DNA and Genetics Archives - Bill Chesnut MD

Specific genes associated with marijuana addiction

“A genetic factor in cannabis dependence severity is important for the public to know. Look into the paragraph of Design, Setting, and Participants to appreciate the quality of this research. A 90% association of this genetic factor with another psychiatric condition or addiction is stunning.

The first paragraph is an announcement in the popular media. I looked up the original article and publish that article’s abstract below the horizontal line.” Bill Chesnut, MD

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Researchers identify specific genes associated with marijuana addiction

TIME (3/30, Szalavitz) reports that “specific genes associated with marijuana addiction have been identified – and some of them are also linked to increased risk for depression and schizophrenia.” Researchers arrived at this conclusion after studying “the genes of nearly 15,000 people from three different groups.” The study’s findings may “help explain why 90% of people with marijuana addictions also suffer from another psychiatric condition or addiction.” The study was published online in JAMA Psychiatry.

Below is the abstract of that original research publication March 30, 2016.

Online First >

Original Investigation | March 30, 2016

Genome-wide Association Study of Cannabis Dependence Severity, Novel Risk Variants, and Shared Genetic Risks ONLINE FIRST

Richard Sherva, PhD¹; Qian Wang, MS²; Henry Kranzler, MD^3,4; Hongyu Zhao, PhD^2,5,6,7; Ryan Koesterer, MS¹; Aryeh Herman, PsyD⁸; Lindsay A. Farrer, PhD^1,9,10,11,12; Joel Gelernter, MD^7,8,13,14

JAMA Psychiatry. Published online March 30, 2016. doi:10.1001/jamapsychiatry.2016.0036

ABSTRACT

Importance Cannabis dependence (CAD) is a serious problem worldwide and is of growing importance in the United States because cannabis is increasingly available legally. Although genetic factors contribute substantially to CAD risk, at present no well-established specific genetic risk factors for CAD have been elucidated.

Objective To report findings for DSM-IV CAD criteria from association analyses performed in large cohorts of African American and European American participants from 3 studies of substance use disorder genetics.

Design, Setting, and Participants This genome-wide association study for DSM-IV CAD criterion count was performed in 3 independent substance dependence cohorts (the Yale-Penn Study, Study of Addiction: Genetics and Environment [SAGE], and International Consortium on the Genetics of Heroin Dependence [ICGHD]). A referral sample and volunteers recruited in the community and from substance abuse treatment centers included 6000 African American and 8754 European American participants, including some from small families. Participants from the Yale-Penn Study were recruited from 2000 to 2013. Data were collected for the SAGE trial from 1990 to 2007 and for the ICGHD from 2004 to 2009. Data were analyzed from January 2, 2013, to November 9, 2015.

Main Outcomes and Measures Criterion count for DSM-IV CAD.

Results Among the 14 754 participants, 7879 were male, 6875 were female, and the mean (SD) age was 39.2 (10.2) years. Three independent regions with genome-wide significant single-nucleotide polymorphism associations were identified, considering the largest possible sample. These included rs143244591 (β = 0.54,P = 4.32 × 10⁻¹⁰ for the meta-analysis) in novel antisense transcript RP11-206M11.7;rs146091982 (β = 0.54,P = 1.33 × 10⁻⁹ for the meta-analysis) in the solute carrier family 35 member G1 gene (SLC35G1); andrs77378271 (β = 0.29, P = 2.13 × 10⁻⁸ for the meta-analysis) in the CUB and Sushi multiple domains 1 gene (CSMD1). Also noted was evidence of genome-level pleiotropy between CAD and major depressive disorder and for an association with single-nucleotide polymorphisms in genes associated with schizophrenia risk. Several of the genes identified have functions related to neuronal calcium homeostasis or central nervous system development.

Conclusions and Relevance These results are the first, to our knowledge, to identify specific CAD risk alleles and potential genetic factors contributing to the comorbidity of CAD with major depression and schizophrenia.

Insufficient maternal D3 during pregnancy may increase the risk of MS in offspring.

“Know your Vitamin D3 total blood test level! Don’t assume it is normal only because you live a normal life. My view is that every adult should have one “screening” blood test of their Vitamin D3. Its easy, cheap and risk free to correct. The Mayo Clinic in their wellness division thinks there patients do best if there Vit D3 test (250hydroxy Vitmain D3 total) is around 5- ng/dl. I have seen many orthopedic problems resolve when correcting a Vitamin D deficiency.” Bill Chesnut, MD.

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JAMA NEUROLOGY

Vitamin D Status During Pregnancy and Risk of Multiple Sclerosis in Offspring of Women in the Finnish Maternity Cohort _ Original Investigation | March 07, 2016 Kassandra L. Munger, ScD¹; Julia Åivo, MD²; Kira Hongell, MD²; Merja Soilu-Hänninen, MD²; Heljä-Marja Surcel, PhD³; Alberto Ascherio, MD, DrPH^1,4

Importance Vitamin D has been associated with a decreased risk of multiple sclerosis (MS) in adulthood; however, some, but not all, previous studies have suggested that in utero vitamin D exposure may be a risk factor for MS later in life.

Objective To examine whether serum 25-hydroxyvitamin D (25[OH]D) levels in early pregnancy are associated with risk of MS in offspring.

Design, Setting, and Participants Prospective, nested case-control study in the Finnish Maternity Cohort conducted in May 2011. We identified 193 individuals with a diagnosis of MS before December 31, 2009, whose mothers are in the Finnish Maternity Cohort and had an available serum sample from the pregnancy with the affected child. We matched 176 cases with 326 controls on region of birth in Finland, date of maternal serum sample collection, date of mother’s birth, and date of child’s birth.

Main Outcomes and Measures Maternal serum 25(OH)D levels were measured using a chemiluminescence assay. The risk of MS among offspring and association with maternal 25(OH)D levels were the main outcomes. Conditional logistic regression was used and further adjusted for sex of the child, gestational age at the time of sample collection, and season of sample collection to estimate the relative risks and 95% CIs.

Results Of the 193 cases in the study, 163 were female. Of the 331 controls in the study, 218 were female. Seventy percent of serum samples were collected during the first trimester of pregnancy. The mean (SD) maternal vitamin D levels were in the insufficient vitamin D range, but higher in maternal control than case samples (15.02 [6.41] ng/mL vs 13.86 [5.49] ng/mL [to convert to nanomoles per liter, multiply by 2.496]). Maternal vitamin D deficiency (25[OH]D levels <12.02 ng/mL) during early pregnancy was associated with a nearly 2-fold increased risk of MS in the offspring (relative risk, 1.90; 95% CI, 1.20-3.01; P = .006) compared with women who did not have deficient 25(OH)D levels. There was no statistically significant association between the risk of MS and increasing serum 25(OH)D levels (P = .12).

Conclusions and Relevance Insufficient maternal 25(OH)D during pregnancy may increase the risk of MS in offspring.

Inheritance is a cause of frozen shoulder

“Inheritance is a cause of frozen shoulder. Here is a fascinating study showing the value of meta-analysis using many studies to find correlations. The editor of Journal of Bone and Joint Surgery is commenting on a recently published research article in their journal. This commentary gives the original publication perspective and is easier to read.“ Bill Chesnut, MD

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JBJS Reviews Editor’s Choice–Genes and Frozen Shoulder_Ortho Commentary JBJS Feb 26, 2016.

As new advances in medical technology lead to treatments for injuries and diseases, one concept that has emerged is the importance of genetic predisposition to health, sickness, and functional recovery after trauma. Indeed, as the future of medicine will most likely concentrate on health as opposed to health care, understanding the genetic predisposition to medical conditions will become paramount. In the February 2016 issue of JBJS Reviews, Prodromidis and Charalambous focus on the role of genetics in the development and treatment of frozen shoulder. This article represents a careful analysis of the relationship between genetics and disease.

Frozen shoulder, or adhesive capsulitis, is a common condition that leads to functional loss and impairment of activities of daily living. However, despite the prevalence of this condition, its pathogenesis is not fully understood. Prodromidis and Charalambous performed a systematic review and meta-analysis in order to assess the evidence that suggests a genetic link to frozen shoulder.

The investigators performed a literature search of MEDLINE, EMBASE, and CINAHL using relevant keywords and found an initial 5506 studies. After further screening, seven studies were analyzed. The results were fascinating. One study, involving 1828 twin pairs, showed an 11.6% prevalence and demonstrated a heritability of 42% for frozen shoulder after adjusting for age. In a second study, involving 273 patients, 20% of patients with frozen shoulder had a positive family history involving a first-degree relative. A third study, involving 87 patients, showed that 29% of patients with frozen shoulder had a first-degree relative with this condition.

Two further studies evaluated racial predilection. One of these studies (50 patients) showed a substantially higher number of white patients with frozen shoulder than black patients with the condition. The other study (87 patients) showed that being born or having parents or grandparents who were born in the British Isles were risk factors for this condition.

Finally, four immunological studies investigated HLA-B27 as a risk factor for frozen shoulder. A meta-analysis of two of these studies with clearly defined controls showed higher rates of HLA-B27 positivity in patients with this condition as compared with controls (p < 0.001). Thomas Einhorn, Editor

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Scientists may be able force cancer into dormant state

“This medical breakthrough is exciting. New technology development in other fields, nanochemistry, is used in a lab experiment to cause a cancer to stay dormant. This is the full discussion from UPI. I also included a Tel Aviv University Faculty Information paragraph describing what this scientist is doing.” Bill Chesnut, MD

Scientists may be able force cancer into dormant state Prof. Ronit Satchi-Fainaro ______________UPI Report 2.24.16.

Based on the knowledge that healthy people can live full lives with dormant cancer cells in their bodies never causing a health problem, scientists in Israel found a method to turn the cells off by using a drug that blocks their ability to grow. The proof-of-concept drug prevents osteosarcoma, or bone cancer, cells from communicating with healthy cells around them, stopping growth in lab experiments, ‘Tel Aviv’ University researchers report. The researchers found three microRNAs at low levels in aggressive tumors but at much higher levels in dormant tumors. In a dish, the researchers introduced selected microRNAs to cancer cells, finding they had less of ability to communicate with normal cells. We saw that the osteosarcoma cells treated with the selected microRNAs were unable to recruit blood vessels to feed their growth, Dr. Ronit Satchi-Fainaro, head of the cancer angiogenesis and nanomedicine laboratory at ‘Tel Aviv’ University, said in a press release. In order to keep these microRNAs stable in the blood, we needed to encapsulate them in a nanoparticle that circulates in healthy blood vessels, but that disembark and deliver the drug therapy at the leaky blood vessels that exist at tumor sites. We designed a nanomedicine that would have a special activation method at the tumor site in the target cell. For the study, published in ACS Nano, the researchers tested the nanoparticle wrapper method of delivering the microRNAs to the tumor site in mice. Mice treated with the drug survived for six months with the cancer, which Satchi-Fainaro said is the equivalent of 25 years of human life. In addition to planning for clinical trials using the nanomedicine developed at her lab, Satchi-Fainaro said research for similar ways to send other cancers into a dormant phase is underway. We wanted to understand what causes the cancer cells to ‘switch on’ in these cases, Satchi-Fainaro said. As long as cancer cells remain asymptomatic and dormant, cancer is a manageable disease. Many people live with thyroid lesions without their knowledge, for example. Ours is a very optimistic approach, and we believe it could apply to other cancers as well. .

____________________________________________________________

FROM TEL AVIV UNIVERSITY FACULTY INFORMATION:

Angiogenic Switch Using Rationally-Designed Theranostic Nanomedicines

Our research interests include investigations related to tumor biology, tumor dormancy, mechanism of action of angiogenesis inhibitors, self-assembly of polymeric architectures and novel approaches to target cancer. Throughout, we have maintained an interest in understanding the biological rationale for the design of polymer therapeutics suitable for transfer into clinical testing. Our primary interests are the molecular basis of tumor angiogenesis and the rational design of polymer therapeutics. Our research includes identification and characterization of genes and microRNAs associated with the switch from a dormant avascular tumor phenotype to a fast-growing angiogenic tumor in human cancers and their corresponding mouse models. We focus on the design and characterization of novel drug delivery platforms, including dendrimers and hyperbranched polymer–based nanoparticles, and the design of highly-selective targeting molecules integrating biology, chemistry, protein engineering, computational approaches, material sciences and nanotechnology to selectively guide drugs into pathological sites. Our vision is that novel approaches to target anticancer, anti-angiogenic drugs, miRNA and siRNAs to endothelial and tumor cells to potentially treat angiogenesis-dependent diseases could transform cancer into a chronically-manageable disease.

Neanderthal DNA may predispose some people to nicotine addiction, mood disorders

“This is a study of 28,000 people by evolutionary geneticists. It helps understand that some of the maladies we have some from “bad code.” The original study is here for more details: http://science.sciencemag.org/content/351/6274/737.full .” Bill Chesnut, MD

Nicotine addiction and mood disorders associated with Neanderthal Genes. “Neanderthal DNA may predispose some people to nicotine addiction, mood disorders.”

The Washington Post (2/11, Nutt) reports in “Speaking of Science” that the “first-ever study directly comparing Neanderthal DNA to the human genome confirmed a wide range of health-related associations.” Lead author John Capra, PhD, an evolutionary geneticist at Vanderbilt University, said, “Our main finding is that Neanderthal DNA does influence clinical traits in modern humans.” The article explains that “snippets of Neanderthal DNA contribute to the contemporary risk for myriad ills, including heart attack, nicotine addiction, and mood disorders as well as incontinence, foot calluses and precancerous skin lesions.”

The Wall Street Journal (2/11, Long, Subscription Publication) reports that to arrive at these conclusions, the researchers compared electronic health records from 28,000 people of European ancestry with genomes from fossilized Neanderthal bones. The study was published online in the journal Science.

Study offers clues to genetic abnormality of C4 genes associated with schizophrenia

“The January 2016 AMA newsletter reports DNA testing showing an abnormality of the C4 genes associated with a much higher incidence of schizophrenia. Other recent publications report improvements in schizophrenia if treatment began early and involve the family.” Bill Chesnut, MD

Study offers clues to biology behind schizophrenia

On its front page, the New York Times (1/27, A1, Carey, Subscription Publication) reports that a new study published online Jan. 27 in Nature takes “a significant step toward understanding the cause of schizophrenia,” providing “the first rigorously tested insight into the biology behind any common psychiatric disorder.”

In “Science Now,” the Los Angeles Times (1/27, Healy) reports, “After conducting genetic tests on nearly 65,000 people, the scientists followed a trail of clues to a group of genes in the” major histocompatibility complex (MHC) “called C4 genes.” Investigators “found that people with certain variants of C4 genes had unusually high odds of developing schizophrenia, even in the absence of other genetic risks.” By demonstrating “a link between C4 and synaptic pruning,” the study “builds on theories that the over-editing of brain connections in late adolescence might be ‘a contributing cause’ of schizophrenia.”

The Washington Post (1/27, Nutt) reports in “Speaking of Science” that in people “with schizophrenia, a variation in a single position in the DNA sequence marks too many synapses for removal and that pruning goes out of control,” resulting in “an abnormal loss of gray matter.” According to the Post, the “study offers a new approach to schizophrenia research, which has been largely stagnant for decades.”

AMA News 1.28.16

Nearly one-third of all cancer cases may be linked to inherited genes

“This report needs wide dissemination and understanding. There are several common sense conclusions. One is that not all cancers can be prevented, so searching for cancer proactively is warranted. Some of the searches involve blood tests that are usually negative, leading some to conclude they aren’t necessary as a part of prevention. Another conclusion is to know your family cancer history, first and second generation, including aunts, uncles and cousins. Tell you providers that you have this family history and want to be carefully managed. Know the list of common inheritable cancers listed here.” Bill Chesnut, MD

Nearly one-third of all cancer cases may be linked to inherited genes, research finds

On its website, NBC News (1/6, Fox) reports that research published in the Journal of the American Medical Association suggests that approximately one-third “of all cancer cases can be blamed on inherited genes.”

STAT (1/6, Swetlitz) reports that investigators looked at data on “identical and fraternal twins in Denmark, Finland, Norway, and Sweden, who were part of the Nordic Twin Study of Cancer.”

Newsweek (1/6, Firger) reports that the researchers found that “overall heritability for cancer was 33 percent among the entire study population, and notably higher for certain types of cancers.” Newsweek adds, “Significant heritability was found in 58 percent of diagnosed skin melanomas, 57 percent of prostate cancers, 43 percent of non-melanoma skin cancers, 39 percent of ovarian cancers, 38 percent of kidney cancers, 31 percent of breast cancers and 27 percent of uterine cancers.”

HealthDay (1/6, Thompson) reports that the researchers also “identified a set of cancers in which genetics play a very small role.” This group includes “lung cancer (18 percent), colon cancer (15 percent), rectal cancer (14 percent), and head and neck cancer (9 percent).”

JAMA Newsletter 1.7.16.

Children conceived using infertility treatment at no greater risk of developmental problems

“This is happy news to broadcast. Wanting children and considering infertility treatment causes concerns that, maybe, are not really a concern. Yeah for babies and for the parents who want them desperately. My heart goes out to them each and every one.” Bill Chesnut, MD

Children conceived using infertility treatment at no greater risk of developmental problems, study suggests

Reuters (1/5, Doyle) reports that a new study conducted at the Eunice Kennedy Shriver National Institute of Child Health and Human Development suggests that “children conceived with assisted reproductive technology have similar early childhood development as other children.” However, researchers found that those conceived using fertility treatments were more often born as twins or multiple births prompting lead author Edwina H. Yeung to encourage fertility specialist to use techniques that decrease the risk of multiple births.

HealthDay (1/5, Norton) reports that for the study, Yeung’s team “followed over 5,800 children born in New York state between 2008 and 2010,” including 1,830 children conceived using fertility treatments. Overall, the researchers found that those conceived using reproductive technology “were no more likely to show developmental delays at the age of 3 than their peers whose parents conceived naturally.” The findings were published in JAMA Pediatrics.

AMA Wire newsletter, January 2015.

A new drug is showing remarkable efficacy in treating allergic conditions

“A new drug is showing remarkable efficacy in treating allergic conditions, primarily eczema. The side effects are trivial considering the morbidity of atopic eczema. This publication demonstrates that it’s also effective in nasal polyps for people who are affected by allergies and have sinus polyps develop.

Dupilumab is in clinical trials now. The government site for clinical trials, clinical trials.gov, predicts release in November 2016.

I anticipate that there will the other uses of this remarkable technique of inhibiting the blood cells involved in the inflammatory response of allergies.” Bill Chesnut, MD

Effect of Subcutaneous Dupilumab on Nasal Polyp Burden in Patients With Chronic Sinusitis and Nasal PolyposisA Randomized Clinical Trial

Claus Bachert, MD, PhD^1,2; Leda Mannent, MD³; Robert M. Naclerio, MD⁴; Joaquim Mullol, MD, PhD⁵; Berrylin J. Ferguson, MD⁶; Philippe Gevaert, MD, PhD¹; Peter Hellings, MD, PhD⁷; Lixia Jiao, PhD⁸; Lin Wang, PhD⁸; Robert R. Evans, PharmD⁹; Gianluca Pirozzi, MD, PhD⁸; Neil M. Graham, MD, MPH⁹; Brian Swanson, PhD⁸; Jennifer D. Hamilton, PhD⁹; Allen Radin, MD⁹; Namita A. Gandhi, PhD⁹; Neil Stahl, PhD⁹; George D. Yancopoulos, MD, PhD⁹; E. Rand Sutherland, MD, MPH¹⁰

ABSTRACT

Importance Dupilumab has demonstrated efficacy in patients with asthma and atopic dermatitis, which are both type 2 helper T-cell–mediated diseases.

Objective To assess inhibition of interleukins 4 and 13 with dupilumab in patients with chronic sinusitis and nasal polyposis.

Design, Setting, and Participants A randomized, double-blind, placebo-controlled parallel-group study conducted at 13 sites in the United States and Europe between August 2013 and August 2014 in 60 adults with chronic sinusitis and nasal polyposis refractory to intranasal corticosteroids with 16 weeks of follow-up.

Interventions Subcutaneous dupilumab (a 600 mg loading dose followed by 300 mg weekly; n = 30) or placebo (n = 30) plus mometasone furoate nasal spray for 16 weeks.

Main Outcomes and Measures Change in endoscopic nasal polyp score (range, 0-8; higher scores indicate worse status) at 16 weeks (primary end point). Secondary end points included Lund-Mackay computed tomography (CT) score (range, 0-24; higher scores indicate worse status), 22-item SinoNasal Outcome Test score (range, 0-110; higher scores indicating worse quality of life; minimal clinically important difference ≥8.90), sense of smell assessed using the University of Pennsylvania Smell Identification Test (UPSIT) score (range, 0-40; higher scores indicate better status), symptoms, and safety.

Results Among the 60 patients who were randomized (mean [SD] age, 48.4 years [9.4 years]; 34 men [56.7%]; 35 with comorbid asthma), 51 completed the study. The least squares (LS) mean change in nasal polyp score was −0.3 (95% CI, −1.0 to 0.4) with placebo and −1.9 (95% CI, −2.5 to −1.2) with dupilumab (LS mean difference, −1.6 [95% CI, −2.4 to −0.7]; P < .001). The LS mean difference between the 2 groups for the Lund-Mackay CT total score was −8.8 (95% CI, −11.1 to −6.6; P < .001). Significant improvements with dupilumab were also observed for the 22-item SinoNasal Outcome Test (LS mean difference between groups, −18.1 [95% CI, −25.6 to −10.6]; P < .001) and sense of smell assessed by UPSIT (LS mean difference, 14.8 [95% CI, 10.9 to 18.7]; P < .001). The most common adverse events were nasopharyngitis (33% in the placebo group vs 47% in the dupilumab group), injection site reactions (7% vs 40%, respectively), and headache (17% vs 20%).

Conclusions and Relevance Among adults with symptomatic chronic sinusitis and nasal polyposis refractory to intranasal corticosteroids, the addition of subcutaneous dupilumab to mometasone furoate nasal spray compared with mometasone alone reduced endoscopic nasal polyp burden after 16 weeks. Further studies are needed to assess longer treatment duration, larger samples, and direct comparison with other medications.

Trial Registration clinicaltrials.gov Identifier: NCT01920893

Chronic sinusitis, an inflammatory condition of the sinuses, is common with estimates of prevalence as high as 12% in Western populations.1^,2 It is characterized by specific symptoms often lasting for many years including nasal congestion, discharge and postnasal drip, decreased or lost sense of smell, facial pain and pressure, headache, and the consequences thereof.3 Based on endoscopic findings, the condition can be divided into chronic sinusitis with or without nasal polyposis. Typically observed in the context of eosinophilic inflammation of the upper airways, nasal polyps originate in the sinuses and obstruct the sinus and nasal passages.

Medical management of chronic sinusitis with nasal polyposis focuses on controlling tissue inflammation and, depending on severity, includes use of intranasal corticosteroids, nasal saline irrigation, antibiotics, or short-course oral steroids.3 In patients in whom polyps and symptoms persist despite medical treatment, surgical excision is considered. However, disease recurrence after surgery approaches 50% in patients with tissue eosinophilia,⁴ and resolution of symptoms, including sense of smell loss, is often incomplete.

Epidemiological data from a large European cohort indicate that chronic sinusitis is associated with a 3.5-fold increase in comorbid asthma prevalence.5 Although type 2 helper T-cell inflammation is implicated in this association, the mechanisms of this association have not been fully elucidated.6^–8

Dupilumab is a fully human monoclonal antibody to the interleukin 4 (IL-4) receptor α subunit, which inhibits signaling of IL-4 and IL-13, 2 cytokines central to type 2 helper T-cell–mediated inflammation. Dupilumab has demonstrated clinical efficacy in the type 2 helper T-cell–mediated diseases of asthma and atopic dermatitis,9^–11 and also improved sinonasal symptoms in patients with asthma.9

We hypothesized that the addition of dupilumab to intranasal corticosteroids would improve endoscopic, radiographic, and patient-reported measures of disease activity in those with chronic sinusitis and nasal polyposis, while also improving lung function and disease control in patients with comorbid asthma.