Inherited factors play a major role in the predisposition to nonalcoholic fatty liver disease (NAFLD), and the rs738409 CfiG polymorphism of PNPLA3/adiponutrin, encoding for the isoleucine-to-methionine substitution at residue 148 (I148M) protein variant, has recently been recognized as a major determinant of liver fat content. However, the effect of the rs738409 polymorphism on the severity of liver fibrosis in patients with NAFLD is still unknown. In this study, we considered 253 Italian patients, 179 healthy controls, and 71 family trios with an affected child with NAFLD. Analyses were replicated in 321 patients from the United Kingdom. The rs738409 polymorphism was determined by TaqMan assays. Liver histology was scored according to Kleiner et al. Hepatic expression of genes regulating liver damage was assessed by real-time polymerase chain reaction in 52 patients. The rs738409 GG genotype was more prevalent in patients than in controls (14% versus 3%, adjusted odds ratio [OR] 5 3.29, 95% confidence interval [CI] 5 1.8-6.9), and in the family study, the G allele was overtransmitted to affected children (P 5 0.001). In Italian and United Kingdom patients, adiponutrin genotype influenced alanine aminotransferase levels and the severity of steatosis. Adiponutrin genotype was associated with the expression of genes involved in the steatosis-related liver damage, including the proapoptotic molecule Fas ligand. In the whole series combined, adiponutrin genotype was associated with steatosis grade >1 (OR 5 1.35, 95% CI 5 1.04-1.76), nonalcoholic steatohepatitis (OR 5 1.5, 95% CI 5 1.12-2.04), and fibrosis stage >1 (OR 5 1.5, 95% CI 5 1.09-2.12), independent of age, body mass index, and diabetes. Adiponutrin genotype demonstrated a dose effect with heterozygote risk intermediate between CC and GG homozygotes. Conclusion: In patients with NAFLD, adiponutrin rs738409 CfiG genotype, encoding for I148M, is associated with the severity of steatosis and fibrosis and the presence of nonalcoholic steatohepatitis. (HEPATOLOGY 2010;51:1209-1217 Abbreviations: ALT, alanine aminotransferase; FASL, Fas ligand; FFA, free fatty acid; HDL, high-density lipoprotein; INSR, insulin receptor; LDL, low-density lipoprotein; mRNA, messenger RNA; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; PNPLA3, patatin-like phospholipase-3; PPARa, peroxisome proliferator-activated receptor-a; qRT-PCR, quantitative real-time polymerase chain reaction; a-SMA, a-smooth muscle actin; SNP, single-nucleotide polymorphism; SREBP1c, steroid regulatory element binding protein 1c.From the

Carriage of the SOD2 C47T polymorphism is associated with more advanced fibrosis in NASH.

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Vitamin D deficiency is associated with several diseases including multiple sclerosis (MS). Several factors influence vitamin D levels and its optimal multi-function maintenance. Our objective was to assess quantifiable variables influencing vitamin D level and metabolism in MS patients from Kuwait. In a case-control study involving 50 MS patients, and 50 healthy control individuals for which plasma vitamin D levels, supplement use, vitamin D receptor (VDR) variants, and skin pigmentation indices were ascertained; we found overall vitamin D levels to be deficient in both groups, and supplement use to be common practice. VDR variants TaqI and BsmI associated with MS risk, and ApaI associated with low disease progression. VDR variant FokI associated with higher vitamin D levels in both groups. We conclude that several quantifiable variables related to vitamin D associate with MS suggesting a possible clinical immuno-modulatory application of vitamin D for MS patients in Kuwait.

Background ABO blood groups have been linked to susceptibility to infection with certain microorganisms, including coronaviruses. We examined the relationship between blood group and clinical outcomes in individuals infected with severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) and compared their blood group distribution with the general population. Methods At the inception of the pandemic, all individuals testing positive for SARS‐CoV‐2 in Kuwait were admitted to one designated coronavirus disease 2019 (COVID‐19) hospital and enrolled in a prospective registry. Patients admitted from February 24 to May 27, 2020, were stratified according to blood group. As a control, blood groups of 3,730,027 anonymized individuals representing almost Kuwait's entire population were obtained from a national database. Results Of 3305 SARS‐CoV‐2–positive patients, 37.1%, 25.5%, 28.9%, and 8.5% were groups O, A, B, and AB, respectively. Univariate analysis revealed no significant differences in severe clinical outcomes or death among the blood groups. However, multivariable analysis demonstrated that group A individuals had higher odds of developing pneumonia compared with non–group A (adjusted odds ratio 1.32, 95% confidence interval 1.02–1.72, p < .036). Compared with the general population, the COVID‐19 cohort had a lower frequency of group O, equivalent frequency of A, and higher frequency of B and AB. No significant difference in the RhD group was found. Conclusion This study supports potential involvement of the ABO blood group system in predisposing to infection with SARS‐CoV‐2 in an unselected population. Examination of the mechanistic link between blood group and COVID‐19 and its implications on controlling the current pandemic is warranted.

The role interethnic genetic differences play in plasma lipid level variation across populations is a global health concern. Several genes involved in lipid metabolism and transport are strong candidates for the genetic association with lipid level variation especially lipoprotein lipase (LPL). The objective of this study was to re-sequence the full LPL gene in Kuwaiti Arabs, analyse the sequence variation and identify variants that could attribute to variation in plasma lipid levels for further genetic association. Samples (n = 100) of an Arab ethnic group from Kuwait were analysed for sequence variation by Sanger sequencing across the 30 Kb LPL gene and its flanking sequences. A total of 293 variants including 252 single nucleotide polymorphisms (SNPs) and 39 insertions/deletions (InDels) were identified among which 47 variants (32 SNPs and 15 InDels) were novel to Kuwaiti Arabs. This study is the first to report sequence data and analysis of frequencies of variants at the LPL gene locus in an Arab ethnic group with a novel “rare” variant (LPL:g.18704C>A) significantly associated to HDL (B = -0.181; 95% CI (-0.357, -0.006); p = 0.043), TG (B = 0.134; 95% CI (0.004–0.263); p = 0.044) and VLDL (B = 0.131; 95% CI (-0.001–0.263); p = 0.043) levels. Sequence variation in Kuwaiti Arabs was compared to other populations and was found to be similar with regards to the number of SNPs, InDels and distribution of the number of variants across the LPL gene locus and minor allele frequency (MAF). Moreover, comparison of the identified variants and their MAF with other reports provided a list of 46 potential variants across the LPL gene to be considered for future genetic association studies. The findings warrant further investigation into the association of g.18704C>A with lipid levels in other ethnic groups and with clinical manifestations of dyslipidemia.

BackgroundAPOAI, a member of the APOAI/CIII/IV/V gene cluster on chromosome 11q23-24, encodes a major protein component of HDL that has been associated with serum lipid levels. The aim of this study was to determine the genetic association of polymorphisms in the APOAI promoter region with plasma lipid levels in a cohort of healthy Kuwaiti volunteers.MethodsA 435 bp region of the APOAI promoter was analyzed by re-sequencing in 549 Kuwaiti samples. DNA was extracted from blood taken from 549 healthy Kuwaiti volunteers who had fasted for the previous 12 h. Univariate and multivariate analysis was used to determine allele association with serum lipid levels.ResultsThe target sequence included a partial segment of the promoter region, 5’UTR and exon 1 located between nucleotides −141 to +294 upstream of the APOAI gene on chromosome 11. No novel single nucleotide polymorphisms (SNPs) were observed. The sequences obtained were deposited with the NCBI GenBank with accession number [GenBank: JX438706]. The allelic frequencies for the three SNPs were as follows: APOAI rs670G = 0.807; rs5069C = 0.964; rs1799837G = 0.997 and found to be in HWE. A significant association (p < 0.05) was observed for the APOAI rs670 polymorphism with increased serum LDL-C. Multivariate analysis showed that APOAI rs670 was an independent predictive factor when controlling for age, sex and BMI for both LDL-C (OR: 1.66, p = 0.014) and TC (OR: 1.77, p = 0.006) levels.ConclusionThis study is the first to report sequence analysis of the APOAI promoter in an Arab population. The unexpected positive association found between the APOAI rs670 polymorphism and increased levels of LDL-C and TC may be due to linkage disequilibrium with other polymorphisms in candidate and neighboring genes known to be associated with lipid metabolism and transport.