Systematic analysis of molecular defects in the ferrochelatase gene from patients with erythropoietic protoporphyria.

Erythropoietic protoporphyria (EPP; MIM 177000) is an inherited disorder caused by partial deficiency of ferrochelatase (FECH), the last enzyme in the heme biosynthetic pathway. In EPP patients, the FECH deficiency causes accumulation of free protoporphyrin in the erythron, associated with a painful skin photosensitivity. In rare cases, the massive accumulation of protoporphyrin in hepatocytes may lead to a rapidly progressive liver failure. The mode of inheritance in EPP is complex and can be either autosomal dominant with low clinical penetrance, as it is in most cases, or autosomal recessive. To acquire an in-depth knowledge of the genetic basis of EPP, we conducted a systematic mutation analysis of the FECH gene, following a procedure that combines the exon-by-exon denaturing-gradient-gel-electrophoresis screening of the FECH genomic DNA and direct sequencing. Twenty different mutations, 15 of which are newly described here, have been characterized in 26 of 29 EPP patients of Swiss and French origin. All the EPP patients, including those with liver complications, were heterozygous for the mutations identified in the FECH gene. The deleterious effect of all missense mutations has been assessed by bacterial expression of the respective FECH cDNAs generated by site-directed mutagenesis. Mutations leading to a null allele were a common feature among three EPP pedigrees with liver complications. Our systematic molecular study has resulted in a significant enlargement of the mutation repertoire in the FECH gene and has shed new light on the hereditary behavior of EPP.     

Jacobsen syndrome

Erythropoietic protoporphyria (EPP) is an inherited disorder of the haem metabolic pathway characterised by accumulation of protoporphyrin in blood, erythrocytes and tissues, and cutaneous manifestations of photosensitivity. EPP has been reported worldwide, with prevalence between 1:75,000 and 1:200,000. It usually manifests in early infancy upon the first sun exposures. EPP is characterised by cutaneous manifestations of acute painful photosensitivity with erythema and oedema, sometimes with petechiae, together with stinging and burning sensations upon exposure to sunlight, without blisters. These episodes have a variable severity depending on the exposure duration and may result in chronic permanent lesions on exposed skin. As protoporphyrin is a lipophilic molecule that is excreted by the liver, EPP patients are at risk of cholelithiasis with obstructive episodes, and chronic liver disease that might evolve to rapid acute liver failure. In most patients, EPP results from a partial deficiency of the last enzyme of the haem biosynthetic pathway, ferrochelatase, EC 4.99.1.1/FECH (encoded by the FECH gene). EPP appears to be inherited as an autosomal dominant disease, the clinical expression of which is modulated by the presence of the hypomorphic FECH IVS3-48C allele trans, but recessive inheritance with two mutated FECH alleles has also been described. In about 2% of patients, overt disease was recently shown to be caused by gain-of-function mutations in the erythroid-specific aminolevulinic acid synthase 2 (ALAS2/ALAS, EC 2.3.1.27) gene and named X-linked dominant protoporphyria. Diagnosis is established by finding increased levels of protoporphyrin in plasma and red blood cells, and detection of a plasma fluorescence peak at 634 nm. Investigations for hepatic involvement, ferrochelatase activity level, genetic analysis (FECH mutations, presence of the hypomorphic FECH IVS3-48C allele trans and ALAS2 mutations) and family studies are advisable. Differential diagnosis includes phototoxic drug reactions, hydroa vacciniforme, solar urticaria, contact dermatitis, angio-oedema and, in some cases, other types of porphyria. Management includes avoidance of exposure to light, reduction of protoporphyrin levels and prevention of progression of possible liver disease to liver failure. As the major risk in EPP patients is liver disease, a regular follow-up of hepatic involvement is essential. Sequential hepatic and bone marrow transplantation should be considered as a suitable treatment for most severe cases of EPP with hepatic involvement. EPP is a lifelong disorder whose prognosis depends on the evolution of the hepatic disease. However, photosensitivity may have a significant impact on quality of life of EPP patients.     

DRB genotyping supports recessive inheritance of DR3-associated susceptibility to insulin-dependent diabetes mellitus.

The mode of inheritance of HLA-associated susceptibility to insulin-dependent diabetes mellitus was investigated by the antigen genotype frequency among patients method in a white Caucasian population and a North Indian Asian population. DR genotypes were determined by DRB/DQB RFLP analysis. In white Caucasians, simple recessive and simple additive inheritance of a single HLA-associated disease susceptibility allele were rejected (P less than .025 and P less than 10(-6), respectively). The data were compatible with a three-allele model of disease susceptibility. In North Indian Asians, simple additive inheritance was rejected (P less than 10(-6)). The observed genotype frequencies were compatible with a single DR3-associated disease susceptibility allele which is inherited recessively. These data show that study of DR genotypes in populations of different ethnic origins may further the understanding of inherited susceptibility to insulin-dependent diabetes mellitus.     

A genotype-phenotype correlation between null-allele mutations in the ferrochelatase gene and liver complication in patients with erythropoietic protoporphyria.

Erythropoietic protoporphyria (EPP), an inborn error of heme metabolism, causes in the majority of the patients only a symptom of photosensitivity. However, around 2% of the EPP sufferers develop liver complication in the form of liver cirrhosis and progressive liver failure. Mutations in the human ferrochelatase (FECH) gene causing EPP are highly heterogeneous and mostly family-specific. Actually, 62 FECH mutations have been published, 48 of them are "null allele" mutations inducing the formation of a truncated protein. The remaining 14 are missense mutations. In contrast to the null allele mutations, the latter lead to substitution of a single amino acid residue in the protein molecule and generate an enzyme that, although functionally impaired, is in its full length. In order to study the association between "null allele" mutation and liver complication, we combined our data with those in the literature. A total of 112 EPP patients were counted among 93 EPP families with a known FECH mutation. All 18 EPP patients who had severe liver complication carried a "null allele" mutation. In contrast, none of the 20 patients who carried a missense mutation had developed liver complication till the time of study (Fisher's exact test, p<0.05). High protoporphyrin blood concentration are considered to be a sign of an increased risk of liver disease. No correlation of protoporphyrin blood level with the type of mutation, was found, if patients with overt liver disease were excluded from the sample. Furthermore, no significant association of the liver complication with the location of the mutation within the FECH gene was found (Fisher exact test p = 0.46). These available data indicate a significant genotype-phenotype correlation between "null allele" mutation and protoporphyrin related liver disease in EPP. Although the risk for a EPP patient with a missense mutation to develop liver disease cannot be totally eliminated based on these data, it is comparably low.     

Loss-of-Function Ferrochelatase and Gain-of-Function Erythroid-Specific 5-Aminolevulinate Synthase Mutations Causing Erythropoietic Protoporphyria and X-Linked Protoporphyria in North American Patients Reveal Novel Mutations and a High Prevalence of X-Linked Protoporphyria

Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are inborn errors of heme biosynthesis with the same phenotype but resulting from autosomal recessive loss-of-function mutations in the ferrochelatase (FECH) gene and gain-of-function mutations in the X-linked erythroid-specific 5-aminolevulinate synthase (ALAS2) gene, respectively. The EPP phenotype is characterized by acute, painful, cutaneous photosensitivity and elevated erythrocyte protoporphyrin levels. We report the FECH and ALAS2 mutations in 155 unrelated North American patients with the EPP phenotype. FECH sequencing and dosage analyses identified 140 patients with EPP: 134 with one loss-of-function allele and the common IVS3-48T>C low expression allele, three with two loss-of-function mutations and three with one loss-of-function mutation and two low expression alleles. There were 48 previously reported and 23 novel FECH mutations. The remaining 15 probands had ALAS2 gain-of-function mutations causing XLP: 13 with the previously reported deletion, c.1706_1709delAGTG, and two with novel mutations, c.1734delG and c.1642C>T(p.Q548X). Notably, XLP represented ~10% of EPP phenotype patients in North America, two to five times more than in Western Europe. XLP males had twofold higher erythrocyte protoporphyrin levels than EPP patients, predisposing to more severe photosensitivity and liver disease. Identification of XLP patients permits accurate diagnosis and counseling of at-risk relatives and asymptomatic heterozygotes.     

Modulation of the phenotype in dominant erythropoietic protoporphyria by a low expression of the normal ferrochelatase allele.

Erythropoietic protoporphyria (EPP) is a monogenic inherited disorder of the heme biosynthetic pathway due to ferrochelatase (FC) deficiency. EPP is generally considered to be transmitted as an autosomal dominant disease with incomplete penetrance, although autosomal recessive inheritance has been documented at the enzymatic and molecular level in some families. In the dominant form of EPP, statistical analysis of FC activities documented a significantly lower mean value in patients than in asymptomatic carriers, suggesting a more complex mode of inheritance. To account for these findings, we tested a multiallelic inheritance model in one EPP family in which the enzymatic data were compatible with this hypothesis. In this EPP family, the specific FC gene mutation was an exon 10 skipping (delta Ex10), resulting from a G deletion within the exon 10 consensus splice donor site. The segregation of all FC alleles within the family was followed using the delta Ex10 mutation and a new intragenic dimorphism (1520 C/T). mRNAs transcribed from each FC allele were then subjected to relative quantification by a primer extension assay and to absolute quantification by a ribonuclease protection assay. The data support the hypothesis that in this family the EPP phenotype results from the coinheritance of a low output normal FC allele and a mutant delta Ex10 allele.     

Association between Fc receptor-like 3 C169T polymorphism and risk of systemic lupus erythematosus: a meta-analysis

To investigate the association between Fc receptor-like 3 (FCRL3) C169T polymorphism and susceptibility to systemic lupus erythematosus (SLE). We surveyed studies on the FCRL3 C169T polymorphism and SLE using comprehensive Medline search and review of the references. Meta-analysis was performed for genotypes CC (recessive effect), CC+CT (dominant effect) and C allele in fixed effects model or random effects model. Five identified studies included 1,944 SLE patients and 4,528 non-SLE controls. Three out of five identified studies included populations of Asian descent, and two included populations of European descent. The overall odds ratio (OR) of the CC genotype was 1.21(95% confidence interval [CI], 1.04–1.40). Stratification by ethnicity indicated that the CC genotype was associated with SLE in Asian-derived population (OR, 1.23; 95% CI, 1.03–1.47). No association was detected in European-derived population (OR, 1.17; 95% CI, 0.90–1.52). This meta-analysis fails to show significant association of CC+CT genotypes and C allele with SLE in overall, European-derived and Asian-derived populations. In summary, this meta-analysis demonstrates that the FCRL3 169CC genotype (recessive effect) may confer susceptibility to SLE, especially in Asian-derived population.     

Human ferrochelatase: a novel mutation in patients with erythropoietic protoporphyria and an isoform caused by alternative splicing

Erythropoietic protoporphyria (EPP), attributable to deficiency of ferrochelatase activity (FECH), is characterised mainly by cutaneous photosensitivity. To define the molecular defect in two EPP-affected siblings and their parents in a Swiss family, ferrochelatase cDNA was amplified by the polymerase chain reaction (PCR) and subjected to sequence analysis. A 5-bp deletion (T580G584) was identified on one allele of the ferrochelatase gene in both patients and their mother. Screening of the mutation among family members by RsaI digestion of PCR-amplified genomic DNA revealed autosomal dominant inheritance associated with abnormal protoporphyrin concentration and enzyme activity. We also isolated ferrochelatase cDNAs containing a 18-bp insertion (part of the intron 2 sequence) between exons 2 and 3; this corresponded to six extra amino acids (YESNIR) inserted between Arg-65 and Lys-66 of the known ferrochelatase. This isoform was identified initially in mRNAs derived from both alleles of the ferrochelatase gene in one patient. Its existence was confirmed in six additional EPP patients, in five out of seven controls, and in four different cell lines (fibroblast, muscle, hepatoma and myelogenous leukaemia). This isoform, roughly 20% of the total ferrochelatase mRNA, was generated through splicing at a second donor site in intron 2 and its presence was not linked to EPP.     

IGF1(CA)19 and IGFBP-3-202A/C Gene Polymorphism and Cancer Risk: A Meta-analysis

Insulin-like growth factor 1 (IGF1)(CA)19 and insulin-like growth factor-binding protein-3 (IGFBP-3)-202A/C gene polymorphisms had been focused by many epidemiological studies recently, which were associated with common cancer risk including colorectal, breast, prostate, and lung cancer. However, the findings of epidemiological investigations are not coincident. We did a systematic review and meta-analysis of case–control studies, including studies nested in cohorts, of the association between IGF1(CA)19 and IGFBP-3-202A/C gene polymorphism and prostate, colorectal, premenopausal and postmenopausal breast cancer. We identified 17 eligible studies (24 datasets), which included 9,744 cases and 11,332 controls. The result displays that individuals carrying (CA)19 allele had a subtly decreased risk of all cancer sites [OR(95 % CI) 0.92(0.87,0.97); 0.882(0.809,0.962); 0.902(0.849,0.958)] and postmenopausal breast cancer [OR(95 % CI) 0.893(0.832,0.959); 0.834(0.719,0.968); 0.862(0.776,0.958)] in allele contrast model, CA19/CA19 vs. non-CA19/non-CA19 model, and recessive genetic model. In subgroup analysis according to ethnicities, (CA)19 repeat polymorphism had an increased risk of common cancers in Asian [OR (95 % CI) of allele contrast model: 1.105(1.000,1.224); additive model: 1.103(0.844,1.441), 1.197(1.013,1.413); recessive model: 1.039(0.831,1.300); and dominant model: 1.191(1.030,1.376)]. On the other hand, IGFBP-3-202A/C gene polymorphism did not seem to be associated with all the cancer sites in any genetic model and ethnicity. In conclusion, the result of this meta-analysis indicates that the IGF1(CA)19 polymorphism is a candidate gene polymorphism for cancer susceptibility regardless of environmental factors, especially in Asian.     

The risk of new‐onset cancer associated with HFE C282Y and H63D mutations: evidence from 87,028 participants

To investigate the association between mutation of HFE (the principal pathogenic gene in hereditary haemochromatosis) and risk of cancer, we conducted a meta‐analysis of all available case–control or cohort studies relating to two missense mutations, C282Y and H63D mutations. Eligible studies were identified by searching databases including PubMed, Embase and the ISI Web of Knowledge. Overall and subgroup analyses were performed and odds ratios (ORs) combined with 95% confidence intervals (CIs) were applied to evaluate the association between C282Y mutation, H63D mutation and cancer risk. Sensitivity and cumulative analyses were used to evaluate the stability of the results. A total of 36 eligible studies were included, comprising 13,680 cases and 73,348 controls. C282Y was significantly associated with elevated cancer risk in a recessive genetic model (OR: 1.991, 95% CI: 1.448–2.737). On subgroup analysis stratified by cancer type, statistically significantly increased cancer risks were found for breast cancer, colorectal cancer and hepatocellular carcinoma in a recessive model. When stratified by territory, a significantly increased risk of cancer was found in Oceanic populations in a recessive model and in Asian populations in an allele model and dominant model. H63D mutation did not significantly increase overall cancer risk in any genetic model. However, when, stratified by territory, an increased cancer risk was found in the Asian population in an allele and dominant. C282Y but not H63D mutation was related to elevated cancer risk. Further large‐scale studies considering gene–environment interactions and functional research should be conducted to further investigate this association.     

European ACP1*C allele has recessive deleterious effects on early life viability

The acid phosphatase locus (ACP1) is a classical polymorphism that has been surveyed in hundreds of human populations worldwide. Among individuals of European ancestry, the ACP1*C allele occurs with an average frequency of approximately 0.05, whereas it is nearly absent in all other human populations. It has been hypothesized that this allele is maintained by overdominant selection among European populations. Here, we analyze ACP1 protein polymorphism data from more than 50,000 individuals previously surveyed in 67 populations across Europe as well as inheritance data from more than 6,000 European parent-offspring pairs to assess the signature of natural selection currently acting on this allele. Although we see a significant excess of ACP1*C heterozygotes relative to Hardy-Weinberg expectations, we find no evidence that natural selection favors ACP1*C heterozygotes. Instead, ACP1*C appears to have a strongly deleterious and recessive fitness effect. We observed only 48.9% of expected homozygous offspring from heterozygous parents and significantly fewer homozygotes than expected within populations. Because parent-offspring pairs indicate a significant deficiency of ACP1*C homozygotes, we infer that viability selection is acting on ACP1*C homozygotes very early in life, perhaps before birth. We estimate that approximately 1.2% of all couples of European ancestry are composed of individuals who both carry the APC1*C allele. As such, selection against ACP1*C homozygotes may represent a nonnegligible contribution to the overall number of spontaneous abortions among women of European ancestry and may cause substantial fertility reductions among some combinations of parental genotypes.     

The pathogenicity of the Pro1148Ala substitution in the FBN1 gene: causing or predisposing to Marfan syndrome and aortic aneurysm, or clinically innocent?

In individuals with the Marfan syndrome (MFS), mutations have been identified in the fibrillin-1 gene (FBN1) at 15q21.1. A proline-to-alanine change at position 1148 in exon 27 (Pro1148Ala) has been reported in probands with MFS, aortic aneurysm or Marfanoid-craniosynostosis. It was suggested that this mutation could be a risk factor for aortic dilatation, since it was rarely observed in control populations. To investigate further the pathogenicity of this substitution, we screened 416 unrelated control individuals by allele-specific oligonucleotide (ASO) hybridization. We found 16 individuals who carried the alanine allele (3.8%), 3 of whom were homozygous. Five were of Latin American and eight were of Asian extraction. We also screened 133 probands with MFS, aortic aneurysm or related connective tissue disorders and found 4 (3%) that were heterozygous for the 1148Ala allele. All positive results were confirmed by DNA sequencing. In 20 individuals with 1148Ala, we confirmed the association with the rarer A allele at the IVS27-5G→A polymorphism. Our results suggest that the Pro1148Ala change is a polymorphism of ancient evolutionary origin that is more prevalent in Asian and Latin American than in Caucasian or African populations. Received: 4 October 1996 / Revised: 3 December 1996     

Polymorphism of the <Emphasis Type="Italic">CD36</Emphasis> Gene and Cardiovascular Risk Factors in Patients with Coronary Artery Disease Manifested at a Young Age

This study investigates potential associations between CD36 gene variants and the presence of risk factors in Caucasians with coronary artery disease (CAD) manifested at a young age. The study group consisted of 90 patients; the men were ≤ 50 years old and the women were ≤ 55 years old. Amplicons of exons 4 and 5 including fragments of introns were analyzed by DHPLC. Two polymorphisms were found: IVS3-6 T/C (rs3173798) and IVS4-10 G/A (rs3211892). The C allele of the IVS3-6 T/C polymorphism was associated with higher prevalence of obesity and diabetes, higher hsCRP, lower Lp(a) serum concentrations, and younger age at myocardial infarction. The A allele of the IVS4-10 G/A polymorphism was associated with older age of myocardial infarction and higher white blood cell count. The functional role of CD36 polymorphisms in CAD development needs further research.     

Associations between FCGR2A rs1801274, FCGR3A rs396991, FCGR3B NA1/NA2 polymorphisms and periodontitis: a meta-analysis

The aim of this study was to determine whether the Fcγ receptors (FCGRs) polymorphisms confer susceptibility to periodontitis in ethnically different populations. We did a literature search using PubMed and Embase, and conducted a meta-analysis on the associations between the FCGR2A H131R (rs1801274), FCGR3A F158V (rs396991), and FCGR3B NA1/NA2 polymorphisms and periodontitis using allele contrast, the recessive model, the dominant model, and the homozygote contrast. A total of 17 separate comparisons with 1,421 patients with periodontitis and 1,454 controls, involving six Caucasian, six East Asian, two African and one South Asian population were considered in the meta-analysis. Meta-analysis of the FCGR2A H131R polymorphism showed no association between periodontitis and the FCGR2A R allele (OR = 0.987, 95 % CI = 0.881–1.107, p = 0.827). Stratification by ethnicity revealed an association between the RR+RH genotype with periodontitis in Caucasian population (OR = 0.624, 95 % CI = 0.479–0.813, p = 4.7 × 10^?5), but not in East Asian, and African populations. Meta-analysis of the FCGR3A F158V polymorphism revealed an association between the FCGR3A V allele and periodontitis is in Caucasians (OR = 1.457, 95 % CI = 1.014–2.092, p = 0.042), but not in East Asians and Africans. In addition, analysis using the dominant model and homozygote contrast showed the same pattern for the FCGR3A V allele. Meta-analysis of the FCGR3B NA1/NA2 polymorphism using the recessive model revealed a significant association between the NA2/NA2 genotype and periodontitis in aggressive periodontitis (OR = 2.853, 95 % CI = 1.673–4.863, 1.1 × 10^?5). This meta-analysis demonstrates that the FCGR2A, and FCGR3A polymorphisms may confer susceptibility to periodontitis in Caucasians, and that the FCGR3B polymorphism may be associated with susceptibility to aggressive periodontitis.     

Association of the − 1082G/A polymorphism in the interleukin-10 gene with systemic lupus erythematosus: A meta-analysis

A great many studies have investigated the − 1082G/A polymorphism (rs1800896) in the interleukin-10 gene (IL10) with SLE susceptibility, but the results are inconsistent and inconclusive. The aim of this meta-analysis was in order to more precisely estimate the relationship. The databases of Pubmed and Web of Science updated to Oct, 2012 were retrieved. Odds ratio (OR) and corresponding 95% confidence interval (95%CI.) as effect size were calculated by fixed-effect model. Analysis for allele contrast of stratification by ethnicity in either Asian or Caucasian, as well as in overall population indicated no significant association (Overall: OR 1.096, 95%CI. 0.995–1.207; Asian: OR 1.204, 95%CI.: 0.944–1.535; Caucasian: OR 1.075, 95%CI.: 0.961–1.202). Analysis for recessive model showed no association in overall populations and in Caucasian (Overall: OR 1.135, 95%CI.: 0.945–1.362; Caucasian: OR 1.069, 95%CI.: 0.882–1.296), but significant association in Asian (OR: 2.848; 95%CI.: 1.194–6.791). Analysis for dominant model indicated that the variant G allele carriers (GG + GA) may have increased the risk of SLE when compared with the homozygote AA in overall populations and in Caucasian (Overall: OR 1.203, 95%CI.: 1.029–1.407; Caucasian: OR 1.233, 95%CI.: 1.014–1.499), but not in Asian (OR: 1.154; 95%CI.: 0.856–1.557). Significant association was found by using homozygote contrast model in overall populations and Asian (Overall: OR 1.303, 95%CI.: 1.031–1.648; Asian: OR 3.206, 95%CI.: 1.241–8.284), while no association was found in Caucasian (OR: 1.209; 95%CI.: 0.940–1.556). The results provided evidence for the association between the IL10 − 1082G/A polymorphism and the risk of SLE. To confirm these findings, more case–control studies with subtle study design based on adequately sized populations are required.     

Association of IL-6 and MMP-3 gene polymorphisms with susceptibility to adolescent idiopathic scoliosis: a meta-analysis

Recently, several institutions have investigated the associations of MMP-3-1171 5A/6A and IL-6-174-G/C gene polymorphisms with adolescent idiopathic scoliosis (AIS), while reports from different institutions are not consistent. Therefore, we, comprehensively and systematically performed this meta-analysis to detect whether the two gene polymorphisms are correlated with AIS. From January 1994 to October 2015, all case–control studies focussed on the relationship between the two aforementioned gene polymorphisms and the susceptibility to AIS were retrieved from bibliographic databases. A total of 16 articles were found, of which five consisted of 944 cases and 1177 controls, were finally included after being assessed by two reviewers. We calculated the pooled odds ratio (OR) with 95% confidence interval (95% CI) to assess the associations. The pooled data analyses were based on allele contrast, homozygote, heterozygote, dominant and recessive models. Overall, there was no significant association of IL-6-174-G/C gene polymorphism with AIS risk. Significant association was observed in homozygote model of MMP-3-1171-5A/6A gene polymorphism (5A5A versus 6A6A: OR = 1.69, 95% CI = 1.11–2.58, P = 0.02). When stratified into Caucasian and Asian populations, positive association was found in Caucasian population (5A versus 6A: OR = 1.43, 95% CI = 1.11–1.84, P = 0.006; 5A5A versus 6A6A: OR = 1.90, 95% CI = 1.13–3.19, P = 0.015); however, there was no significant association in Asian population. The present study concluded that 5A5A genotype of MMP-3-1171 5A/6A gene polymorphism was associated with AIS, especially in Caucasian population. However, no significant association was detected between IL-6-174-G/C gene polymorphism and AIS.     

Association between the ENPP1 K121Q Polymorphism and Risk of Diabetic Kidney Disease: A Systematic Review and Meta-Analysis

The potential association between the K121Q (A/C, rs1044498) polymorphism in the ectonucleotide pyrophosphatase/phosphodiesterase (ENPP1) gene and risk of diabetic kidney disease (DKD) has been investigated. Nevertheless, the effect of this variant on DKD risk is still under debate, and conflicting results have been reported. To this date, no meta-analysis has evaluated the association of the K121Q polymorphism with DKD. This paper describes the first meta-analysis conducted to evaluate whether the ENPP1K121Q polymorphism is associated with DKD. A literature search was conducted to identify all case-control or cross-sectional studies that evaluated associations between the ENPP1K121Q polymorphism and DKD. Pooled odds ratios (OR) and 95% confidence intervals (95% CI) were calculated for allele contrast, additive, dominant and recessive inheritance models. Seven studies were eligible for inclusion in the meta-analysis, providing data on 3571 type 1 or type 2 diabetic patients (1606 cases with DKD and 1965 diabetic controls without this complication). No significant heterogeneity was observed among the studies included in the meta-analysis when assuming different inheritance models (I^² < 50% or P > 0.10 for the entire sample and after stratification by ethnicity). Meta-analysis results revealed significant associations between the K121Q polymorphism and risk of DKD in Asians and Europeans when assuming the different inheritance models analyzed. The most powerful association was observed for the additive model (OR = 1.74, 95% CI 1.27-2.38 for the total sample). In conclusion, the present meta-analysis detected a significant association between the ENPP1K121Q polymorphism and increased susceptibility of DKD in European and Asian populations.     

Ferrochelatase gene mutations in erythropoietic protoporphyria: focus on liver disease.

A deficiency of ferrochelatase (FECH) activity underlies the excess accumulation of protoporphyrin that occurs in erythropoietic protoporphyria (EPP). In some patients, protoporphyrin accumulation causes liver damage that necessitates liver transplantation. The purpose of this study was to determine if specific mutations in the FECH gene are present in patients who develop liver disease. FECH cDNA and all 11 exons and their flanking intron regions in the FECH gene were amplified and sequenced by specific polymerase chain reactions. Gene mutations were determined in 34 individuals from 24 families: 14 had liver disease, 10 necessitating liver transplantation. All individuals were heterozygous for mutations that altered the coding region of FECH mRNA. The mutations in patients with liver disease were heterogenous, but usually caused a major structural alterations in the FECH protein, most commonly as a result of exon skipping in FECH mRNA. However, the mutations could not account for the severe phenotype by themselves, since the same mutations were found in asymptomatic family members of patients with liver disease and in patients from families in which liver disease was not present. Other genetic factors, and possibly acquired factors, also must be critical to the development of this severe phenotype in EPP.