Kidney epithelial targeted mitochondrial transcription factor A deficiency results in progressive mitochondrial depletion associated with severe cystic disease.

Abnormal mitochondrial function is a well-recognized feature of acute and chronic kidney diseases. To gain insight into the role of mitochondria in kidney homeostasis and pathogenesis, we targeted mitochondrial transcription factor A (TFAM), a protein required for mitochondrial DNA replication and transcription that plays a critical part in the maintenance of mitochondrial mass and function. To examine the consequences of disrupted mitochondrial function in kidney epithelial cells, we inactivated TFAM in sine oculis-related homeobox 2-expressing kidney progenitor cells. TFAM deficiency resulted in significantly decreased mitochondrial gene expression, mitochondrial depletion, inhibition of nephron maturation and the development of severe postnatal cystic disease, which resulted in premature death. This was associated with abnormal mitochondrial morphology, a reduction in oxygen consumption and increased glycolytic flux. Furthermore, we found that TFAM expression was reduced in murine and human polycystic kidneys, which was accompanied by mitochondrial depletion. Thus, our data suggest that dysregulation of TFAM expression and mitochondrial depletion are molecular features of kidney cystic disease that may contribute to its pathogenesis.

Gaussia Luciferase as a Reporter for Quorum Sensing in Staphylococcus aureus.

Gaussia luciferase (GLuc) is a secreted protein with significant potential for use as a reporter of gene expression in bacterial pathogenicity studies. To date there are relatively few examples of its use in bacteriology. In this study we show that GLuc can be functionally expressed in the human pathogen Staphylococcus aureus and furthermore show that it can be used as a biosensor for the agr quorum sensing (QS) system which employs autoinducing peptides to control virulence. GLuc was linked to the P3 promoter of the S. aureusagr operon. Biosensor strains were validated by evaluation of chemical agent-mediated activation and inhibition of agr. Use of GLuc enabled quantitative assessment of agr activity. This demonstrates the utility of Gaussia luciferase for in vitro monitoring of agr activation and inhibition.

Reconstructive Management Options of Delayed Complications Following Bladder Outlet Surgery.

PURPOSE OF REVIEW: Technological advancements in urologic endoscopy within the last decades have improved outcomes following bladder outlet reduction surgery while minimizing risks of short- and intermediate-term complications. This review aims to examine late complications of endoscopic reduction of the prostate and the various treatment options available. RECENT FINDINGS: Urinary incontinence, ejaculatory dysfunction, urethral strictures, bladder neck contractures, and fistula formations are the most common delayed complications following bladder outlet reduction surgery. Evaluation of these complications typically involves a combination of endoscopic examination, urodynamic findings, pelvic imaging, and review of pre-existing symptoms. Treatment options range from conservative measures such as pelvic floor muscle therapy to complex reconstructive procedures including anti-incontinence surgery, urethral reconstruction, and permanent urinary diversion. Although rare, late complications of bladder outlet reduction surgery are important to recognize in order to manage appropriately. Careful evaluation involving multiple diagnostic modalities with consideration for referral to a dedicated reconstructive urologist may be warranted in complex cases.

Extracorporeal Shock Wave Therapy: Current Perspectives and Future Directions.

PURPOSE OF REVIEW: Since its introduction, extracorporeal shock wave lithotripsy (ESWL) has undergone a variety of changes; however, it remains one of the most utilized treatment modalities for urolithiasis. The goal of this review is to provide the practicing urologist an update on contemporary trends, new technologies, and related controversies in utilizing ESWL for stone treatment. RECENT FINDINGS: ESWL use has come under scrutiny with a shift in focus to cost-effectiveness and healthcare outcomes. Fortunately, advances in lithotripter technology have spawned several generations of devices that strive to improve stone-free rates and decrease complications. Most of all, a focus on patient selection criteria has helped improve procedural success. Years of experience utilizing ESWL for stone treatment have helped urologists better optimize its use and minimize complications. Improvements in technique along with more stringent patient and stone selection have helped ESWL remain a mainstay in the treatment of stone disease.

Multiple SNP testing improves risk prediction of first venous thrombosis.

There are no risk models available yet that accurately predict a person's risk for developing venous thrombosis. Our aim was therefore to explore whether inclusion of established thrombosis-associated single nucleotide polymorphisms (SNPs) in a venous thrombosis risk model improves the risk prediction. We calculated genetic risk scores by counting risk-increasing alleles from 31 venous thrombosis-associated SNPs for subjects of a large case-control study, including 2712 patients and 4634 controls (Multiple Environmental and Genetic Assessment). Genetic risk scores based on all 31 SNPs or on the 5 most strongly associated SNPs performed similarly (areas under receiver-operating characteristic curves [AUCs] of 0.70 and 0.69, respectively). For the 5-SNP risk score, the odds ratios for venous thrombosis ranged from 0.37 (95% confidence interval [CI], 0.25-0.53) for persons with 0 risk alleles to 7.48 (95% CI, 4.49-12.46) for persons with more than or equal to 6 risk alleles. The AUC of a risk model based on known nongenetic risk factors was 0.77 (95% CI, 0.76-0.78). Combining the nongenetic and genetic risk models improved the AUC to 0.82 (95% CI, 0.81-0.83), indicating good diagnostic accuracy. To become clinically useful, subgroups of high-risk persons must be identified in whom genetic profiling will also be cost-effective.

A Blunt Scrotal Trauma With More Than Meets the Eye.

Extrarenal Wilms' tumors (ERWT) are exceedingly rare with an estimated occurrence of 0.5%-1% of all Wilms' tumors.1 ERWT was first described by Moyson et al in 1961 with the most commonly reported extrarenal sites in the retroperitoneum, inguinal region, uterus and ovaries.2 Here we detail a patient who presented to our institution with a blunt scrotal trauma that was later diagnosed with primary paratesticular ERWT.

NGS-defined measurable residual disease (MRD) after initial chemotherapy as a prognostic biomarker for acute myeloid leukemia.

Treated AML patients often have measurable residual disease (MRD) due to persisting low-level clones. This study assessed whether residual post-treatment somatic mutations, detected by NGS, were significantly prognostic for subsequent clinical outcomes. AML patients (n = 128) underwent both pre-and post-treatment testing with the same 42-gene MRD-validated NGS assay. After induction, 59 (46%) patients were mutation-negative (0.0024 VAF detection limit) and 69 (54%) had ≥1 persisting NGS-detectable mutation. Compared with NGS-negative patients, NGS-positive patients had shorter overall survival (17 months versus median not reached; P = 0.004; hazard ratio = 2.2 [95% CI: 1.3-3.7]) and a shorter time to relapse (14 months versus median not reached; P = 0.014; HR = 1.9 [95% CI: 1.1-3.1]). Among 95 patients with a complete morphologic remission (CR), 43 (45%) were MRD-positive by NGS and 52 (55%) were MRD-negative. These MRD-positive CR patients had a shorter overall survival (16.8 months versus median not reached; P = 0.013; HR = 2.1 [95% CI: 1.2-3.9]) than did the MRD-negative CR patients. Post-treatment persisting MRD positivity, defined by the same NGS-based test used at diagnosis, is thus a more sensitive biomarker for low-level leukemic clones compared to traditional non-molecular methods and is prognostic of subsequent relapse and death.

Facilitating Mental Health Treatment Through Proactive Screening and Concierge Services in the Workplace.

OBJECTIVE: The aim of this study is to determine if a proactive employer-sponsored mental health program closed gaps in detection and treatment of mental health conditions. METHODS: Of n = 56,442 eligible, n = 8170 (14.5%) participated in the optional screening. Participants with mental health risk were offered care concierge services including support, care planning, and connection to care. Difference in behavioral health care utilization, diagnoses, and prescriptions were evaluated postintervention through claims analysis. RESULTS: Compared with controls (n = 2433), those receiving concierge services (n = 369) were more likely to fill mental health prescriptions (adjusted hazards ratio [HR], 1.2; 1.0-1.5; P = 0.042), use professional mental health services (adjusted HR, 1.4; 1.1-1.8; P = 0.02), and use new mental health services (adjusted HR, 1.9; 1.2-2.8; P = 0.004) in the following 6 months. CONCLUSIONS: This proactive mental health program with care concierge services identified risk, connected individuals to mental health care, and facilitated mental health treatment, among program participants.

Polymorphisms and noncardioembolic stroke in three case-control studies.

BACKGROUND: Gene variants associated with disease could reveal novel mechanisms. We searched for single nucleotide polymorphisms (SNPs) associated with noncardioembolic stroke (nonCES). METHODS: We tested 24,926 SNPs in or near genes for association with nonCES in the Vienna Study (551 cases, 815 controls) and then evaluated the associated SNPs in the UCSF-CC Study (570 cases, 1,604 controls) first in pooled DNA samples and then in individual DNA samples. We then asked whether the risk alleles of the SNPs associated with increased risk in both studies were also associated with increased risk of nonCES in the German Study (728 cases, 1,041 controls). RESULTS: Six of the 46 SNPs that were associated with nonCES in both the Vienna and the UCSF-CC Studies were also associated with nonCES in the German Study: rs362277 in HTT (OR 1.39, 90% CI 1.12-1.71), rs2924914 near CSMD1 (OR 1.22, 90% CI 1.04-1.43), rs1264352 near DDR1 (OR 1.20, 90% CI 1.02-1.41), rs544115 in NEU3 (OR 1.63, 90% CI 1.02-2.62), rs12481805 in UMODL1 (OR 1.31, 90% CI 1.01-1.81), and rs2857595 near NCR3 (OR 1.15, 90% CI 1.00-1.32). Accounting for multiple testing of 46 SNPs, these 6 SNPs had a false discovery rate of 0.69. CONCLUSIONS: Some of the 6 SNPs may be associated with nonCES but most may be false positives. These 6 SNPs merit investigation in additional nonCES study populations.

Vascular associated gene variants in patients with preeclampsia: results from the Danish National Birth Cohort.

OBJECTIVE: Preeclampsia has been linked to subsequent vascular disease with many shared predisposing factors. We investigated the association between severe preeclampsia, and its subtypes, and specific vascular-related polymorphisms. DESIGN: The study was a retrospective nested case-cohort design. SETTING: Pregnant Danish women participating in the Danish National Birth Cohort. Population. 263 cases of severe preeclampsia and 1851 random controls were selected from the Danish National Birth Cohort. METHODS: We validated all cases of severe preeclampsia and genotyped for 108 single nucleotide polymorphisms (SNPs) that were selected based on previous publications on the association with vascular disease. Logistic models were used for statistical analyses. MAIN OUTCOME MEASURES: Maternal polymorphisms in genomic models. RESULTS: We found 17 of 108 SNPs associated with severe preeclampsia (p < 0.05). Women homozygous for the rs1799983 in NOS3 were 1.6-fold [95% confidence interval (CI) 1.0-2.4] more likely to develop severe preeclampsia. Women homozygous for the rs1010 SNP in VAMP8 were twofold (95%CI 1.1-3.5) more likely to deliver preterm when preeclampsia was present. Women homozygous for the rs10811661 SNP were 2.1-fold (95%CI 1.1-3.9) more likely to develop severe preeclampsia and 3.7-fold (95%CI 1.1-12.4) more likely to deliver a small-for-gestational age child when preeclampsia was present. All associations are available as Supporting Information. CONCLUSION: We found several vascular-associated SNPs linked to severe preeclampsia; however, most of these associations are probably by pure chance, which warrants replication and further translational research. To date, no specific SNP has yet proven valuable in a clinical setting in predicting preeclampsia.

Workplace Outreach Program Improves Management of Chronic Kidney Disease.

OBJECTIVE: Assess whether an employee outreach program improved management of chronic kidney disease (CKD). METHODS: Participants with suspected CKD (eGFR <60 mL/min/1.73m 2 ) identified in employee health assessments in 2017 and 2018 were contacted by phone and offered physician consultation. Subsequent nephrologist visits at 11 months of follow up were compared between those who were (outreach group) and were not (control group) successfully contacted. RESULTS: Most CKD risk factors at baseline were similar in outreach and control groups. At the end of the follow-up, outreach participants had more than 2-fold greater incidence of visiting a nephrologist compared with controls (HR = 2.3; 95% CI 1.2-4.2, P = 0.01), after adjusting for potential confounders. Conclusions: Employee outreach program increased utilization of nephrologist care.

Urine leaks in children sustaining blunt renal trauma.

BACKGROUND: Few consensus statements exist to guide the timely diagnosis and management of urine leaks in children sustaining blunt renal trauma (BRT). The aims of this study were to characterize kidney injuries among children who sustain BRT, evaluate risk factors for urine leaks, and describe the negative impact of urinoma on patient outcomes and resource consumption. METHODS: A retrospective review was performed of 347 patients, younger than 19 years, who presented with BRT to a single American College of Surgeons-verified Level I Pediatric Trauma Center between 2005 and 2020. Frequency of and risk factors for urine leak after BRT were evaluated, and impact on patient outcomes and resource utilization were analyzed. RESULTS: In total, 44 (12.7%) patients developed urine leaks, which exclusively presented among injury Grade 3 (n = 5; 11.4%), Grade 4 (n = 27; 61.4%), and Grade 5 (n = 12; 27.3%). A minority of urine leaks (n = 20; 45.5%) were discovered on presenting CT scan but all within 3 days. Kidney-specific operative procedures (nephrectomy, cystoscopy with J/ureteral stent, percutaneous nephrostomy) were more common among urine leak patients (n = 17; 38.6%) compared with patients without urine leaks (n = 3; 1.0%; p = 0.001). Patients with urine leak had more frequent febrile episodes during hospital stay (n = 24; 54.5%; p = 0.001) and showed increased overall 90-day readmission rates (n = 14; 33.3%; p < 0.001). Independent risk factors that associated with urine leak were higher grade (odds ratio [OR], 7.9; 95% confidence interval [CI], 2.6-24.3; p < 0.001), upper-lateral quadrant injuries (OR, 2.9; 95% CI, 1.2-7.1; p = 0.02), and isolated BRT (OR, 2.6; 95% CI, 1.0-6.5; p = 0.04). CONCLUSION: In a large cohort of children sustaining BRT, urine leaks result in considerable morbidity, including more febrile episodes, greater 90-day readmission rates, and increased operative or image-guided procedures. This study is the first to examine the relationship between kidney quadrant injury and urine leaks. Higher grade (Grade 4-5) injury, upper lateral quadrant location, and isolated BRT were independently predictive of urine leaks. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level III.

Genetic variants in the KIF6 region and coronary event reduction from statin therapy.

A single nucleotide polymorphism (SNP) in KIF6, a member of the KIF9 family of kinesins, is associated with differential coronary event reduction from statin therapy in four randomized controlled trials; this SNP (rs20455) is also associated with the risk for coronary heart disease (CHD) in multiple prospective studies. We investigated whether other common SNPs in the KIF6 region were associated with event reduction from statin therapy. Of the 170 SNPs in the KIF6 region investigated in the Cholesterol and Recurrent Events trial (CARE), 28 were associated with differential event reduction from statin therapy (P (interaction) < 01 in Caucasians, adjusted for age and sex) and were further investigated in the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction 22 (PROVE IT-TIMI22) and West of Scotland Coronary Prevention Study (WOSCOPS). These analyses revealed that two SNPs (rs9462535 and rs9471077), in addition to rs20455, were associated with event reduction from statin therapy (P (interaction) < 0.1 in each of the three studies). The relative risk reduction ranged from 37 to 50% (P < 0.01) in carriers of the minor alleles of these SNPs and from -4 to 13% (P > 0.4) in non-carriers. These three SNPs are in high linkage disequilibrium with one another (r (2) > 0.84). Functional studies of these variants may help to understand the role of KIF6 in the pathogenesis of CHD and differential response to statin therapy.

Assessment of the Association of Vitamin D Level With SARS-CoV-2 Seropositivity Among Working-Age Adults.

Importance: Low vitamin D levels have been reported to be associated with increased risk of SARS-CoV-2 infection. Independent, well-powered studies could further our understanding of this association. Objective: To examine whether low levels of vitamin D are associated with SARS-CoV-2 seropositivity, an indicator of previous infection. Design, Setting, and Participants: This is a cohort study of employees and spouses who elected to be tested for SARS-CoV-2 IgG as part of an annual employer-sponsored health screening program conducted in August to November 2020. This program includes commonly assessed demographic, biometric, and laboratory variables, including total vitamin D measurement. Baseline (prepandemic) levels of vitamin D and potential confounders were obtained from screening results from the previous year (September 2019 to January 2020). Data analysis was performed from December 2020 to March 2021. Exposures: Low total serum 25-hydroxyvitamin D, defined as either less than 20 ng/mL or less than 30 ng/mL. Main Outcomes and Measures: The main outcome was SARS-CoV-2 seropositivity, as determined with US Food and Drug Administration emergency use-authorized assays. The association of SARS-CoV-2 seropositivity with vitamin D levels was assessed by multivariable logistic regression analyses and propensity score analyses. Results: The 18 148 individuals included in this study had test results for SARS-CoV-2 IgG in 2020 and vitamin D levels from the prepandemic and pandemic periods. Their median (interquartile range) age was 47 (37-56) years, 12 170 (67.1%) were women, 900 (5.0%) were seropositive, 4498 (24.8%) had a vitamin D level less than 20 ng/mL, and 10 876 (59.9%) had a vitamin D level less than 30 ng/mL before the pandemic. In multivariable models adjusting for age, sex, race/ethnicity, education, body mass index, blood pressure, smoking status, and geographical location, SARS-CoV-2 seropositivity was not associated with having a vitamin D level less than 20 ng/mL before (odds ratio [OR], 1.04; 95% CI, 0.88-1.22) or during (OR, 0.93; 95% CI, 0.79-1.09) the pandemic; it was also not associated with having a vitamin D level less than 30 ng/mL before (OR, 1.09; 95% CI, 0.93-1.27) or during (OR, 1.05; 95% CI, 0.91-1.23) the pandemic. Similar results were observed in propensity score analyses. SARS-CoV-2 seropositivity was associated with obesity (OR, 1.26; 95% CI, 1.08-1.46), not having a college degree (OR, 1.40; 95% CI, 1.21-1.62), and Asian (OR, 1.46; 95% CI, 1.13-1.87), Black (OR, 2.74; 95% CI, 2.25-3.34), Hispanic (OR, 2.65; 95% CI, 2.15-3.27), American Indian or Alaska Native, and Native Hawaiian or other Pacific Islander (OR, 2.01; OR, 1.54-2.62) race/ethnicity, and was inversely associated with high blood pressure (OR, 0.82; 95% CI, 0.70-0.96), smoking (OR, 0.60; 95% CI, 0.47-0.78), and residing in the US Northeast (OR, 0.75; 95% CI, 0.62-0.92) and West (OR, 0.54; 95% CI, 0.44-0.67). Conclusions and Relevance: In this cohort study, SARS-CoV-2 seropositivity was not associated with low levels of vitamin D independently of other risk factors.

Association of changes in lipid levels with changes in vitamin D levels in a real-world setting.

In clinical trials, vitamin D supplementation has been reported to reduce serum levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG) but not high-density lipoprotein cholesterol (HDL-C). In this cohort study we evaluated the association between changes in vitamin D (25-hydroxyvitamin D) and changes in lipid levels in a real-world setting. Changes in lipid levels over a 1-year period were evaluated among individuals whose vitamin D levels increased (group 1) or decreased (group 2) by ≥ 10 ng/mL in year 2018 versus 2017 (cohort 1; n = 5580), in 2019 versus 2018 (cohort 2, n = 6057), or in 2020 versus 2019 (cohort 3, n = 7249). In each cohort, levels of TC, LDL-C, and TG decreased in group 1 and increased in group 2. Between-group differences in average changes in the 3 cohorts ranged from 10.71 to 12.02 mg/dL for TC, from 7.42 to 8.95 mg/dL for LDL-C, and from 21.59 to 28.09 mg/dL for TG. These differences were significant after adjusting for age, sex, race, education, body mass index, blood pressure, smoking status, geographical location, and baseline levels of vitamin D and lipids (P < 0.001). Changes in vitamin D levels were not significantly associated with changes in HDL-C levels.

KIF6 Trp719Arg polymorphism and the effect of statin therapy in elderly patients: results from the PROSPER study.

BACKGROUND: Statin therapy has been found to substantially and significantly reduce coronary events in carriers of the KIF6 719Arg variant (rs20455) but not in noncarriers. We investigated whether, among the elderly, statin therapy also significantly reduced coronary events in carriers but not in noncarriers. DESIGN AND METHODS: Among 5,752 patients of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) study, we assessed the effect of pravastatin, compared with placebo, on coronary events according to 719Arg carrier status using proportional hazards models. RESULTS: Since benefit from statin therapy in elderly patients has been primarily shown among those with prior vascular disease, we performed analyses in PROSPER patients with prior disease and found that pravastatin therapy significantly reduced events in 719Arg carriers [hazards ratio (HR): 0.66, 95% confidence interval (CI): 0.52-0.86] but not in noncarriers (HR: 0.94, 95% CI: 0.69-1.28), P=0.09 for interaction between treatment and carrier status. Among those without prior disease, no significant benefit was observed in either carriers or noncarriers. Among those with prior vascular disease in the placebo arm, Trp719Arg heterozygotes were at significantly greater risk, compared with noncarriers (HR: 1.36, 95% CI: 1.03-1.81, P=0.03); the HR of 719Arg carriers, compared with noncarriers, was 1.28 (95% CI: 0.98-1.69, P=0.07). CONCLUSION: Elderly carriers of the KIF6 719Arg variant with prior vascular disease received significant benefit from pravastatin therapy; no benefit was observed in noncarriers with prior disease or in those without prior disease (carriers or noncarriers).

F9 Malmö, factor IX and deep vein thrombosis.

BACKGROUND: We recently reported the association between the Malmö sequence variant in F9 (rs6048) and deep vein thrombosis. DESIGN AND METHODS: We aimed to study whether the association between F9 Malmö and deep vein thrombosis is explained by linkage disequilibrium with nearby single-nucleotide polymorphisms, and whether the association is explained biologically by F9 Malmö affecting factor IX antigen levels or activation of factor IX. We investigated the association of F9 Malmö and 28 nearby single-nucleotide polymorphisms with deep vein thrombosis in men from two case-control studies, LETS (n=380) and MEGA (n=1,469). We assessed the association of F9 Malmö with factor IX antigen level in male control subjects from LETS (n=191) and two subsets of MEGA (n=823 and n=484) and the association with endogenous thrombin potential in LETS control men. We studied the association between F9 Malmö and factor IX activation peptide in 1,199 healthy middle-aged men from the NPHS-II cohort. RESULTS: In the combined LETS and MEGA studies, the odds ratio (95% confidence interval) for the G allele of F9 Malmö, compared with the A allele, was 0.80 (0.69-0.93). One single-nucleotide polymorphism in F9, rs422187, was strongly linked to F9 Malmö (r(2)=0.94) and was similarly associated with deep vein thrombosis. No other single-nucleotide polymorphism or haplotype tested was more strongly associated. Factor IX antigen level, factor IX activation peptide levels and endogenous thrombin potential did not differ between F9 Malmö genotypes. CONCLUSIONS: The F9 Malmö sequence variant was the most strongly associated with deep vein thrombosis among common single-nucleotide polymorphisms in the region. However, the biological mechanism by which F9 Malmö affects risk remains unknown.

Association between ADAMTS1 matrix metalloproteinase gene variation, coronary heart disease, and benefit of statin therapy.

OBJECTIVE: The purpose of this study was to investigate the association between the Ala227Pro polymorphism in the ADAMTS1 metalloproteinase gene and coronary heart disease and benefit from statin therapy in 2 independent cohorts. METHODS AND RESULTS: The frequency of the ADAMTS1 227Pro minor allele was 0.24 in 2421 male subjects from CARE, a randomized trial of pravastatin versus placebo. In the placebo arm, homozygotes (6.3% of study population) had a significantly increased risk of fatal coronary disease or nonfatal myocardial infarction (D/MI) compared with noncarriers (OR 2.12, 95% CI 1.07 to 4.19, P=0.03), and in the entire study the benefit of pravastatin in reducing the risk of D/MI was greater in these subjects (OR 0.21, 95% CI 0.06 to 0.69) than in heterozygotes (OR 0.74, 95% CI 0.48 to 1.14) or noncarriers (OR 0.99, 95% CI 0.68 to 1.42; P(interaction)=0.044). Results were tested in 1565 male subjects from WOSCOPS, also a randomized trial of pravastatin versus placebo. Similar to the results in CARE, in the placebo arm subjects homozygous for the minor allele were at increased risk of D/MI (OR 1.72, P=0.052) and in the entire study the benefit of pravastatin in reducing D/MI was greater in these subjects (OR 0.24, 95% CI 0.09 to 0.68) than in heterozygotes (OR 0.73, 95% CI 0.48 to 1.11) or noncarriers (OR 0.65, 95% CI 0.20 to 2.09) (P(interaction)=0.029). CONCLUSIONS: In men not on pravastatin, those homozygous for the 227Pro allele of ADAMTS1 have a nearly 2-fold increased risk of coronary heart disease events compared with noncarriers. In this high-risk group, treatment with pravastatin is highly efficacious, reducing the odds of fatal coronary disease or nonfatal MI by approximately 75%, as compared with 25% in noncarriers or heterozygotes.

A polymorphism in the protease-like domain of apolipoprotein(a) is associated with severe coronary artery disease.

OBJECTIVES: The purpose of this study was to identify genetic variants associated with severe coronary artery disease (CAD). METHODS AND RESULTS: We used 3 case-control studies of white subjects whose severity of CAD was assessed by angiography. The first 2 studies were used to generate hypotheses that were then tested in the third study. We tested 12,077 putative functional single nucleotide polymorphisms (SNPs) in Study 1 (781 cases, 603 controls) and identified 302 SNPs nominally associated with severe CAD. Testing these 302 SNPs in Study 2 (471 cases, 298 controls), we found 5 (in LPA, CALM1, HAP1, AP3B1, and ABCG2) were nominally associated with severe CAD and had the same risk alleles in both studies. We then tested these 5 SNPs in Study 3 (554 cases, 373 controls). We found 1 SNP that was associated with severe CAD: LPA I4399M (rs3798220). LPA encodes apolipoprotein(a), a component of lipoprotein(a). I4399M is located in the protease-like domain of apolipoprotein(a). Compared with noncarriers, carriers of the 4399M risk allele (2.7% of controls) had an adjusted odds ratio for severe CAD of 3.14 (confidence interval 1.51 to 6.56), and had 5-fold higher median plasma lipoprotein(a) levels (P=0.003). CONCLUSIONS: The LPA I4399M SNP is associated with severe CAD and plasma lipoprotein(a) levels.