Immunologic Heterogeneity in 2 Cartilage-Hair Hypoplasia Patients With a Distinct Clinical Course.

BACKGROUND AND OBJECTIVE: Cartilage-hair hypoplasia (CHH) syndrome is a rare autosomal recessive syndrome associated with skeletal dysplasia, varying degrees of combined immunodeficiency (CID), short stature, hair hypoplasia, macrocytic anemia, increased risk of malignancies, and Hirschsprung disease. To provide clinical and immunological insights obtained from 2 unrelated patients who displayed clinical characteristics of CHH. METHODS: Two patients with suspected CHH syndrome due to skeletal dysplasia and immunodeficiency underwent an immunological and genetic work-up using flow cytometry, next-generation sequencing (NGS) of the immune repertoire, and Sanger sequencing to identify the underlying defects. RESULTS: Patient 1 presented with low birth weight and skeletal dysplasia. Newborn screening was suggestive of T-cell immunodeficiency, as T-cell receptor excision circle levels were undetectable. Both the T-cell receptor (TCR) Vß and TCR-g (TRG) repertoires were restricted, with evidence of clonal expansion. Genetic analysis identified compound heterozygous RMRP variants inherited from both parents. Patient 2 presented with recurrent lung and gastrointestinal infections, skeletal dysplasia, failure to thrive, and hepatomegaly. The polyclonal pattern of the TCRß repertoire was normal, with only slight overexpression of TCR-ßV20 and restricted expression of Vßs. TRG expressed a normal diverse repertoire, similar to that of the healthy control sample. Genetic analysis identified biallelic novel regulatory variants in RMRP. Both parents are carriers of this mutation. CONCLUSION: Our findings demonstrate how the immunological work-up, supported by genetic findings, can dramatically change treatment and future outcome in patients with the same clinical syndrome.

[Lack of medical or dental care: Impact on health expenditures for people with chronic disease]. / L'effet du non-recours aux soins médicaux et dentaires sur les dépenses de santé des personnes ayant une maladie chronique.

BACKGROUND: People with chronic disease often have dental (especially periodontal) disorders. Nevertheless, people with chronic disease seek dental care less often than others. We wanted to know if there is a relationship between the consumption of medical care and the consumption of dental care, and if so if the relationship is especially strong for people with chronic disease. METHODS: We conducted a longitudinal study that combined two data-sets: consumption data from the French National Health Insurance Fund and health and socioeconomic welfare data collected with a dedicated national survey. We studied healthcare expenditure and analyzed the association between healthcare consumption, health status and healthcare expenditure over a four-year period (2010-2013). RESULTS: People who did not seek medical or dental care in 2010 exhibited irregular consumer behavior thereafter. This pattern was particularly evident among those with chronic disease whose healthcare expenditures did not stabilize during the study period compared with the rest of the study population. Among people who did not seek medical care in 2010, variation in average dental care expenditure was 91% in people with chronic disease versus 42% for those without chronic disease. Lack of medical care during the first year of the study was also associated with greater expenditure-delay in people with chronic disease (77%) compared with 15% in people without chronic disease. CONCLUSION: The lack of medical or dental care in 2010 for people with chronic disease did not lead to an increase in medical and dental consumption in the following years. The catch-up delay was longer than four years. This highlights a problem of monitoring and identifies a marginalized population within the healthcare system.

[Stereotactic body radiation therapy for hepatocellular carcinoma: Results from a retrospective multicentre study]. / Radiothérapie en conditions stéréotaxiques du carcinome hépatocellulaire : résultats d'une étude rétrospective multicentrique.

PURPOSE: The purpose of this paper was to describe local control, overall survival, progression-free survival and toxicity of CyberKnife®-based stereotactic body radiation therapy of hepatocellular carcinoma. MATERIAL AND METHODS: Records of all the patients treated for hepatocellular carcinoma at the Eugene-Marquis cancer centre, Rennes and the Bretonneau hospital, Tours (France), between November 2010 and December 2016, were reviewed. Radiation therapy was performed as a salvage treatment, while awaiting liver transplantation or if no other treatment was possible. RESULTS: One hundred and thirty-six patients were consecutively included in the study. The median follow-up was 13months. Median total dose prescribed, fractionation and overall treatment time were respectively 45Gy, three fractions and 5 days. Overall survival, progression-free survival and local control rates at 1year and 2years were 79.8 % and 63.5 %, 61.3 % and 39.4 %; 94.5 % and 91 %. Two grade 3 acute toxicity events and two grade 4 late toxicity events corresponding to a duodenal ulcer have been reported. Seven patients underwent classic radiation-induced hepatitis and 13 patients showed non-classical radiation-induced hepatitis. Barcelona Clinic Liver Cancer stage, World Health Organisation grade and planning target volume were correlated with overall survival in univariate Cox analysis. CONCLUSION: Stereotactic body radiation therapy is effective and well-tolerated for inoperable hepatocellular carcinoma or as a bridge to liver transplantation. Toxicity is mainly related to cirrhotic background and requires a selection of patients and strict dose constraints.

Folliculin regulates mTORC1/2 and WNT pathways in early human pluripotency.

To reveal how cells exit human pluripotency, we designed a CRISPR-Cas9 screen exploiting the metabolic and epigenetic differences between naïve and primed pluripotent cells. We identify the tumor suppressor, Folliculin(FLCN) as a critical gene required for the exit from human pluripotency. Here we show that FLCN Knock-out (KO) hESCs maintain the naïve pluripotent state but cannot exit the state since the critical transcription factor TFE3 remains active in the nucleus. TFE3 targets up-regulated in FLCN KO exit assay are members of Wnt pathway and ESRRB. Treatment of FLCN KO hESC with a Wnt inhibitor, but not ESRRB/FLCN double mutant, rescues the cells, allowing the exit from the naïve state. Using co-immunoprecipitation and mass spectrometry analysis we identify unique FLCN binding partners. The interactions of FLCN with components of the mTOR pathway (mTORC1 and mTORC2) reveal a mechanism of FLCN function during exit from naïve pluripotency.

Brûlures chimiques: notre série sur 25 ans.

Chemical burns raise diagnostic and treatment issues because they have specific appearances and evolution. Our objective was to study the characteristics of chemical burns and to assess the quality of our treatment. This retrospective observational study examined the records of all patients admitted for chemical burns to the burn treatment center of Saint Louis Hospital in Paris from January 1, 1990, through December 31, 2015. During this period, 162 patients came to our center for chemical burn treatment. Most of them were men (67%). The majority of the burns were caused by alkalis (27%) and resulted from workplace accidents (29%). The average time before consultation was 5.36 days. The areas mainly damaged were the hands (36%) and the burn areas averaged 1.2% of the total body surface area (TBSA). Forty-eight patients had at least one deep patch. In total, 59 patients (36.4%) were hospitalized for an average duration of 4.18 days. Thirty-eight of them underwent surgery. Lastly, 92% of the operations had been anticipated from the first consultation. In our center, the population affected, the circumstances and the topography of our patients' burns were similar to the data from the literature. It appears that the principal specificity of our series is a very low body surface burned. This can be attributed to the prevention measures we have in France and underlines their importance. Only 8% of the patients who had surgery were underestimated or their burns became deeper secondarily. This number is lower than the data from other series.

Comparison of complete versus partial mesh removal for the treatment of chronic mesh infection after abdominal wall hernia repair.

PURPOSE: Treatment of chronic mesh infections (CMI) after parietal repair is difficult and not standardized. Our objective was to present the results of a standardized surgical treatment including maximal infected mesh removal. METHODS: Patients who were referred to our center for chronic mesh infection were analyzed according to CMI risk factors, initial hernia prosthetic cure, CMI characteristics and treatments they received to achieve a cure. RESULTS: Thirty-four patients (mean age 54 ± 13 years; range 23-72), were included. Initial prosthetic cure consisted of 26 incisional hernias and eight groin or umbilical hernias of which 21% were considered potentially contaminated because of three intestinal injuries, two stomas and two strangulated hernias. The mesh was synthetic in all cases. CMI appeared after a mean of 83 days (range 30-6740) and was characterized by chronic leaking in 52 cases (50%), an abscess in 22 cases (21%) and synchronous hernia recurrence in 17 cases (16.5%). Eighty-six reinterventions were necessary, including 36 mesh removals (42%), and 13 intestinal resections for entero-cutaneous fistula (15%). The CMI persistence rate was 81% (35 reinterventions out of 43) when mesh removal was voluntarily limited to infected and/or not incorporated material, but was 44% when mesh removal was voluntarily complete (19 reinterventions out of 43; p < 0.001). On average, 3.4 interventions (1-11) were necessary to achieve a cure, after 2.8 years (0-6). Fourteen incisional hernia recurrences occurred (41%). CONCLUSIONS: Treatment of chronic mesh infection is lengthy and resource-intensive, with a high risk of hernia recurrence. Maximal mesh removal is mandatory.

Reirradiation of gliomas under stereotactic conditions: Prognostic factors for survival without relapse or side effects, a retrospective study at Tours regional university hospital (France).

PURPOSE: To search for factors correlated with relapse-free survival following stereotactic reirradiation in patients with recurrent glioma following radiochemotherapy and evaluate tolerance to this treatment. PATIENTS AND METHODS: Initial radiotherapy was given according to the protocol of Stupp and al. Reirradiation was performed using the CyberKnife® system. Patients could have had surgical resection initially and at the time of recurrence. We analysed 13 patients treated between July 2010 and September 2014. The median age was 55 years. The doses delivered ranged from 20 to 36Gy, in one to ten fractions. RESULTS: Median survival after stereotactic radiotherapy was 14 months. Survival without relapse was 3.7 months. Factors significantly influencing duration of relapse-free survival were: age (P=0.04), total dose (P=0.02), dose per fraction (P=0.04) and number of fractions (P=0.01). We found no correlation between gross tumour volume, clinical target volume, grade of tumour or prescription isodose and relapse-free survival following radiochemotherapy. Three patients developed radionecrosis. CONCLUSION: Reirradiation under stereotactic conditions is well tolerated. A dose of more than 30Gy delivered in 5 or more fractions seems to prolong relapse-free survival.

[Pseudotumor cerebri due to taking minocycline]. / Pseudotumeur cérébrale due à la prise de minocycline.

The cerebral pseudotumor (PTC) is defined by the increase in cerebrospinal fluid (CSF) pressure, a normal composition of the latter in the absence of identified intracranial structural abnormalities, in particular by neuroimaging. The pathophysiology of PTC is poorly understood although its diagnostic criteria are well established. Drugs such as minocycline, tetracycline and doxycycline have been repeatedly implicated as a causative factor in PTC. The prognosis of PTC related to minocycline, reported in the literature is quite variable. Some authors suggest a benign condition with spontaneous healing by stopping the antibiotic, while others report permanent loss of vision. A 12-year-old girl is admitted to the emergency room for progressively progressive pulsatile temporal headaches associated with diplopia. The patient reported the use of minocycline 50 mg / d for five months, prescribed by her attending physician as part of an acne treatment. PTC will be demonstrated by severe papillary edema and cerebral NMR will demonstrate an enlargement of the subarachnoid space around the optic nerves. After three lumbar punctures, the condition of the patient stabilized and there was a marked improvement in headache despite the persistence of bilateral papillary edema. This work describes a clinical case of PTC induced by the use of minocycline and reviews the physiopathology, the diagnosis and the management of this one.

La pseudotumeur cérébrale (PTC) est définie par l'augmentation de la pression du liquide céphalo- rachidien (LCR), une composition normale de ce dernier en l'absence d'anomalies structurelles intracrânienne identifiée, en particulier par neuro- imagerie. La physiopathologie de la PTC est mal comprise bien que ses critères de diagnostic soient bien établis. Les médicaments tels que la minocycline, la tétracycline et la doxycycline ont été mis à plusieurs reprises en cause comme un facteur causal dans la PTC. Le pronostic de PTC lié à la minocycline, rapporté dans la littérature est tout à fait variable. Certains auteurs suggèrent une affection bénigne avec une guérison spontanée par l'arrêt de l'antibiotique, tandis que d'autres signalent une perte de vision permanente. Une jeune fille de 12 ans est admise aux urgences pour des céphalées temporales pulsatiles apparues de manière progressive, associée à de la diplopie. La patiente rapporte la prise de minocycline 50 mg/j depuis cinq mois, prescrite par son médecin traitant dans le cadre d'un traitement contre l'acné. La PTC sera objectivée par un œdème papillaire sévère et la RMN cérébrale mettra en évidence un élargissement de l'espace sous-arachnoïdien autour des nerfs optiques. Après réalisation de trois ponctions lombaires de décharge, l'état de la patiente s'est stabilisé et on note une nette amélioration des céphalées malgré la persistance de l'œdème papillaire bilatéral. Ce travail décrit un cas clinique de PTC induite par la prise de minocycline et revoit la physiopathologie, le diagnostic et la prise en charge de celle-ci.

In vivo modeling of neuronal function, axonal impairment and connectivity in neurodegenerative and neuropsychiatric disorders using induced pluripotent stem cells.

Modeling neurological diseases using human embryonic or patient-derived induced pluripotent stem cells (iPSCs) improves the understanding of molecular and cellular changes underlying these diseases and can lead to new, potentially personalized therapies. Changes in expression of axon guidance cues and altered cytoskeletal maintenance have been implicated in neurodegenerative and neuropsychiatric disorders. To date, most of the iPSC patient-derived cellular dysfunction and phenotypic studies have been performed in vitro. To study the intrinsic axonal impairments and neuronal connectivity deficits in human disease iPSC-derived neurons we propose to graft these cells into the physiological three-dimensional multi-structural environment of the central nervous system of rodent models to obtain relevant in vivo data. Such human iPSC in vivo chimeric models can allow for neuronal maturation, capture neuropathological phenotypes of axonal and connectivity impairments, and serve as target engagement and drug validation studies using human cells, thus highly relevant for advancement of the drug development process in the late pre-clinical stages.

[Management of gliomas]. / Prise en charge des gliomes.

Gliomas are the most frequent primary brain tumors. Their care is difficult because of the proximity of organs at risk. The treatment of glioblastoma includes surgery followed by chemoradiation with the protocol of Stupp et al. The addition of bevacizumab allows an increase in progression-free survival by 4 months but it does not improve overall survival. This treatment is reserved for clinical trials. Intensity modulation radiotherapy may be useful to reduce the neurocognitive late effects in different types of gliomas. In elderly patients an accelerated radiotherapy 40 Gy in 15 fractions allows a similar survival to standard radiotherapy. O(6)-methylguanine-DNA methyltransferase (MGMT) status may help to choose between chemotherapy and radiotherapy. There is no standard for the treatment of recurrent gliomas. Re-irradiation in stereotactic conditions allows a median survival of 8 to 12.4 months. Anaplastic gliomas with 1p19q mutation have a greater sensibility to chemotherapy by procarbazine, lomustine and vincristine. Chemoradiotherapy in these patients has become the standard treatment. Many studies are underway testing targeted therapies, their place in the therapeutic management and new radiotherapy techniques.

Seasonal variation in basal metabolic rates among the Yakut (Sakha) of Northeastern Siberia.

OBJECTIVES: Previous research has shown that indigenous circumpolar populations have elevated basal metabolic rates (BMRs), yet few studies have explored whether metabolic rates increase during the winter. This study addresses this gap by examining seasonal variation in BMR and its associations with thyroid function and lifestyle factors among the Yakut (Sakha) of Siberia. METHODS: Anthropometric dimensions, BMR, and thyroid hormone levels (free triiodothyronine [fT3], free thyroxine [fT4], thyroid-stimulating hormone [TSH]) were measured on two occasions (July/August, 2009 and January 2011) on a sample of 94 Yakut (Sakha) adults (35 men, 59 women) from the rural village of Berdygestiakh, Sakha Republic, Russia. RESULTS: Seasonal changes in BMR varied by age. Younger Yakut adults (19-49 years) showed significant elevations in winter-time BMR of 6% (P < 0.05), whereas older individuals (≥50 years) showed modest declines (2%; n.s.). Both younger and older Yakut men and women showed increased respiratory quotients during the winter. FT3 and fT4 levels significantly declined during the winter in both younger and older Yakut men and women (P < 0.05). Lifestyle factors were significant predictors of BMR variation, particularly among older men and women. CONCLUSIONS: Among the Yakut, increased wintertime BMR was observed among younger but not older adults, whereas all adults showed sharp reductions in free thyroid hormone levels during the winter. Among men, greater participation in subsistence activities was associated with increased BMRs and greater fat oxidation. Among women, variation in food use had the strongest impact on metabolic function.

Genome-wide association study of primary dentition pit-and-fissure and smooth surface caries.

Dental caries continues to be the most common chronic disease in children today. Despite the substantial involvement of genetics in the process of caries development, the specific genes contributing to dental caries remain largely unknown. We performed separate genome-wide association studies of smooth and pit-and-fissure tooth surface caries experience in the primary dentitions of self-reported white children in two samples from Iowa and rural Appalachia. In total, 1,006 children (ages 3-12 years) were included for smooth surface analysis, and 979 children (ages 4-14 years) for pit-and-fissure surface analysis. Associations were tested for more than 1.2 million single nucleotide polymorphisms, either genotyped or imputed. We detected genome-wide significant signals in KPNA4 (p value = 2.0E-9), and suggestive signals in ITGAL (p value = 2.1E-7) and PLUNC family genes (p value = 2.0E-6), thus nominating these novel loci as putative caries susceptibility genes. We also replicated associations observed in previous studies for MPPED2 (p value = 6.9E-6), AJAP1 (p value = 1.6E-6) and RPS6KA2 (p value = 7.3E-6). Replication of these associations in additional samples, as well as experimental studies to determine the biological functions of associated genetic variants, are warranted. Ultimately, efforts such as this may lead to a better understanding of caries etiology, and could eventually facilitate the development of new interventions and preventive measures.

Evidence for the role of EPHX2 gene variants in anorexia nervosa.

Anorexia nervosa (AN) and related eating disorders are complex, multifactorial neuropsychiatric conditions with likely rare and common genetic and environmental determinants. To identify genetic variants associated with AN, we pursued a series of sequencing and genotyping studies focusing on the coding regions and upstream sequence of 152 candidate genes in a total of 1205 AN cases and 1948 controls. We identified individual variant associations in the Estrogen Receptor-ß (ESR2) gene, as well as a set of rare and common variants in the Epoxide Hydrolase 2 (EPHX2) gene, in an initial sequencing study of 261 early-onset severe AN cases and 73 controls (P=0.0004). The association of EPHX2 variants was further delineated in: (1) a pooling-based replication study involving an additional 500 AN patients and 500 controls (replication set P=0.00000016); (2) single-locus studies in a cohort of 386 previously genotyped broadly defined AN cases and 295 female population controls from the Bogalusa Heart Study (BHS) and a cohort of 58 individuals with self-reported eating disturbances and 851 controls (combined smallest single locus P<0.01). As EPHX2 is known to influence cholesterol metabolism, and AN is often associated with elevated cholesterol levels, we also investigated the association of EPHX2 variants and longitudinal body mass index (BMI) and cholesterol in BHS female and male subjects (N=229) and found evidence for a modifying effect of a subset of variants on the relationship between cholesterol and BMI (P<0.01). These findings suggest a novel association of gene variants within EPHX2 to susceptibility to AN and provide a foundation for future study of this important yet poorly understood condition.

[Arthroscopic assessment of articular fractures of distal radius osteosyntheses by percutaneous pins]. / Bilan arthroscopique des fractures articulaires du radius distal ostéosynthésées par des techniques d'embrochage percutanée.

OBJECTIVES: We studied the radiological results of percutaneous pinning in articular fractures of the distal radius. We did not, thereby, have a method of direct ligamentous and articular assessment. We realized an anatomical arthroscopic assessment at six weeks of osteosynthesis of wrists. The purpose was to study the correlation between the presence of anatomical lesions and the functional result. METHODS: Thirty-five patients presenting an articular fracture with posterior displacement were included; 30 women and five men. The mean age was 62 years. All the patients were right -handed and this was the fractured side in 18 patients. The patients had clinical and radiological follow-up at three, six, 12 weeks and one year. Surgical techniques were Py or Kapandji pinning. An arthroscopy of the wrist was carried out at six weeks from the fixation at pin removal. An assessment of ligamentous lesions and quality of articular reduction was performed. RESULTS: Twenty-eight per cent of the patients had ligamentous lesions. Nine patients presented an interfragmentary distance greater than 1mm. Two patients had an articular step as high as 2mm. CONCLUSIONS: Clinical examination did not show any correlation between the anatomical imperfections noted at the time of arthroscopy and the function of the wrist at one year postoperative, regardless of the technique used.

Quality of life after esophagectomy and endoscopic therapy for Barrett's esophagus with dysplasia.

Esophagectomy (EG) and endoscopic therapy (ET) can eradicate Barrett's esophagus with early neoplasia. Their relative effect on quality of life is unknown. The 36-item Short Form Health Survey (SF-36) and Gastrointestinal Quality of Life Index (GIQLI) questionnaires were sent to all patients who underwent either EG or ET at our institution over the last 9 years. Groups were stratified by age and American Society of Anesthesia (ASA) class. Surveys were sent to 77 patients and completed by 14 EG (50%) and by 28 ET patients (57%). The average time between treatment and survey was 4 years in the ET group and 5 years in the EG group. There were no significant differences in SF-36 scores between EG and ET patients except for superior physical functioning among EG patients 65 and older QOL scores among EG and ET groups were not significantly different than sex age-matched controls. GIQLI scores were similar between ET and EG patients of all ages (P= 0.60). GIQLI scores were higher among younger ET patients than young EG patients (P= 0.049). GIQLI scores also tended to be higher among ASA 1 and 2 ET patients than ASA 1 and 2 EG patients, but this did not reach statistical significance (P= 0.09). EG and ET for early Barrett's neoplasia appear to have similar impact on QOL 1 year or more after treatment compared with age-matched controls. Negative QOL impact appears to be greater for younger patients undergoing EG than for ET.

Are dark-skinned people really protected from ultraviolet radiation?

BACKGROUND: Premature ageing of the skin (photoageing) results from the action of ultraviolet radiation (UVR) on skin. One of the histopathological findings of photoageing is the presence of solar elastosis in the dermis. Skin pigmentation is protective against UVR. AIM: To evaluate the presence of solar elastosis in dark-skinned people. METHODS: Normal facial skin biopsies of 147 dark-skinned and 140 light-skinned people were examined histopathologically for solar elastosis. The degree of solar elastosis was graded on a five-point scale by a panel of dermatopathologists blinded to patient demographics. RESULTS: There were 112 of 140 (80%) light-skinned and 50 of 147 (34%) dark-skinned patients with high-grade solar elastosis. In the dark-skinned patient group, high-grade solar elastosis was seen in 29 of 61 (47.5%) Hispanic and 5 of 49 (10.2%) African American subjects. CONCLUSIONS: Dark-skinned people are not completely protected from the effects of UVR.

Training in the private sector: what works and how do we increase opportunities?

In Australia 61% of elective surgery takes place in private hospitals where current opportunities for surgical education and training (SET) are limited. The situation will shortly be compounded because of the large increase in local medical graduates, many of whom will aspire to be surgeons. How and where to train these extra surgeons to meet the expanding needs of the community must be addressed. Two models of private sector training are reviewed both of which involved combined training in both private and public sectors. Two second-year (SET 2) positions were created from one public hospital SET position by using the private sector for 3.5 days per week for 3 months of a 6-month rotation. The second model was applicable to post-fellowship training with a fairly even split between public and private sector responsibilities. In the first year, four registrars shared the two 6-month rotations for the SET 2 position. Trainees did the required minimum procedures (range 109-139) with primary operating targets of 20-25% (range 21-32%). The post-fellowship position in colorectal surgery was greatly enhanced by the private sector involvement with regard to operating experience as well as meeting part of the remuneration of the trainee. Successful models for training within the private sector in Australia can be found. To expand training in the private sector there will need to be a cultural shift in the perceptions of surgeons, patients, administrators, and trainees. Funding for posts may be available to those private hospitals that can meet the Royal Australasian College of Surgeons' accreditation standards for posts and hospitals.

Genome-wide association analyses suggested a novel mechanism for smoking behavior regulated by IL15.

Cigarette smoking is the leading preventable cause of death in the United States. Although smoking behavior has a significant genetic determination, the specific genes and associated mechanisms underlying the smoking behavior are largely unknown. Here, we carried out a genome-wide association study on smoking behavior in 840 Caucasians, including 417 males and 423 females, in which we examined approximately 380,000 single nucleotide polymorphisms (SNPs). We found that a cluster of nine SNPs upstream from the IL15 gene were associated with smoking status in males, with the most significant SNP, rs4956302, achieving a P-value (8.80 x 10(-8)) of genome-wide significance. Another SNP, rs17354547 that is highly conserved across multiple species achieved a P-value of 5.65 x 10(-5). These two SNPs, together with two additional SNPs (rs1402812 and rs4956396) were selected from the above nine SNPs for replication in an African-American sample containing 1251 subjects, including 412 males and 839 females. The SNP rs17354547 was replicated successfully in the male subgroup of the replication sample; it was associated with smoking quantity (SQ), the Heaviness of Smoking Index (HSI) and the Fagerstrom Test for Nicotine Dependence (FTND), with P-values of 0.031, 0.0046 and 0.019, respectively. In addition, a haplotype formed by rs17354547, rs1402812 and rs4956396 was also associated with SQ, HSI and FTND, achieving P-values of 0.039, 0.0093 and 0.0093, respectively. To further confirm our findings, we carried out an in silico replication study of the nine SNPs in a Framingham Heart Study sample containing 7623 Caucasians from 1731 families, among which, 3491 subjects were males and 4132 were females. Again, the male-specific association with smoking status was observed, for which seven of the nine SNPs achieved significant P-values (P<0.05) and two achieved marginally significant P-values (P<0.10) in males. Several of the nine SNPs, including the highly conserved one across species, rs17354547, are located at potential transcription factor binding sites, suggesting transcription regulation as a possible function for these SNPs. Through this function, the SNPs may modulate the gene expression of IL15, a key cytokine regulating immune function. As the immune system has long been recognized to influence drug addiction behavior, our association findings suggest a novel mechanism for smoking addiction involving immune modulation through the IL15 pathway.