The gout epidemic in French Polynesia: a modelling study of data from the Ma'i u'u epidemiological survey.

BACKGROUND: Gout is the most common cause of inflammatory arthritis worldwide, particularly in Pacific regions. We aimed to establish the prevalence of gout and hyperuricaemia in French Polynesia, their associations with dietary habits, their comorbidities, the prevalence of the HLA-B*58:01 allele, and current management of the disease. METHODS: The Ma'i u'u survey was epidemiological, prospective, cross-sectional, and gout-focused and included a random sample of adults from the general adult population of French Polynesia. It was conducted and data were collected between April 13 and Aug 16, 2021. Participants were randomly selected to represent the general adult population of French Polynesia on the basis of housing data collected during the 2017 territorial census. Each selected household was visited by a research nurse from the Ma'i u'u survey who collected data via guided, 1-h interviews with participants. In each household, the participant was the individual older than 18 years with the closest upcoming birthday. To estimate the frequency of HLA-B*58:01, we estimated HLA-B haplotypes on individuals who had whole-genome sequencing to approximately 5× average coverage (mid-pass sequencing). A subset of individuals who self-reported Polynesian ancestry and not European, Chinese, or other ancestry were used to estimate Polynesian-ancestry specific allele frequencies. Bivariate associations were reported for weighted participants; effect sizes were estimated through the odds ratio (OR) of the association calculated on the basis of a logistic model fitted with weighted observations. FINDINGS: Among the random sample of 2000 households, 896 participants were included, 140 individuals declined, and 964 households could not be contacted. 22 participants could not be weighted due to missing data, so the final weighted analysis included 874 participants (449 [51·4%] were female and 425 [48·6%] were male) representing the 196 630 adults living in French Polynesia. The estimated prevalence of gout was 14·5% (95% CI 9·9-19·2), representing 28 561 French Polynesian adults, that is 25·5% (18·2-32·8) of male individuals and 3·5% (1·0-6·0) of female individuals. The prevalence of hyperuricaemia was estimated at 71·6% (66·7-76·6), representing 128 687 French Polynesian adults. In multivariable analysis, age (OR 1·5, 95% CI 1·2-1·8 per year), male sex (10·3, 1·8-60·7), serum urate (1·6, 1·3-2·0 per 1 mg/dL), uraturia (0·8, 0·8-0·8 per 100 mg/L), type 2 diabetes (2·1, 1·4-3·1), BMI more than 30 kg/m2 (1·1, 1·0-1·2 per unit), and percentage of visceral fat (1·7, 1·1-2·7 per 1% increase) were associated with gout. There were seven heterozygous HLA-B*58:01 carriers in the full cohort of 833 individuals (seven [0·4%] of 1666 total alleles) and two heterozygous carriers in a subset of 696 individuals of Polynesian ancestry (two [0·1%]). INTERPRETATION: French Polynesia has an estimated high prevalence of gout and hyperuricaemia, with gout affecting almost 15% of adults. Territorial measures that focus on increasing access to effective urate-lowering therapies are warranted to control this major public health problem. FUNDING: Variant Bio, the French Polynesian Health Administration, Lille Catholic University Hospitals, French Society of Rheumatology, and Novartis.

Pleiotropic associations of heterozygosity for the SERPINA1 Z allele in the UK Biobank.

Homozygosity for the SERPINA1 Z allele causes α1-antitrypsin deficiency, a rare condition that can cause lung and liver disease. However, the effects of Z allele heterozygosity on nonrespiratory phenotypes, and on lung function in the general population, remain unclear. We conducted a large, population-based study to determine Z allele effects on >2400 phenotypes in the UK Biobank (N=303 353). Z allele heterozygosity was strongly associated with increased height (ß=1.02 cm, p=3.91×10-68), and with other nonrespiratory phenotypes including increased risk of gall bladder disease, reduced risk of heart disease and lower blood pressure, reduced risk of osteoarthritis and reduced bone mineral density, increased risk of headache and enlarged prostate, as well as with blood biomarkers of liver function. Heterozygosity was associated with higher height-adjusted forced expiratory volume in 1 s (FEV1) (ß=19.36 mL, p=9.21×10-4) and FEV1/forced vital capacity (ß=0.0031, p=1.22×10-5) in nonsmokers, whereas in smokers, this protective effect was abolished. Furthermore, we show for the first time that sex modifies the association of the Z allele on lung function. We conclude that Z allele heterozygosity and homozygosity exhibit opposing effects on lung function in the UK population, and that these associations are modified by smoking and sex. In exploratory analyses, heterozygosity for the Z allele also showed pleiotropic associations with nonrespiratory health-related traits and disease risk.

A Noncoding Variant Near PPP1R3B Promotes Liver Glycogen Storage and MetS, but Protects Against Myocardial Infarction.

CONTEXT: Glycogen storage diseases are rare. Increased glycogen in the liver results in increased attenuation. OBJECTIVE: Investigate the association and function of a noncoding region associated with liver attenuation but not histologic nonalcoholic fatty liver disease. DESIGN: Genetics of Obesity-associated Liver Disease Consortium. SETTING: Population-based. MAIN OUTCOME: Computed tomography measured liver attenuation. RESULTS: Carriers of rs4841132-A (frequency 2%-19%) do not show increased hepatic steatosis; they have increased liver attenuation indicative of increased glycogen deposition. rs4841132 falls in a noncoding RNA LOC157273 ~190 kb upstream of PPP1R3B. We demonstrate that rs4841132-A increases PPP1R3B through a cis genetic effect. Using CRISPR/Cas9 we engineered a 105-bp deletion including rs4841132-A in human hepatocarcinoma cells that increases PPP1R3B, decreases LOC157273, and increases glycogen perfectly mirroring the human disease. Overexpression of PPP1R3B or knockdown of LOC157273 increased glycogen but did not result in decreased LOC157273 or increased PPP1R3B, respectively, suggesting that the effects may not all occur via affecting RNA levels. Based on electronic health record (EHR) data, rs4841132-A associates with all components of the metabolic syndrome (MetS). However, rs4841132-A associated with decreased low-density lipoprotein (LDL) cholesterol and risk for myocardial infarction (MI). A metabolic signature for rs4841132-A includes increased glycine, lactate, triglycerides, and decreased acetoacetate and beta-hydroxybutyrate. CONCLUSIONS: These results show that rs4841132-A promotes a hepatic glycogen storage disease by increasing PPP1R3B and decreasing LOC157273. rs4841132-A promotes glycogen accumulation and development of MetS but lowers LDL cholesterol and risk for MI. These results suggest that elevated hepatic glycogen is one cause of MetS that does not invariably promote MI.

Exome sequencing and characterization of 49,960 individuals in the UK Biobank.

The UK Biobank is a prospective study of 502,543 individuals, combining extensive phenotypic and genotypic data with streamlined access for researchers around the world1. Here we describe the release of exome-sequence data for the first 49,960 study participants, revealing approximately 4 million coding variants (of which around 98.6% have a frequency of less than 1%). The data include 198,269 autosomal predicted loss-of-function (LOF) variants, a more than 14-fold increase compared to the imputed sequence. Nearly all genes (more than 97%) had at least one carrier with a LOF variant, and most genes (more than 69%) had at least ten carriers with a LOF variant. We illustrate the power of characterizing LOF variants in this population through association analyses across 1,730 phenotypes. In addition to replicating established associations, we found novel LOF variants with large effects on disease traits, including PIEZO1 on varicose veins, COL6A1 on corneal resistance, MEPE on bone density, and IQGAP2 and GMPR on blood cell traits. We further demonstrate the value of exome sequencing by surveying the prevalence of pathogenic variants of clinical importance, and show that 2% of this population has a medically actionable variant. Furthermore, we characterize the penetrance of cancer in carriers of pathogenic BRCA1 and BRCA2 variants. Exome sequences from the first 49,960 participants highlight the promise of genome sequencing in large population-based studies and are now accessible to the scientific community.

Differences in geometric strength at the contralateral hip between men with hip fracture and non-fractured comparators.

Older men sustain excess bone mineral density (BMD) declines after hip fracture; however, BMD provides no information on mechanical structure and strength. The aim was to assess whether changes in hip bone geometry in older men after hip fracture differ than that expected with aging. Two cohorts were used: Baltimore Hip Studies 7th cohort (BHS-7) and Baltimore Men's Osteoporosis Study (MOST). The sample (N = 170) included older Caucasian men with hip fracture that were propensity score matched (1:1) to community-dwelling non-fractured comparators. Hip Structural Analysis (HSA) calculated aerial BMD and metrics of bone structural strength: cross-sectional bone area (CSA), cortical outer diameter (OD), section modulus (SM), and centroid position (CP). Mixed-effect models estimated changes in HSA parameters and adjusted robust regression models evaluated between-cohort differences in annual percent change at the narrow neck (NN), intertrochanteric (IT), and femoral shaft (FS). Hip fracture was associated with statistically greater declines in NN CSA (ß = -2.818; 95% CI: -3.300%, -2.336%), SM (ß = -1.896%; 95% CI: -2.711%, -1.080%) and CP (ß = -0.884%; 95% CI: -0.889%, -0.880%) and significantly larger increases in NN OD (ß = 0.187%; 95% CI: 0.185%, 0.190%). Differences in IT HSA parameters were like the NN but larger in magnitude, while there were favorable changes in FS geometry where fragility fractures are rare. Findings indicate there are declines in bone structure and strength at the NN and IT regions of the proximal femur in older men during hip fracture recovery that far exceed what occurs during normal aging.

Genotype, resilience and function and physical activity post hip fracture.

BACKGROUND: Individuals who are resilient are more likely to engage in functional tasks and exercise post hip fracture. There may be a genetic predisposition to being resilient. OBJECTIVES: This study tested the direct and indirect association of 10 candidate genes, age, cognition, gender, comorbidities, pain and social activity on resilience, function and exercise post hip fracture. METHOD: This was a descriptive study including 172 community dwelling older adults. Measures included: age, gender, cognition (Modified Mini Mental Status Exam), comorbidities, social activities (self-report), DNA (GRM1, NTRK1, NTRK2, GNB3, NPY, SLC6A15. SLC6A4, BDNF, CR1TR1, FKBP5), pain (areas of pain and Numeric Rating Scale), function (Physical and Instrumental Activities of Daily Living; Lower Extremity Gains Score; Short Physical Performance Battery; Grip Strength) and exercise (Yale Physical Activity Scale). RESULTS: The majority of participants were Caucasian (93%), 50% were women and the average age was 81.09 (SD = 7.42). There were significant associations between resilience and single nucleotide polymorphisms from GRM1, NTRK1, NTRK2, GNB3, NPY and SLC6A15. Resilience, age, cognition, social activity, pain and genetic variability were directly and/or indirectly associated with exercise and/or function. DISCUSSION: This study highlights the importance of resilience for engagement in exercise and function after hip fracture and provides preliminary evidence for a genetic role for resilience.

Insulin Resistance Exacerbates Genetic Predisposition to Nonalcoholic Fatty Liver Disease in Individuals Without Diabetes.

The accumulation of excess fat in the liver (hepatic steatosis) in the absence of heavy alcohol consumption causes nonalcoholic fatty liver disease (NAFLD), which has become a global epidemic. Identifying metabolic risk factors that interact with the genetic risk of NAFLD is important for reducing disease burden. We tested whether serum glucose, insulin, insulin resistance, triglyceride (TG), low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, body mass index (BMI), and waist-to-hip ratio adjusted for BMI interact with genetic variants in or near the patatin-like phospholipase domain containing 3 (PNPLA3) gene, the glucokinase regulatory protein (GCKR) gene, the neurocan/transmembrane 6 superfamily member 2 (NCAN/TM6SF2) gene, and the lysophospholipase-like 1 (LYPLAL1) gene to exacerbate hepatic steatosis, estimated by liver attenuation. We performed association analyses in 10 population-based cohorts separately and then meta-analyzed results in up to 14,751 individuals (11,870 of European ancestry and 2,881 of African ancestry). We found that PNPLA3-rs738409 significantly interacted with insulin, insulin resistance, BMI, glucose, and TG to increase hepatic steatosis in nondiabetic individuals carrying the G allele. Additionally, GCKR-rs780094 significantly interacted with insulin, insulin resistance, and TG. Conditional analyses using the two largest European ancestry cohorts in the study showed that insulin levels accounted for most of the interaction of PNPLA3-rs738409 with BMI, glucose, and TG in nondiabetic individuals. Insulin, PNPLA3-rs738409, and their interaction accounted for at least 8% of the variance in hepatic steatosis in these two cohorts. Conclusion: Insulin resistance, either directly or through the resultant elevated insulin levels, more than other metabolic traits, appears to amplify the PNPLA3-rs738409-G genetic risk for hepatic steatosis. Improving insulin resistance in nondiabetic individuals carrying PNPLA3-rs738409-G may preferentially decrease hepatic steatosis.

Meta-Analysis of Genomewide Association Studies Reveals Genetic Variants for Hip Bone Geometry.

Hip geometry is an important predictor of fracture. We performed a meta-analysis of GWAS studies in adults to identify genetic variants that are associated with proximal femur geometry phenotypes. We analyzed four phenotypes: (i) femoral neck length; (ii) neck-shaft angle; (iii) femoral neck width, and (iv) femoral neck section modulus, estimated from DXA scans using algorithms of hip structure analysis. In the Discovery stage, 10 cohort studies were included in the fixed-effect meta-analysis, with up to 18,719 men and women ages 16 to 93 years. Association analyses were performed with ∼2.5 million polymorphisms under an additive model adjusted for age, body mass index, and height. Replication analyses of meta-GWAS significant loci (at adjusted genomewide significance [GWS], threshold p ≤ 2.6 × 10-8 ) were performed in seven additional cohorts in silico. We looked up SNPs associated in our analysis, for association with height, bone mineral density (BMD), and fracture. In meta-analysis (combined Discovery and Replication stages), GWS associations were found at 5p15 (IRX1 and ADAMTS16); 5q35 near FGFR4; at 12p11 (in CCDC91); 11q13 (near LRP5 and PPP6R3 (rs7102273)). Several hip geometry signals overlapped with BMD, including LRP5 (chr. 11). Chr. 11 SNP rs7102273 was associated with any-type fracture (p = 7.5 × 10-5 ). We used bone transcriptome data and discovered several significant eQTLs, including rs7102273 and PPP6R3 expression (p = 0.0007), and rs6556301 (intergenic, chr.5 near FGFR4) and PDLIM7 expression (p = 0.005). In conclusion, we found associations between several genes and hip geometry measures that explained 12% to 22% of heritability at different sites. The results provide a defined set of genes related to biological pathways relevant to BMD and etiology of bone fragility. © 2019 American Society for Bone and Mineral Research.

Identification of new therapeutic targets for osteoarthritis through genome-wide analyses of UK Biobank data.

Osteoarthritis is the most common musculoskeletal disease and the leading cause of disability globally. Here, we performed a genome-wide association study for osteoarthritis (77,052 cases and 378,169 controls), analyzing four phenotypes: knee osteoarthritis, hip osteoarthritis, knee and/or hip osteoarthritis, and any osteoarthritis. We discovered 64 signals, 52 of them novel, more than doubling the number of established disease loci. Six signals fine-mapped to a single variant. We identified putative effector genes by integrating expression quantitative trait loci (eQTL) colocalization, fine-mapping, and human rare-disease, animal-model, and osteoarthritis tissue expression data. We found enrichment for genes underlying monogenic forms of bone development diseases, and for the collagen formation and extracellular matrix organization biological pathways. Ten of the likely effector genes, including TGFB1 (transforming growth factor beta 1), FGF18 (fibroblast growth factor 18), CTSK (cathepsin K), and IL11 (interleukin 11), have therapeutics approved or in clinical trials, with mechanisms of action supportive of evaluation for efficacy in osteoarthritis.

Exome-chip meta-analysis identifies association between variation in ANKRD26 and platelet aggregation.

Previous genome-wide association studies (GWAS) have identified several variants associated with platelet function phenotypes; however, the proportion of variance explained by the identified variants is mostly small. Rare coding variants, particularly those with high potential for impact on protein structure/function, may have substantial impact on phenotype but are difficult to detect by GWAS. The main purpose of this study was to identify low frequency or rare variants associated with platelet function using genotype data from the Illumina HumanExome Bead Chip. Three family-based cohorts of European ancestry, including ~4,000 total subjects, comprised the discovery cohort and two independent cohorts, one of European and one of African American ancestry, were used for replication. Optical aggregometry in platelet-rich plasma was performed in all the discovery cohorts in response to adenosine diphosphate (ADP), epinephrine, and collagen. Meta-analyses were performed using both gene-based and single nucleotide variant association methods. The gene-based meta-analysis identified a significant association (P = 7.13 × 10-7) between rare genetic variants in ANKRD26 and ADP-induced platelet aggregation. One of the ANKRD26 SNVs - rs191015656, encoding a threonine to isoleucine substitution predicted to alter protein structure/function, was replicated in Europeans. Aggregation increases of ~20-50% were observed in heterozygotes in all cohorts. Novel genetic signals in ABCG1 and HCP5 were also associated with platelet aggregation to ADP in meta-analyses, although only results for HCP5 could be replicated. The SNV in HCP5 intersects epigenetic signatures in CD41+ megakaryocytes suggesting a new functional role in platelet biology for HCP5. This is the first study to use gene-based association methods from SNV array genotypes to identify rare variants related to platelet function. The molecular mechanisms and pathophysiological relevance for the identified genetic associations requires further study.

Factors influencing longitudinal changes of circulating liver enzyme concentrations in subjects randomized to placebo in four clinical trials.

Liver enzyme concentrations are measured as safety end points in clinical trials to detect drug-related hepatotoxicity, but little is known about the epidemiology of these biomarkers in subjects without hepatic dysfunction who are enrolled in drug trials. We studied alanine and aspartate aminotransferase (ALT and AST) in subjects randomized to placebo who completed assessments over 36 mo in a cardiovascular outcome trial [the Stabilisation of Atherosclerotic Plaque by Initiation of Darapladib Therapy ("STABILITY") trial; n = 4,264; mean age: 64.2 yr] or over 12 mo in three trials that enrolled only subjects with type 2 diabetes (T2D) [the DIA trials; n = 308; mean age: 62.4 yr] to investigate time-dependent relationships and the factors that might affect ALT and AST, including body mass index (BMI), T2D, and renal function. Multivariate linear mixed models examined time-dependent relationships between liver enzyme concentrations as response variables and BMI, baseline T2D status, hemoglobin A1c levels, and renal function, as explanatory variables. At baseline, ALT was higher in individuals who were men, <65 yr old, and obese and who had glomerular filtration rate (GFR) >60 ml·min-1·1.73 m-2. ALT was not significantly associated with T2D at baseline, although it was positively associated with HbA1c. GFR had a greater impact on ALT than T2D. ALT concentrations decreased over time in subjects who lost weight but remained stable in individuals with increasing BMI. Weight change did not alter AST concentrations. We provide new insights on the influence of time, GFR, and HbA1c on ALT and AST concentrations and confirm the effect of sex, age, T2D, BMI, and BMI change in subjects receiving placebo in clinical trials. NEW & NOTEWORTHY Clinical trials provide high-quality data on liver enzyme concentrations from subjects randomized to placebo that can be used to investigate the epidemiology of these biomarkers. The adjusted models show the influence of sex, age, time, renal function, type 2 diabetes, HbA1c, and body mass index on alanine aminotransferase and aspartate aminotransferase concentrations and their relative importance. These factors need to be considered when assessing potential signals of hepatotoxicity in trials of new drugs and in clinical trials investigating subjects with nonalcoholic fatty liver disease.

Assessment of rosacea symptom severity by genome-wide association study and expression analysis highlights immuno-inflammatory and skin pigmentation genes.

Rosacea is a common, chronic skin disease of variable severity with limited treatment options. The cause of rosacea is unknown, but it is believed to be due to a combination of hereditary and environmental factors. Little is known about the genetics of the disease. We performed a genome-wide association study (GWAS) of rosacea symptom severity with data from 73 265 research participants of European ancestry from the 23andMe customer base. Seven loci had variants associated with rosacea at the genome-wide significance level (P < 5 × 10-8). Further analyses highlighted likely gene regions or effector genes including IRF4 (P = 1.5 × 10-17), a human leukocyte antigen (HLA) region flanked by PSMB9 and HLA-DMB (P = 2.2 × 10-15), HERC2-OCA2 (P = 4.2 × 10-12), SLC45A2 (P = 1.7 × 10-10), IL13 (P = 2.8 × 10-9), a region flanked by NRXN3 and DIO2 (P = 4.1 × 10-9), and a region flanked by OVOL1and SNX32 (P = 1.2 × 10-8). All associations with rosacea were novel except for the HLA locus. Two of these loci (HERC-OCA2 and SLC45A2) and another precedented variant (rs1805007 in melanocortin 1 receptor) with an association P value just below the significance threshold (P = 1.3 × 10-7) have been previously associated with skin phenotypes and pigmentation, two of these loci are linked to immuno-inflammation phenotypes (IL13 and PSMB9-HLA-DMA) and one has been associated with both categories (IRF4). Genes within three loci (PSMB9-HLA-DMA, HERC-OCA2 and NRX3-DIO2) were differentially expressed in a previously published clinical rosacea transcriptomics study that compared lesional to non-lesional samples. The identified loci provide specificity of inflammatory mechanisms in rosacea, and identify potential pathways for therapeutic intervention.

Erratum: Large meta-analysis of genome-wide association studies identifies five loci for lean body mass.

A correction to this article has been published and is linked from the HTML version of this article.

Phenome-wide association study using research participants' self-reported data provides insight into the Th17 and IL-17 pathway.

A phenome-wide association study of variants in genes in the Th17 and IL-17 pathway was performed using self-reported phenotypes and genetic data from 521,000 research participants of 23andMe. Results replicated known associations with similar effect sizes for autoimmune traits illustrating self-reported traits can be a surrogate for clinically assessed conditions. Novel associations controlling for a false discovery rate of 5% included the association of the variant encoding p.Ile684Ser in TYK2 with increased risk of tonsillectomy, strep throat occurrences and teen acne, the variant encoding p.Arg381Gln in IL23R with a decrease in dandruff frequency, the variant encoding p.Asp10Asn in TRAF3IP2 with risk of male-pattern balding, and the RORC regulatory variant (rs4845604) with protection from allergies. This approach enabled rapid assessment of association with a wide variety of traits and investigation of traits with limited reported associations to overlay meaningful phenotypic context on the range of conditions being considered for drugs targeting this pathway.

Genetic Determinants of Radiographic Knee Osteoarthritis in African Americans.

OBJECTIVE: The etiology of knee osteoarthritis (OA), the most common form of arthritis, is complex and may differ by race or ethnicity. In recent years, genetic studies have identified many genetic variants associated with OA, but nearly all the studies were conducted in European whites and Asian Americans. Few studies have focused on the genetics of knee OA in African Americans. METHODS: We performed a genome-wide association study of radiographic knee OA in 1217 African Americans from 2 North American cohort studies: 590 subjects from the Johnston County Osteoarthritis Project and 627 subjects from the Osteoarthritis Initiative. Analyses were conducted in each cohort separately and combined in an inverse variance fixed effects metaanalysis, which were then included in pathway analyses. We additionally tested 12 single-nucleotide polymorphisms robustly associated with OA in European white populations for association in African Americans. RESULTS: We identified a genome-wide significant variant in LINC01006 (minor allele frequency 12%; p = 4.11 × 10-9) that is less common in European white populations (minor allele frequency < 3%). Five other independent loci reached suggestive significance (p < 1 × 10-6). In pathway analyses, dorsal/ventral neural tube patterning and iron ion transport pathways were significantly associated with knee OA in African Americans (false discovery rate < 0.05). We found no evidence that previously reported OA susceptibility variants in European whites were associated with knee OA in African Americans. CONCLUSION: These results highlight differences in the genetic architecture of knee OA between African American and European whites. This finding underscores the need to include more diverse populations in OA genetics studies.

Oxaliplatin-Induced Peripheral Neuropathy and Identification of Unique Severity Groups in Colorectal Cancer.

CONTEXT: Oxaliplatin-induced peripheral neuropathy (OIPN) is a dose-limiting toxicity of oxaliplatin and affects most colorectal cancer patients. OIPN is commonly evaluated by patient symptom report, using scales to reflect impairment. They do not discriminate between unique grouping of symptoms and signs, which impedes prompt identification of OIPN. OBJECTIVE: The objective of this study was to identify clusters of symptoms and signs that differentiated underlying clinical severity and segregated patients within our population into OIPN subgroups. METHODS: Chemotherapy-naive colorectal cancer patients (N = 148) receiving oxaliplatin were administered the Total Neuropathy Score clinical (TNSc©), which includes symptom report (sensory, motor, autonomic) and sensory examination (pin sense, vibration, reflexes). The TNSc was administered before chemotherapy initiation (T0) and after cumulative doses of oxaliplatin 510-520 mg/m2 (T1) and 1020-1040 mg/m2 of oxaliplatin (T2). Using mean T2 TNSc scores, latent class analysis grouped patients into OIPN severity cohorts. RESULTS: Latent class analysis categorized patients into four distinct OIPN groups: low symptoms and low signs (n = 54); low symptoms and intermediate signs (n = 44); low symptoms and high signs (n = 21); and high symptoms and high signs (n = 29). No differences were noted among OIPN groups on age, sex, chemotherapy regimen, or cumulative oxaliplatin dose. CONCLUSION: We identified OIPN patient groups with distinct symptoms/signs, demonstrating variability of OIPN presentation regardless of cumulative oxaliplatin dose. Over half of the sample had positive findings on OIPN examination despite little or no symptoms. Sensory examination of all patients receiving oxaliplatin is indicated for timely identification of OIPN, which will allow earlier symptom management.

Large meta-analysis of genome-wide association studies identifies five loci for lean body mass.

Lean body mass, consisting mostly of skeletal muscle, is important for healthy aging. We performed a genome-wide association study for whole body (20 cohorts of European ancestry with n = 38,292) and appendicular (arms and legs) lean body mass (n = 28,330) measured using dual energy X-ray absorptiometry or bioelectrical impedance analysis, adjusted for sex, age, height, and fat mass. Twenty-one single-nucleotide polymorphisms were significantly associated with lean body mass either genome wide (p < 5 × 10-8) or suggestively genome wide (p < 2.3 × 10-6). Replication in 63,475 (47,227 of European ancestry) individuals from 33 cohorts for whole body lean body mass and in 45,090 (42,360 of European ancestry) subjects from 25 cohorts for appendicular lean body mass was successful for five single-nucleotide polymorphisms in/near HSD17B11, VCAN, ADAMTSL3, IRS1, and FTO for total lean body mass and for three single-nucleotide polymorphisms in/near VCAN, ADAMTSL3, and IRS1 for appendicular lean body mass. Our findings provide new insight into the genetics of lean body mass.Lean body mass is a highly heritable trait and is associated with various health conditions. Here, Kiel and colleagues perform a meta-analysis of genome-wide association studies for whole body lean body mass and find five novel genetic loci to be significantly associated.

Functional analysis of PCSK2 coding variants: A founder effect in the Old Order Amish population.

AIMS: In humans, noncoding variants of PCSK2, the gene encoding prohormone convertase 2 (PC2), have been previously associated with risk for and age of onset of type 2 diabetes (T2D). The aims of this study were to identify coding variants in PCSK2; to determine their possible association with glucose handling; and to determine functional outcomes for coding variants in biochemical studies. METHODS: Exome-wide genotyping was performed on 1725 Old Order Amish (OOA) subjects. PCSK2 coding variants were tested for association with diabetes-related phenotypes. In vitro analyses using transfected human PC2-encoding constructs were performed to determine the impact of each mutation on PC2 activity. RESULTS: We identified 10 rare missense coding variants in PCSK2 in various genomic databases. R430W (rs200711626) is greatly enriched in the OOA population (MAF 4.3%). This variant is almost twice as common (MAF 7.4%) in OOA individuals with T2D as in OOA individuals with normal or with normal/impaired glucose tolerance (MAF 3.9% and 2.9%, respectively; p=0.25 and p=0.10). In vitro experiments revealed a broadening of the pH optimum for the R430W variant, which may result in increased activity against PCSK2 substrates. CONCLUSIONS: Although the association of the R430W variation with T2D in the OOA population did not reach significance, based upon the broadened pH profile of R430W PC2, we speculate that the presence of this substitution may result in altered processing of PCSK2 substrates, ultimately leading to increased conversion to diabetes.

Sex-specific effects of serum sulfate level and SLC13A1 nonsense variants on DHEA homeostasis.

CONTEXT: Sulfate is critical in the biotransformation of multiple compounds via sulfation. These compounds include neurotransmitters, proteoglycans, xenobiotics, and hormones such as dehydroepiandrosterone (DHEA). Sulfation reactions are thought to be rate-limited by endogenous sulfate concentrations. The gene, SLC13A1, encodes the sodium-sulfate cotransporter NaS1, responsible for sulfate (re)absorption in the intestines and kidneys. We previously reported two rare, non-linked, nonsense variants in SLC13A1 (R12X and W48X) associated with hyposulfatemia (P = 9 × 10- 20). OBJECTIVE: To examine the effect of serum sulfate concentration and sulfate-lowering genotype on DHEA homeostasis. DESIGN: Retrospective cohort study. SETTING: Academic research. PATIENTS: Participants of the Amish Pharmacogenomics of Anti-Platelet Intervention (PAPI) Study and the Amish Hereditary and Phenotype Intervention (HAPI) Study. MAIN OUTCOME MEASURES: DHEA, DHEA-S, and DHEA-S/DHEA ratio. RESULTS: Increased serum sulfate was associated with decreased DHEA-S (P = 0.03) and DHEA-S/DHEA ratio (P = 0.06) in males but not females. Female SLC13A1 nonsense variant carriers, who had lower serum sulfate (P = 9 × 10- 13 ), exhibited 14% lower DHEA levels (P = 0.01) and 7% higher DHEA-S/DHEA ratios compared to female non-carriers (P = 0.002). Consistent with this finding, female SLC13A1 nonsense variant carriers also had lower total testosterone levels compared to non-carrier females (P = 0.03). CONCLUSIONS: Our results demonstrate an inverse relationship between serum sulfate, and DHEA-S and DHEA-S/DHEA ratio in men, while also suggesting that the sulfate-lowering variants, SLC13A1 R12X and W48X, decrease DHEA and testosterone levels, and increase DHEA-S/DHEA ratio in women. While paradoxical, these results illustrate the complexity of the mechanisms involved in DHEA homeostasis and warrant additional studies to better understand sulfate's role in hormone physiology.

Genome-wide analysis of clopidogrel active metabolite levels identifies novel variants that influence antiplatelet response.

Clopidogrel is one of the most commonly used therapeutics for the secondary prevention of cardiovascular events in patients with acute coronary syndromes. However, considerable interindividual variation in clopidogrel response has been documented, resulting in suboptimal therapy and an increased risk of recurrent events for some patients. In this investigation, we carried out the first genome-wide association study of circulating clopidogrel active metabolite levels in 513 healthy participants to directly measure clopidogrel pharmacokinetics. We observed that the CYP2C19 locus was the strongest genetic determinant of active metabolite formation (P=9.5×10). In addition, we identified novel genome-wide significant variants on chromosomes 3p25 (rs187941554, P=3.3×10) and 17q11 (rs80343429, P=1.3×10), as well as six additional loci that showed suggestive evidence of association (P≤1.0×10). Four of these loci showed nominal associations with on-clopidogrel ADP-stimulated platelet aggregation (P≤0.05). Evaluation of clopidogrel active metabolite concentration may help identify novel genetic determinants of clopidogrel response, which has implications for the development of novel therapeutics and improved antiplatelet treatment for at-risk patients in the future.