < 0.0400) and 0.029-0.069 in T2D patients (2.1 × 10- 10 < P < 0.0428). Moreover, the quintile of TC-related PRS was moderately associated with cIMT in adult women (ß ± SE = 0.011 ± 0.005, Ptrend = 0.0182). Independent of conventional risk factors, the quintile of PRSs for TC [OR (95% CI) = 1.07 (1.03-1.11)], TG [OR (95% CI) = 1.05 (1.01-1.09)], and LDL-C [OR (95% CI) = 1.05 (1.01-1.09)] were significantly associated with increased risk of CHD in T2D patients (4.8 × 10- 4 < P < 0.0197). Further adjustment for baseline lipid drug use notably attenuated the CHD association. CONCLUSIONS: The PRSs derived and validated here highlight the potential for early genomic screening and personalized risk assessment for cardiovascular disease.

Ambient Temperature is A Strong Selective Factor Influencing Human Development and Immunity.

Solar energy, which is essential for the origin and evolution of all life forms on Earth, can be objectively recorded through attributes such as climatic ambient temperature (CAT), ultraviolet radiation (UVR), and sunlight duration (SD). These attributes have specific geographical variations and may cause different adaptation traits. However, the adaptation profile of each attribute and the selective role of solar energy as a whole during human evolution remain elusive. Here, we performed a genome-wide adaptation study with respect to CAT, UVR, and SD using the Human Genome Diversity Project-Centre Etude Polymorphism Humain (HGDP-CEPH) panel data. We singled out CAT as the most important driving force with the highest number of adaptive loci (6 SNPs at the genome-wide 1 × 10-7 level; 401 at the suggestive 1 × 10-5 level). Five of the six genome-wide significant adaptation SNPs were successfully replicated in an independent Chinese population (N = 1395). The corresponding 316 CAT adaptation genes were mostly involved in development and immunity. In addition, 265 (84%) genes were related to at least one genome-wide association study (GWAS)-mapped human trait, being significantly enriched in anthropometric loci such as those associated with body mass index (χ2; P < 0.005), immunity, metabolic syndrome, and cancer (χ2; P < 0.05). For these adaptive SNPs, balancing selection was evident in Euro-Asians, whereas obvious positive and/or purifying selection was observed in Africans. Taken together, our study indicates that CAT is the most important attribute of solar energy that has driven genetic adaptation in development and immunity among global human populations. It also supports the non-neutral hypothesis for the origin of disease-predisposition alleles in common diseases.

Promoter Methylation and Gene Expression of Pin1 Associated with the Risk of Alzheimer's Disease in Southern Chinese.

BACKGROUND: Pin1 is a propyl cis-trans isomerase and it has been associated with age-atonset of Alzheimer's disease (AD) and other pathological characteristics of AD. DNA methylation is one of the gene regulation mechanisms and it might affect the gene expression. OBJECTIVE: This study was aimed to examine the correlation between DNA methylation and gene expression of Pin1 and its effect on the risk of AD in a Chinese population. METHODS: 80 AD patients and 180 normal controls were recruited in this study and their cognitive functions were assessed. Pin1 gene expression and methylation were quantified by real-time RT-PCR and Melting Curve Analysis-Methylation assay (MCA-Meth), respectively. RESULTS: Our finding revealed a positive correlation between methylation and gene expression of Pin1 (p=0.001) and increased Pin1 methylation was predisposed to the risk of AD (p<0.001). CG genotype of Pin1 SNP rs2287839 was associated with higher gene expression of Pin1 (p=0.036) and the effect was only prominent in normal controls as AD patients were already methylated at Pin1 promoter. Furthermore, methylation of Pin1 was associated with better performance in cognition (p=0.018). CONCLUSION: Our result further supported the involvement of Pin1 in AD and the increased level of Pin1 might be a protective factor for AD.

Correlations of health-related quality of life with serum inflammatory indicators IL-8 and mIBI in patients with hepatocellular carcinoma.

PURPOSE: Health-related quality of life (HRQoL) is a significant prognostic factor for overall survival in hepatocellular carcinoma (HCC) patients, and this is independent of stage and liver function. Inflammation plays a significant role in HCC development and progression. It was hypothesized that the inflammatory status of HCC patients may affect their HRQoL. The relationship between HRQoL and inflammatory status was explored using indicators IL-8 level and modified inflammation-based index (mIBI, based on IL-8, C-reactive protein, and albumin). METHODS: From 2007-2011, HCC patients were enrolled prospectively. Baseline HRQoL assessment utilized the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and QLQ-HCC18; clinical and laboratory data were collected at diagnosis. Two summary indices, C30 and HCC18 index-scores, were calculated. Correlation analyses were performed between HRQoL and inflammatory markers. RESULTS: In the 445 patients studied, significant correlations were found between IL-8 levels and EORTC QLQ-C30, QLQ-HCC18, C30, and HCC18 index-scores. The strongest correlated factors were those reflective of constitutional symptoms, namely QLQ-C30 "appetite loss" (with Pearson's correlation coefficient, r=0.322, P<0.0001); QLQ-C30 "fatigue" (r=0.311, P<0.0001); QLQ-C30 "role functioning" (r=-0.305, P<0.0001); QLQ-HCC18 "nutrition" (r=0.317, P<0.0001); and QLQ-HCC18 "fatigue" (r=0.306, P<0.0001). In addition, moderate but significant correlations were also observed with HCC18 index score (r=0.321, P<0.0001), and C30 index score (r=0.306, P<0.0001). HRQoL factors were also significantly correlated with mIBI. CONCLUSION: Baseline HRQoL using the conventional assessments of EORTC QLQ-C30 and QLQ-HCC18, as well as C30 and HCC18 index-scores, significantly correlated with inflammatory indicators (IL-8 level and mIBI) in HCC patients. Among the strongest correlations were those between IL-8 level and the two index-scores, as well as HRQoL aspects that represent constitutional symptoms. When paralleled with molecular findings, traditional HRQoL assessment in HCC has gained a new level of understanding: pattern recognition within an HRQoL instrument could potentially identify patients with more severe inflammatory state.

Publisher Correction: GWAS of bone size yields twelve loci that also affect height, BMD, osteoarthritis or fractures.

The original HTML version of this Article was updated shortly after publication to add links to the Peer Review file.In addition, affiliations 16 and 17 incorrectly read 'School of Medicine Sydney, University of Notre Dame Australia, Sydney, WA, 6160, Australia' and 'St Vincent's Clinical School, University of New South Wales Medicine, University of New South Wales, Sydney, NSW, 2052, Australia.' This has now been corrected in both the PDF and HTML versions of the Article.

The association of liver function and quality of life of patients with liver cancer.

BACKGROUND: Quality of life (QOL) assessments with the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30, QLQ-HCC18, C30 and HCC18 index scores have been shown to be prognostic factors for overall survival (OS) in patients with hepatocellular carcinoma (HCC), independent of disease stage and liver function. Liver function parameters (including bilirubin, albumin, international normalized ratio [INR], Child-Pugh class, ALBI grade, MELD, alkaline phosphatase [ALP]-to-platelet ratio, albumin-to-ALP ratio) have also been found to be independent prognostic factors for OS in HCC patients. There has been scanty data on whether QOL and baseline liver function per se are correlated in HCC patients. This study investigates the correlations between baseline QOL data and liver function variables in HCC patients. METHODS: From 2007 to 2011, 517 patients were enrolled. Baseline QOL was assessed at diagnosis using the EORTC QLQ-C30 and QLQ-HCC18; thereafter C30 and HCC18 index scores were derived. Clinical and laboratory data were collected. For liver function assessment, Child-Pugh class, ALBI grade, MELD, ALP-to-platelet ratio and albumin-to-ALP ratio were derived. Correlation analyses were performed between QOL and liver function data. RESULTS: Complete QOL data were available in 472 HCC patients. After adjusting for clinical variables, significant correlations were found between QOL (QLQ-C30 and QLQ-HCC18) and dichotomized liver function variables (including Child-Pugh class, ALBI grade and the presence of ascites). It was demonstrated that QOL had significant and potentially clinically important correlations with continuous liver function variables (albumin, bilirubin, ALP and albumin-to-ALP ratio), with the highest Spearman's rank correlation coefficient (rho) exceeding 0.4. HCC18 and C30 index scores were also significantly correlated with these liver function variables. HCC18 index score, which had rho up to 0.37, generally performed better than C30 index score, which had rho up to 0.33. CONCLUSIONS: In HCC patients, baseline QOL assessment (using EORTC QLQ-C30, QLQ-HCC18, C30 index-score or HCC18 index-score) is significantly correlated with liver function. Based on the findings of this study, future trials are warranted to assess whether treatment to enhance liver function could improve HCC patients' QOL.

GWAS of bone size yields twelve loci that also affect height, BMD, osteoarthritis or fractures.

Bone area is one measure of bone size that is easily derived from dual-energy X-ray absorptiometry (DXA) scans. In a GWA study of DXA bone area of the hip and lumbar spine (N ≥ 28,954), we find thirteen independent association signals at twelve loci that replicate in samples of European and East Asian descent (N = 13,608 - 21,277). Eight DXA area loci associate with osteoarthritis, including rs143384 in GDF5 and a missense variant in COL11A1 (rs3753841). The strongest DXA area association is with rs11614913[T] in the microRNA MIR196A2 gene that associates with lumbar spine area (P = 2.3 × 10-42, ß = -0.090) and confers risk of hip fracture (P = 1.0 × 10-8, OR = 1.11). We demonstrate that the risk allele is less efficient in repressing miR-196a-5p target genes. We also show that the DXA area measure contributes to the risk of hip fracture independent of bone density.

Discovering Genetic Factors for psoriasis through exhaustively searching for significant second order SNP-SNP interactions.

In this paper, we aim at discovering genetic factors of psoriasis through searching for statistically significant SNP-SNP interactions exhaustively from two real psoriasis genome-wide association study datasets (phs000019.v1.p1 and phs000982.v1.p1) downloaded from the database of Genotypes and Phenotypes. To deal with the enormous search space, our search algorithm is accelerated with eight biological plausible interaction patterns and a pre-computed look-up table. After our search, we have discovered several SNPs having a stronger association to psoriasis when they are in combination with another SNP and these combinations may be non-linear interactions. Among the top 20 SNP-SNP interactions being found in terms of pairwise p-value and improvement metric value, we have discovered 27 novel potential psoriasis-associated SNPs where most of them are reported to be eQTLs of a number of known psoriasis-associated genes. On the other hand, we have inferred a gene network after selecting the top 10000 SNP-SNP interactions in terms of improvement metric value and we have discovered a novel long distance interaction between XXbac-BPG154L12.4 and RNU6-283P which is not a long distance haplotype and may be a new discovery. Finally, our experiments with the synthetic datasets have shown that our pre-computed look-up table technique can significantly speed up the search process.

A network approach to exploring the functional basis of gene-gene epistatic interactions in disease susceptibility.

Motivation: Individual genetic variants explain only a small fraction of heritability in some diseases. Some variants have weak marginal effects on disease risk, but their joint effects are significantly stronger when occurring together. Most studies on such epistatic interactions have focused on methods for identifying the interactions and interpreting individual cases, but few have explored their general functional basis. This was due to the lack of a comprehensive list of epistatic interactions and uncertainties in associating variants to genes. Results: We conducted a large-scale survey of published research articles to compile the first comprehensive list of epistatic interactions in human diseases with detailed annotations. We used various methods to associate these variants to genes to ensure robustness. We found that these genes are significantly more connected in protein interaction networks, are more co-expressed and participate more often in the same pathways. We demonstrate using the list to discover novel disease pathways. Contact: kevinyip@cse.cuhk.edu.hk. Supplementary information: Supplementary data are available at Bioinformatics online.

Profiles of lipids, blood pressure and weight changes among premenopausal Chinese breast cancer patients after adjuvant chemotherapy.

BACKGROUND: Adjuvant chemotherapy improves outcome of patients with early breast cancer. However, chemotherapy may be associated with long term toxicities. In this retrospective cohort study, the objectives were to determine body weight, body mass index (BMI), blood pressure and fasting lipids levels of young premenopausal Chinese breast cancer patients after adjuvant chemotherapy. Potential factors associated with these parameters were identified. METHODS: Eligibility criteria include premenopausal Chinese patients who were diagnosed to have stage I-III breast cancer within 3-10 years, age < 45 and having received adjuvant chemotherapy at the time of breast cancer diagnosis. Information at initial breast cancer diagnosis were retrieved from patients' medical records and include age at diagnosis, tumor characteristics, anti-cancer treatments, blood pressure and body weight and height. At study entry, all patients had additional background demographics collected, as well as blood pressure, body weight and fasting serum lipid profiles measured. Incidence of chemotherapy-related amenorrhoea (CRA) and menopause were determined. Factors associated with weight gain, hypertension and dyslipidaemias were analyzed. RESULTS: Two hundred and eighty patients were studied. The median age at breast cancer diagnosis was 41 years (range: 24-45). The median time from breast cancer diagnosis to study entry was 5.0 years. The median age at study entry was 46.5 years (range: 28-54). 91.1% developed CRA; 48.9% had become menopausal and 10% were peri-menopausal. Between initial breast cancer diagnosis and the time of study entry, the median weight gain was 1.8 kg; 63.2% gained weight by >2%; 52.1% were overweight/obese; 30.7% had hypertension. Abnormal total-cholesterol and LDL-cholesterol occurred in 34.3% and 56.1% respectively. On multivariate analyses, older age was associated with reduced risk while occurrence of CRA and having received taxane-containing regimens were associated with increased risk of weight gain. Oestrogen-receptor positivity was associated with reduced risk while overweight/obese statuses were associated with increased risk of hypertension. Use of tamoxifen was associated with reduced risk of abnormal LDL-cholesterol. Weight gain, overweight/obese, older age, progression to post/peri-menopausal status at study entry, having received corticosteroid premedication before adjuvant chemotherapy and having received taxane-containing adjuvant chemotherapy were associated with increased risk of dyslipidaemias. CONCLUSION: Among young premenopausal Chinese breast cancer patients who had received adjuvant chemotherapy, the current study has revealed that although there was only a median weight gain of 1.8 kg, there was a nearly 60% increase in abnormal BMI. Further, a significant proportion of patients were detected to have hypertension and dyslipidaemias. Interventional studies with lifestyle modifications are warranted.

Whole-genome sequencing identifies rare genotypes in COMP and CHADL associated with high risk of hip osteoarthritis.

We performed a genome-wide association study of total hip replacements, based on variants identified through whole-genome sequencing, which included 4,657 Icelandic patients and 207,514 population controls. We discovered two rare signals that strongly associate with osteoarthritis total hip replacement: a missense variant, c.1141G>C (p.Asp369His), in the COMP gene (allelic frequency = 0.026%, P = 4.0 × 10-12, odds ratio (OR) = 16.7) and a frameshift mutation, rs532464664 (p.Val330Glyfs*106), in the CHADL gene that associates through a recessive mode of inheritance (homozygote frequency = 0.15%, P = 4.5 × 10-18, OR = 7.71). On average, c.1141G>C heterozygotes and individuals homozygous for rs532464664 had their hip replacement operation 13.5 years and 4.9 years earlier than others (P = 0.0020 and P = 0.0026), respectively. We show that the full-length CHADL transcript is expressed in cartilage. Furthermore, the premature stop codon introduced by the CHADL frameshift mutation results in nonsense-mediated decay of the mutant transcripts.

The mechanism of transactivation regulation due to polymorphic short tandem repeats (STRs) using IGF1 promoter as a model.

Functional short tandem repeats (STR) are polymorphic in the population, and the number of repeats regulates the expression of nearby genes (known as expression STR, eSTR). STR in IGF1 promoter has been extensively studied for its association with IGF1 concentration in blood and various clinical traits and represents an important eSTR. We previously used an in-vitro luciferase reporter model to examine the interaction between STRs and SNPs in IGF1 promoter. Here, we further explored the mechanism how the number of repeats of the STR regulates gene transcription. An inverse correlation between the number of repeats and the extent of transactivation was found in a haplotype consisting of three promoter SNPs (C-STR-T-T). We showed that these adjacent SNPs located outside the STR were required for the STR to function as eSTR. The C allele of rs35767 provides a binding site for CCAAT/enhancer-binding-protein δ (C/EBPD), which is essential for the gradational transactivation property of eSTR and FOXA3 may also be involved. Therefore, we propose a mechanism in which the gradational transactivation by the eSTR is caused by the interaction of one or more transcriptional complexes located outside the STR, rather than by direct binding to a repeat motif of the STR.