Association between longevity and cytokine gene polymorphisms. A study in Sardinian centenarians

BACKGROUND AND AIMS: Human longevity seems to be directly correlated with optimal functioning of the immune system, suggesting that some genetic determinants of longevity reside in those polymorphisms for the immune system genes which regulate immune-inflammatory responses, in particular cytokine gene polymorphisms. The frequency of -174C single nucleotide polymorphism (SNP) in the promoter region of the interleukin (IL)-6 gene is increased in Italian male centenarians. Moreover, the frequency of -1082G SNP at the 5' flanking region of the IL-10 gene coding sequence is increased among male centenarians, and that of +874A SNP at the interferon (IFN)-gamma gene was found more frequently in female centenarians. These findings indicate that different alleles at different cytokine gene codings for pro- (IL-6, IFN-gamma) or anti-inflammatory (IL-10) cytokines may affect the individual life-span expectancy, influencing the type and intensity of immune-inflammatory responses against environmental stressors. METHODS: In the present study, we analyzed these IL-6, IL-10 and IFN-gamma gene polymorphisms in 112 (36 male, 76 female) centenarians from the island of Sardinia, whose population shows a genetic background quite different from that of mainland Italy, as well as in 137 sixty-year-old controls from the same geographic area. RESULTS: No significant differences were observed on analyzing IL-6, IL-10 and IFN-gamma polymorphism frequencies among centenarians and controls, either on the whole and when the data were analyzed according to gender. CONCLUSIONS: These data indicate that gene polymorphisms of cytokines playing a major regulatory role in the inflammatory response do not affect life expectancy in the Sardinian population. Thus, cytokine/longevity associations have a population-specific component, being affected by the population-specific gene pool as well as by gene-environment interactions, behaving as survival rather than longevity genes.     

Association between subjective well-being and exceptional longevity in a longevity town in China: a population-based study

To examine the associations of cognitive and emotional facets (measured by life satisfaction [LS], positive affect [PA], negative affect [NA], and affect balance [AB]) of subjective well-being (SWB) with exceptional longevity (EL), we conducted a population-based study with 463 EL individuals (95+, EL group) recruited from a longevity town of Rugao, China (N = 755, with a response rate of 71.6 %), and 926 elderly individuals (60–69, elderly/control group). The population-based controls were sampled from the resident registry according to the gender ratio of the EL group. We found that the EL group had significantly higher levels of LS (30.74 vs. 28.93), PA (3.91 vs. 3.67), and AB (7.89 vs. 7.40) and a lower level of NA (1.02 vs. 1.27) than the elderly group. Multivariate logistic regression analysis revealed that higher levels of LS, PA, AB, and NA were significantly associated with EL, with odds ratios (ORs) of 1.98 (95 % CI, 1.36–2.89), 2.35 (95 % CI, 1.59–3.48), 2.56 (95 % CI, 1.75–3.75), and 0.50 (95 % CI, 0.33–0.74), respectively. Stratification analysis showed that the associations were significant in the healthy subsample, with the following ORs: LS = 2.31, PA = 2.53, AB = 3.05, and NA = 0.39. In conclusion, SWB, with high cognitive and emotional facets, was associated with EL in the healthy Rugao population. The findings imply that interventions that aim to improve elderly individuals’ SWB may promote their quality of life and, ultimately, EL.     

Family clustering in Sardinian longevity: a genealogical approach

This paper aims to discuss the validation and family determinants affecting the longevity of Sardinian centenarians, using a genealogical approach. This preliminary study presents the first results of a genealogical tree reconstruction of selected centenarians aged 105 and over, from certain areas. These are mostly situated in the province of Nuoro, an area with the highest rate of centenarians and where the female-to-male sex ratio tends to be male-biased. An accurate centenarian age validation was performed that required a meticulous examination of numerous civil status records and parish registers. An important finding was that longevity occurs among the ascendants of a particular branch of the family. The data used are still provisional but, should it apply to other validated cases, it would provide empirical evidence of a genetic component in longevity. A more thorough examination of the data available may yield deeper insights into the role played by endogamy and consanguinity.     

Mitochondrial genomes and exceptional longevity in a Chinese population: the Rugao longevity study

Genetic variants of whole mitochondrial DNA (mtDNA) that predispose to exceptional longevity need to be systematically identified and appraised. Here, we conducted a case-control study with 237 exceptional longevity subjects (aged 95–107) and 444 control subjects (aged 40–69) randomly recruited from a “longevity town”—the city of Rugao in China—to investigate the effects of mtDNA variants on exceptional longevity. We sequenced the entire mtDNA genomes of the 681 subjects using a next-generation platform and employed a complete mtDNA phylogenetic analytical strategy. We identified T3394C as a candidate that counteracts longevity, and we observed a higher load of private nonsynonymous mutations in the COX1 gene predisposing to female longevity. Additionally, for the first time, we identified several variants and new subhaplogroups related to exceptional longevity. Our results provide new clues for genetic mechanisms of longevity and shed light on strategies for evaluating rare mitochondrial variants that underlie complex traits.

Electronic supplementary material

The online version of this article (doi:10.1007/s11357-015-9750-8) contains supplementary material, which is available to authorized users.     

Association of HLA-DR and -DQ alleles with idiopathic achalasia.

BACKGROUND & AIMS: Idiopathic achalasia is a motility disorder of the esophagus characterized by incomplete relaxation of the lower esophageal sphincter and a loss of normal peristaltic activity in the body of the esophagus. The loss of inhibitory neurons in the distal esophagus, as well as abnormalities in the vagus nerve, dorsal motor nucleus of the vagus nerve, and autonomic nervous system, have been described in achalasia. Although the underlying cause of idiopathic achalasia is unknown, the diffuse neuronal effects found suggest a possible viral or neurodegenerative mechanism. By use of serological methods, a significant association between the HLA-DQ1 phenotype and idiopathic achalasia has been found, suggesting a possible immunogenetic mechanism. To further define immunogenetics in the pathogenesis of idiopathic achalasia, we performed tissue typing in patients with achalasia to determine their specific HLA phenotypes. Methods: We prospectively studied 32 patients (23 white and 9 black) with idiopathic achalasia. Peripheral blood was collected, and HLA-DR and -DQ typing by polymerase chain reaction with sequence-specific primers was performed. Results were compared with those from 268 racially matched local controls. RESULTS: Idiopathic achalasia and the broad HLA-DQ1 allele were not significantly associated in either population, although a trend was found in white subjects (odds ratio [OR], 2.16; chi2 = 5.36, P corrected [Pc] = 0.0824). Further subtyping in white subjects revealed a significant association between idiopathic achalasia and the DQB1*0602 allele (OR, 3.10; chi2 = 7.32, Pc = 0.0408). A strong trend was also found with the DRB1*15 allele (OR, 2.83; chi2 = 8.11, Pc = 0.0572). In the black population, there was no association between idiopathic achalasia and DQB1*0602 or DRB1*15, but a trend was found with DRB1*12 (OR, 6. 19; chi2 = 5.19, P = 0.0227 uncorrected, Pc = 0.295). CONCLUSIONS: Idiopathic achalasia is associated with HLA alleles in a race-specific manner. These results support an immunogenetic mechanism in the pathogenesis of idiopathic achalasia.     

巴马长寿地区HLA-A基因与长寿的相关性研究

目的 了解巴马地区壮族长寿老人HLA-A基因座位的多态性特点，探讨HLA与长寿的相关性。方法 应用聚合酶链式反应-列特异引物（PCR—SSP）对广西巴马和东兰两县259名90岁以上壮族长寿老人（90～105岁）和214名当地健康、随机抽样的壮族成年人（23—70岁）进行HLA—A座位的基因分型并进行相应等位基因频率比较。结果 在两组人群中，检出率最高的等位基因是HLA—A＊02、-A＊11和-A＊24，其频率之和均超过0．7。其中，长寿组的HLA—A＊11和-A＊26的频率分别为0．283和0．076，明显高于对照组的0．165和0．041（P分别为0．001，0．023）。其余各相应等位基因频率之间的比较无显著差异（P均〉0．05）。相关分析显示，HLA—A＊11和-A＊26与长寿呈正相关（OR分别为1．602及1．847；P分别（0．001及（0．05）。结论 HLA-A＊11和HLA—A＊26可能在巴马地区壮族人群的长寿机制中起一定作用，即是长寿的有利因子之一。     

Association between fasting glucose and C-reactive protein in a Japanese population: the Minoh study

To investigate the association between fasting glucose and C-reactive protein (CRP), we examined 1715 Japanese individuals (723 men and 992 women) aged 40-69 years who did not have medication for hypertension, diabetes, or dyslipidemia, a history of cardiovascular disease or CRP levels>10mg/l. There was a statistically significant unadjusted correlation between CRP and each component of the metabolic syndrome, including fasting glucose, fasting insulin, body mass index, systolic blood pressure, diastolic blood pressure, high-density lipoprotein cholesterol (negative), and triglycerides in both men and women. With adjustment for age, cigarette smoking, alcohol intake, and other components of the metabolic syndrome, the CRP increments (as back-transformed) compared with the lowest tertile of normal fasting glucose were 0.99, 1.05, 1.21, and 1.34mg/l (P for trend=0.008) with the second lowest and highest tertiles of normal fasting glucose, impaired fasting glucose, and type-2 diabetes, respectively in men. The respective adjusted CRP increments were 1.12, 1.23, 1.33, and 1.93mg/l (P for trend<0.001) in women. In the stratified analyses of CRP levels by sex, obesity status, and fasting glucose category or the number of components of the metabolic syndrome, an increase in CRP levels was greater in women than men with obesity and higher fasting glucose category (gender interaction: P<0.001) or an increased number of components of the metabolic syndrome (gender interaction: P=0.003). These results indicate that CRP levels increase continuously across the spectrum of fasting glucose in both sexes. This association is more pronounced in women.     

Association of HLA-DR7 with rheumatic fever in the Brazilian population

OBJECTIVE: Rheumatic fever (RF) is a multisystem inflammatory disease that develops as a sequel of untreated throat infection by the group A beta-hemolytic streptococcus. As HLA antigens are known to be important in controlling immunological responsiveness, studies have investigated HLA antigen association with RF. Studies with Caucasians, Black Americans, and Indians showed associations with HLA-DR4, DR2, and DR3, respectively. One study on a Brazilian population suggested an association with HLA-DR7 and HLA-DR53. We investigated the association between RF and antigens HLA-DR7 and DR53 in the white Brazilian population. METHODS: Thirty-five patients and 209 healthy individuals living in the northern region of the state of Parana, Brazil, were used as test and control groups, respectively. Classical statistical methods were used to compare HLA frequencies between these groups. Results. Data confirmed positive association with HLA-DR7 (46.7 vs. 25.7%; p = 0.015), but not with HLA-DR53 (54.3 vs. 44.5%; p = 0.28). The relative risk and etiologic fractions were 2.4 and 0.27%, respectively. CONCLUSION: Positive association between HLA-DR7 specificity and RF was observed in the white Brazilian population by 2 independent studies, supporting the hypothesis of the involvement of genetic factors in susceptibility of rheumatic fever.     

Association between HLA-DRB1 alleles polymorphism and hepatocellular carcinoma: a meta-analysis

Background  

HLA-DRB1 allele polymorphisms have been reported to be associated with hepatocellular carcinoma susceptibility, but the results of these previous studies have been inconsistent. The purpose of the present study was to explore whether specific HLA-DRB1 alleles (DRB1*07, DRB1*12, DRB1*15) confer susceptibility to hepatocellular carcinoma.     

Association between human leukocytes antigen alleles and chronic hepatitis C virus infection in the Korean population.

BACKGROUND/AIM: Recent data have shown that the clinical outcome of hepatitis C virus (HCV) infection may be influenced by the host genetic factor. The aim of this study was to investigate whether particular human leukocytes antigen (HLA) molecules are associated with the susceptibility to HCV infection in the Korean population. METHODS: One hundred and thirty-seven patients with chronic HCV infection and 206 normal individuals were examined for HLA class I and II molecules. RESULTS: In class I antigens, the frequencies of HLA-A3 (relative risk (RR)=3.5, P<0.04), HLA-B35 (RR=2.0, P<0.03), and HLA-B46 (RR=2.5, P<0.02) significantly increased in chronic HCV carriers compared with the controls. The frequencies of DRB1*0803, DQB1*0601 and DQB1*0604 were significantly higher in chronic HCV carriers than in controls (RR=2.5, P<0.005; RR=1.8, P<0.05; RR=1.9, P<0.04, respectively). On the other hand, the frequencies of DRB1*0301, DQA1*0501 and DQB1*0201 were significantly lower in chronic HCV carriers than in normal controls (RR=0.2, P<0.03; RR=0.4, P<0.004; RR=0.5, P<0.02, respectively). The haplotype DRB1*0803-DQB1*0601 significantly increased (RR=2.5, P<0.02) while the DQA1*0501-DQB1*0201 significantly decreased (RR=0.2, P<0.03) in chronic HCV carriers compared with normal controls. In stratification analysis to investigate the interrelationships among the associated alleles, DRB1*0803 and DQB1*0601 were associated with HLA-B46, particularly in patients with chronic HCV carriers. CONCLUSIONS: These results suggest that particular HLA alleles may have an influence on chronic HCV infection as a host genetic factor in the Korean population.     

Association between HLA-DR antigens and rheumatoid arthritis in Arabs.

Eighty five Arab patients with classical and definite rheumatoid arthritis were typed to determine the prevalence of HLA A, B, C, and DR antigens. A significant increase in the prevalence of HLA-A10, B8, B21, and DR3 was found in comparison with a control population matched for age and sex. HLA-DR5 was significantly decreased in the patient group. The classical association of HLA-DR4 with rheumatoid arthritis could not be confirmed in the Arab patients resident in Kuwait, supporting reported observations in different ethnic groups of associations with HLA antigens other than HLA-DR4 and indicating a heterogeneous genetic susceptibility to rheumatoid arthritis.     

广西巴马长寿人群PON1基因多态性与血脂水平的关系

目的探讨广西巴马长寿人群对氧磷酶-1(PON1)基因rs662位点多态性与血脂水平的关系。方法调查巴马长寿老人151例、无长寿家族史健康成年人198例(对照1组)及南丹无长寿家族史的健康成年人176例(对照2组),分析其PON1基因频率分布特点并比较各基因型人群血脂水平。结果长寿组与对照两组的基因型和等位基因频率差异显著(P0.05),长寿组与对照两组A等位基因频率分别为35.8%和23.0%;长寿组AG基因型的HDL水平高于GG的HDL水平,GG及G等位基因携带者的HDL水平高于对照1组,AG、GG及G等位基因携带者TG水平低于对照两组。结论长寿组与对照两组rs662位点基因型及等位基因频率分布存在差异;巴马长寿人群rs662位点多态性与血脂水平相关。     

Association between hepatitis B virus infection and HLA-DR type in Korea

Although the mechanism of susceptibility to chronic persistent hepatitis B virus (HBV) infection is not well clarified, immunogenetic factors of the host may have a role. Recently, a strong association between HLA-DR13 and the self-limited course of HBV infection has been reported. To determine whether the elimination of HBV is related to a particular HLA allele, we studied the HBV markers and HLA-DR phenotypes of 1,272 Koreans who had visited Yonsei University Medical Center for renal transplantation. They included 330 renal transplant donors. Subjects were categorized into 3 different groups: the "Unexposed Group" (UE; n = 946) with negative HBV markers, the "Chronic Carrier Group" (CC; n = 83), who were hepatitis B surface antigen (HBsAg)-positive, and the "Spontaneously Cleared Group" (SC; n = 243), who were HBsAg-negative with antibodies to HBsAg (anti-HBs) and hepatitis B core antigen (anti-HBc). HLA-DR4 was the most common type in all groups. HLA-DR6 was significantly more frequent in 69 of 243 subjects with SC (28. 4%) than in 8 of 83 subjects with CC (9.6%) (P <.001; relative risk [RR] = 3.72). HLA-DR9 was significantly more frequent in CC than in SC (P <.001; RR = 0.33). HLA-DR13 showed a stronger association with the clearance of HBV than the other HLA-DR6 subgroup. The distribution of HLA-DR phenotypes was similar regardless of renal disease. Our data indicate that HLA-DR6, especially HLA-DR13, is one of the host factors, which influences the immune response to HBV, and may be associated with self-elimination of HBV in Koreans.     

Association between serum C-reactive protein levels and pulse wave velocity: a population-based cross-sectional study in a general population

Arterial stiffness as determined by aortic pulse wave velocity (PWV) has been shown to predict cardiovascular events in high-risk subjects such as those with hypertension or end-stage renal disease. Although it is suspected that low-grade inflammation as represented by increased C-reactive protein (CRP) plays an important role in the progression of atherosclerosis, it is not yet known whether serum CRP levels are associated with PWV. To examine the relationship between brachial-ankle PWV (baPWV) and serum CRP levels, several cardiovascular risk factors including these two markers (baPWV and CRP) were measured in 870 participants (mean age 59 years) randomly selected from a general population. Age, male gender, systolic blood pressure, heart rate, diabetes, and serum CRP levels increased with the quartiles divided by baPWV (all, p<0.01). By multiple regression analysis, age (p<0.001), systolic blood pressure (p<0.001), heart rate (p<0.001), body mass index (p<0.001), and CRP (p<0.01) were significant and independent predictors for baPWV. In conclusion, this cross sectional study has demonstrated in the general population that the arterial stiffness marker baPWV was independently correlated with serum CRP levels after adjustment for other established cardiovascular risks factors. This result suggests that baPWV may be a surrogate marker for atherosclerotic vascular damages including an inflammatory component.     

Association between plasma lipids, and apolipoproteins and coronary artery disease: a cross-sectional study in a low-risk Korean population

BACKGROUND: Due to the lower level of the traditional lipid profiles in Koreans than in the series of patients from the western countries, the need to investigate other lipid parameters to help identify the individuals at high risk of CAD has been emphasized. AIM AND METHODS: To investigate whether apolipoprotein B (apo B), apolipoprotein A-I (apo A-I) and their ratio give additional information to the traditional lipid risk factors for discriminating the individuals at high-risk for coronary artery disease (CAD), 544 subjects, who met the lipid criteria of total cholesterol (TC) <230 mg/dl, low-density lipoprotein cholesterol (LDL-C) <120 mg/dl and high-density lipoprotein cholesterol (HDL-C) >40 mg/dl were recruited. Patients were considered to be CAD(+) if they had > or =50% stenosis in at least one coronary artery. RESULTS: In men, TC and apo B/apo A-I ratio were significantly different between groups with and without CAD after adjusting for age and diabetes (P = 0.037 and 0.035), and in women, triglyceride (TG), HDL-C and apo B/apo A-I ratio were significantly different after adjusting for age, diabetes and smoking status (P = 0.006, 0.007 and 0.030, respectively). In the lowest quartile of TC, TG and LDL-C, and the highest quartile of HDL-C, only apo B/apo A-I ratio was associated with CAD in both men and women. The only variable showing a significant difference between patients with and without CAD was apo B/apo A-I ratio. In models assessing whether apolipoproteins give additional information to traditional lipid risk factors, HDL-C, LDL-C, apo B/apo A-I ratio and in women but not in men, TG and apo B were all independent markers for the presence of CAD. Among the nontraditional lipid factors, only apo B/apo A-I ratio showed its additional value for identifying the presence of CAD. CONCLUSION: Apo B/apo A-I ratio is the only variable that differentiates the patients with CAD from those without and, furthermore, gives additional information to that supplied by traditional lipid risk factors in a low-risk Korean population.