Andrzej Ciechanowicz

A common variant on chromosome 11q13 is associated with atopic dermatitis.

We conducted a genome-wide association study in 939 individuals with atopic dermatitis and 975 controls as well as 270 complete nuclear families with two affected siblings. SNPs consistently associated with atopic dermatitis in both discovery sets were then investigated in two additional independent replication sets totalling 2,637 cases and 3,957 controls. Highly significant association was found with allele A of rs7927894 on chromosome 11q13.5, located 38 kb downstream of C11orf30 (Pcombined = 7.6 × 10−10). Approximately 13% of individuals of European origin are homozygous for rs7927894[A], and their risk of developing atopic dermatitis is 1.47 times that of noncarriers.

Association Screening in the Epidermal Differentiation Complex (EDC) Identifies an SPRR3 Repeat Number Variant as a Risk Factor for Eczema

The genetically determined impairment of the skin barrier is a primary cause of eczema. As numerous genes essential for an intact epidermis reside within the epidermal differentiation complex (EDC), we screened the National Center for Biotechnology Information (NCBI) database for putatively functional polymorphisms in the EDC genes and tested them for association with eczema. We identified 20 polymorphisms with predicted major impact on protein function. Of these, 4 were validated in 94 eczema patients: a nonsense mutation in FLG2 (rs12568784), a stop codon mutation in LCE1D (rs41268500), a 24-bp deletion in SPRR3 (rs28989168), and a frameshift mutation in S100A3 (rs11390146). The minor allele frequencies were 15.1, 6.1, 47.2, and 0.4%, respectively. Association testing of the validated polymorphisms in 555 eczema patients and 375 controls identified a significant effect of rs28989168 (SPRR3) on eczema. The association was replicated in another 1,314 cases and 1,322 controls, yielding an overall odds ratio of 1.30 (95% confidence interval 1.12-1.51; P=0.00067) for a dominant mode of inheritance. Small proline-rich proteins (SPRRs) are crossbridging proteins in the cornified cell envelope (CE), which provides the main barrier function of stratified squamous epithelia. The SPRR3 variant associated with eczema carried an extra 24-bp repeat in the central domain, which may alter the physical properties of the CE.

Plasma concentrations of TNF-α and its soluble receptors sTNFR1 and sTNFR2 in patients with coronary artery disease

Tumour necrosis factor alpha (TNF-alpha) is implicated in post-ischemic myocardial dysfunction. Two distinct TNF-alpha receptors are shed from cell membranes and circulate in plasma as soluble sTNFR1 and sTNFR2 proteins. The aim of the study was to establish factors associated with plasma concentrations of TNF-alpha and its receptors in patients with coronary artery disease (CAD). Since adenosine inhibits the expression of TNF-alpha, two functional polymorphisms in genes encoding enzymes participating in adenosine metabolism, i.e. AMP deaminase-1 (AMPD1, C34T) and adenosine deaminase (ADA, G22A), were analyzed. Plasma concentrations of TNF-alpha, sTNFR1, and sTNFR2 were measured using ELISA in 167 patients with CAD. Common factors significantly associated with higher TNF-alpha, sTNFR1, and sTNFR2 were lower glomerular filtration rate (GFR), older age, higher BNP, lower blood haemoglobin, and the presence of asthma or chronic obstructive pulmonary disease (COPD). Higher TNF-alpha and sTNFR1 concentrations were also associated with the presence of heart failure (HF), lower ejection and shortening fraction, the presence of diabetes or metabolic syndrome, lower serum HDL cholesterol, and higher uric acid. In multivariate analysis the common independent predictors of higher TNF-alpha, sTNFR1, and sTNFR2 were lower GFR, lower HDL cholesterol, higher BNP, and the presence of asthma or COPD. There were no associations between AMPD1 C34T or ADA G22A genotypes and TNF-alpha or its receptors. In conclusion, the concentrations of TNF-alpha, sTNFR1, and sTNFR2 reflect the impairment of cardiac and renal function in patients with CAD. Metabolic syndrome and diabetes are associated with higher plasma concentrations of TNF-alpha and its receptors.

A functional IL-6 receptor (IL6R) variant is a risk factor for persistent atopic dermatitis

BACKGROUND Atopic dermatitis (AD) is a common inflammatory skin disease. Previous studies have revealed shared genetic determinants among different inflammatory disorders, suggesting that markers associated with immune-related traits might also play a role in AD. OBJECTIVE We sought to identify novel genetic risk factors for AD. METHODS We examined the results of all genome-wide association studies from a public repository and selected 318 genetic markers that were significantly associated with any inflammatory trait. These markers were considered candidates and tested for association with AD in a 3-step approach including 7 study populations with 7130 patients with AD and 9253 control subjects. RESULTS A functional amino acid change in the IL-6 receptor (IL-6R Asp358Ala; rs2228145) was significantly associated with AD (odds ratio [OR], 1.15; P = 5 × 10(-9)). Interestingly, investigation of 2 independent population-based birth cohorts showed that IL-6R 358Ala specifically predisposes to the persistent form of AD (ORpersistent AD = 1.22, P = .0008; ORtransient AD = 1.04, P = .54). This variant determines the balance between the classical membrane-bound versus soluble IL-6R signaling pathways. Carriers of 358Ala had increased serum levels of soluble IL-6R (P = 4 × 10(-14)), with homozygote carriers showing a 2-fold increase. Moreover, we demonstrate that soluble IL-6R levels were higher in patients with AD than in control subjects (46.0 vs 37.8 ng/mL, P = .001). Additional AD risk variants were identified in RAD50, RUNX3, and ERBB3. CONCLUSION Our study supports the importance of genetic variants influencing inflammation in the etiology of AD. Moreover, we identified a functional genetic variant in IL6R influencing disease prognosis and specifically predisposing to persistent AD.

Functional polymorphism of matrix metalloproteinase-9 (MMP-9) gene in alcohol dependence: Family and case control study

AIM Matrix metalloproteinases (MMP) are extracellularly acting endopeptidases, whose substrates are extracellular matrix and adhesion proteins. In the gene polymorphism studies MMP-9 has been suggested to be involved in the pathogenesis of heart disease, cancer, bipolar disorder, and schizophrenia. In animal models MMP-9 has been shown to play a key role in a variety of neuronal plasticity phenomena, including learning and memory as well as drug addiction. METHOD We studied 139 families, Caucasians, with no history of psychiatric disorder of ICD-10 other than alcohol or nicotine dependence. The control subjects were 136 unrelated individuals, matched for ethnicity and gender, with no mental disorder. Alcohol and family history of alcoholism were assessed by means of a structured interview, based on the Polish version of SSAGA (Semi-Structured Assessment on Genetics in Alcoholism). RESULTS We found a statistically significant preferential transmission of the T allele (known to produce higher gene transcriptional activity) from parents to alcoholics (59%, p=0.046). In a case-control study genotype TT and T alleles were significantly more frequent in the alcoholics than in the controls (OR=2.6). CONCLUSION Our results suggest that the MMP-9 gene may play a role in the pathogenesis of alcohol dependence.

Experience With Autosomal Dominant Polycystic Kidney Disease in Patients Before and After Renal Transplantation : A 7-Year Observation

OBJECTIVE Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the presence of multiple cysts in both kidneys. Symptoms of the disease may arise either from the presence of cysts or from increasing loss of kidney function. First symptoms usually appear in the third decade of life: lumbar pain, urinary tract infections, arterial hypertension, or renal colic due to cyst rupture or coexistent nephrolithiasis. An early diagnosis, male gender, large kidneys by sonography, arterial hypertension, hematuria, and urinary tract infections are predictive factors of a faster progression of the disease. Our aim was to establish the indications for nephrectomy among symptomatic ADPKD patients before kidney transplantation and to assess the risks of posttransplantation complications among ADPKD patients without nephrectomy. PATIENTS AND METHODS The observed group consisted of 183 patients with ADPKD among whom 50 (27.3%) underwent kidney transplantation during a 7-year observation period (2000-2007). Among those subjects were 3 groups: (I) nephrectomy preceding transplantation; (II) nephrectomy during kidney transplantation; and (III) without nephrectomy. RESULTS Among group I before transplantation we observed: arterial hemorrhage, wound infections, and splenectomy 4 weeks after ADPKD nephrectomy; afterward we observed: urinary tract infections and contralateral cyst infection. Among group II we only observed 1 case of wound infection. Among group III we observed: ascending urinary tract infections, cyst infections, and cyst hemorrhage. Cyst hemorrhage and cyst infections led mainly to ADPKD kidney nephrectomy. During the observation time, 80.95% of grafts were functioning. CONCLUSIONS Unilateral nephrectomy is a well-founded preliminary surgical treatment before kidney transplantation. Bilateral nephrectomy before or during transplantation eliminates ADPKD complications and does not significantly increase general complications. The greatest numbers of complications and of graft losses were observed among the group without pretransplantation nephrectomy.

Lack of Association between Gly460Trp Polymorphism of Alpha-Adducin Gene and Salt Sensitivity of Blood Pressure in Polish Hypertensives

Background: Previous studies have suggested that α-adducin (α-ADD) polymorphism may identify patients with a salt-sensitive form of hypertension. Aim: To investigate the association between Gly460Trp polymorphism of α-ADD and the pattern of blood pressure response to subacute (1 week) salt loading and depletion in young adult thin Polish hypertensives. Methods: The study group consisted of 44 subjects with salt-sensitive hypertension (SS) and 24 subjects with non-salt-sensitive hypertension (SR). Genomic DNA isolated from peripheral blood leukocytes was amplified by PCR method with primers flanking the polymorphic region. The mismatch near to 3′-end of the upstream primer was introduced to create a Nla III restriction site in Trp 460 allele. In addition, excreted fraction of filtered sodium (FENa), plasma renin activity (PRA) and plasma concentrations of aldosterone (ALDO) were determined on normal, low and high salt diets. Results: FENa on normal or high salt diets were significantly lower in the SS hypertensives as compared with the SR patients. PRA in SS group was also significantly lower as compared with results in SR group, but only on high salt diet. No significant difference was detected in frequencies of genotypes and alleles of α-ADD gene between SS and SR subjects. An additional analysis with regard to genotype (Gly/Gly vs. Gly/Trp+Trp/Trp) showed no significant difference in changes of blood pressure as well as in results of laboratory investigations. Conclusion: Our results suggest lack of association between Gly460Trp polymorphism of α-adducin gene and salt sensitivity of blood pressure in Polish hypertensives.

Family-based study of brain-derived neurotrophic factor ( ΒDNF) gene polymorphism in alcohol dependence

Brain-derived neurotrophic factor (BDNF) belongs to a family of proteins related to the nerve growth factor family, which are responsible for the proliferation, survival and differentiation of neurons. BDNF is thought to be involved in the pathogenesis of bipolar disorder, schizophrenia, eating disorders and addiction. We hypothesize that a functionally relevant polymorphism of the BDNF gene promoter may be associated with the pathogenesis of alcohol dependence. We performed an association study of 141 families with alcohol dependence. One hundred and thirty-eight healthy control subjects were matched based on ethnicity and gender. An association between the BDNF Val66Met gene polymorphism and alcoholism was not found.

ADA*2 Allele of the Adenosine Deaminase Gene May Protect against Coronary Artery Disease

Background/Aims: The common G22A polymorphism in the adenosine deaminase (ADA) gene leads to substitution Asp8Asn. The lower activity of the enzyme encoded by A22 (ADA*2) allele may increase tissue concentrations of adenosine, a potent cardioprotective agent. In a case-control study, we investigated the association between ADA polymorphism and coronary artery disease (CAD). Methods: A hundred and seventy-one CAD patients from the north-western part of Poland and 200 consecutive newborns from the same population were genotyped by PCR-RFLP. Results: Twenty-five ADA*1/*2 heterozygotes (12.5%) and 2 ADA*2/*2 homozygotes (1%) were found in the control group, while only 10 *1/*2 heterozygotes (5.9%) and no *2/*2 homozygotes were found in the CAD group. Frequencies of ADA*2 carriers (5.9% vs. 13.5%, p = 0.015) and ADA*2 allele (2.9% vs. 7.3%, p = 0.0083) were lower in CAD patients than in controls. Among CAD patients, a significantly lower proportion of *2 allele carriers was treated with diuretics and ACE inhibitors when compared to *1/*1 wild-type homozygotes. Conclusion: ADA*2 allele may decrease genetic susceptibility to CAD. ADA should be added to the list of candidate genes modifying the risk of cardiovascular diseases.

C677T polymorphism of the methylenetetrahydrofolate reductase gene and the risk of ischemic stroke in Polish subjects

Hyperhomocysteinemia is reported to be an independent risk factor for the development of ischemic stroke. Several studies on genetic variants of methylenetetrahydrofolate reductase (MTHFR, which plays a crucial role in regulation of plasma homocysteine concentration) reported an association between C677T gene polymorphism and stroke in some Asian populations. No study but one detected this association in Caucasians. The purpose of the present case-control study was to find a relationship betweenMTHFR genotypes and stroke in a Polish population.MTHFR genotypes were determined by PCR in 152 patients with ischemic stroke from northwestern Poland and in 135 consecutive newborns from the same population. The TT genotype and the T allele were significantly more frequent in patients than in the control group (11.8% vs. 4.4%, and 34.5% vs. 21.5%,P < 0.01). When males and females were analyzed separately, the differences were statistically significant in both genders. It is concluded that presence of the T allele is a risk factor for ischemic stroke in Polish subjects.