Pulmonary function, genetic predisposition, and the risk of cirrhosis: A prospective cohort study

doi:10.21203/rs.3.rs-3930985/v1

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Pulmonary function, genetic predisposition, and the risk of cirrhosis: A prospective cohort study

https://doi.org/10.21203/rs.3.rs-3930985/v1

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published 01 Jun, 2024

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Background

Pulmonary function is known to be associated with the development of chronic liver disease. However, evidence of the association between pulmonary function and cirrhosis risk is still lacking. This study aimed to investigate the longitudinal associations of pulmonary function with the development of cirrhosis, and to explore whether genetic predisposition to cirrhosis modifies these associations.

Methods

A total of 308,678 participants free of cirrhosis and had undergone spirometry at baseline from the UK Biobank were included. Cirrhosis diagnoses were ascertained through linked hospital records and death registries. Cox proportional hazard models were employed to investigate the longitudinal associations between pulmonary function, genetic predisposition, and cirrhosis risk.

Results

During a median follow-up of 12.0 years, 2,725 incident cirrhosis cases were documented. Compared to individuals with normal spirometry findings, those with preserved ratio impaired spirometry (PRISm) findings (hazard ratio [HR] and 95% confidence interval [CI]: 1.30 [1.16, 1.45]) and airflow obstruction (HR [95%CI]: 1.19 [1.08, 1.32]) had a higher risk of developing cirrhosis after adjustments. These associations were consistent across all categories of genetic predisposition, with no observed modifying effect of genetic predisposition. In joint exposure analyses, the highest risk was observed in individuals with both a high genetic predisposition for cirrhosis and PRISm findings (HR [95% CI]: 1.68 [1.41, 2.00]).

Conclusion

Our findings indicate that worse pulmonary function is a significant risk factor of cirrhosis, irrespective of genetic predisposition.

pulmonary function

genetic risk

PRISm

cirrhosis

prospective cohort

Cirrhosis results from chronic liver damage and inflammation, characterized by diffuse hepatic fibrosis and the substitution of normal liver structures with regenerative liver nodules [1, 2]. The leading causes of cirrhosis include infection by hepatitis B and hepatitis C viruses, alcohol-associated liver disease, and non-alcoholic fatty liver disease (NAFLD) [3, 4]. In 2017, cirrhosis affected over 120 million people worldwide and was responsible for more than 1 million deaths, marking a doubling in prevalence from 1990 to 2017 [5]. Cirrhosis is a significant cause of morbidity and mortality in individuals with chronic liver disease [6]. Notably, cirrhosis is a major risk factor for hepatocellular carcinoma (HCC), with up to 90% of HCC patients occurring in patients with underlying cirrhosis [7]. Beyond its hepatic implications, cirrhosis is associated with extrahepatic diseases, such as cardiovascular disease (CVD) [8], chronic kidney disease [9], and various forms extrahepatic cancer (e.g., breast cancer and lymphoma) [10]. Hence, identifying modifiable risk factors for cirrhosis is crucial.

Pulmonary function parameters, such as forced vital capacity (FVC) and forced expiratory volume in one second (FEV₁), are increasingly recognized for their association with the development of chronic metabolic diseases. These include diabetes [11], CVD [12], inflammatory processes [13], and metabolic syndrome [14]. Notably, NAFLD, often considered a precursor to cirrhosis, has also been linked to pulmonary function in previous research. For instance, a large cohort study in a middle-aged Korean population, encompassing over half a million person-years of follow-up, identified reduced pulmonary function as a risk factor for incident NAFLD [15]. Similarly, a cross-sectional study involving middle-aged and elderly Chinese participants found an association between impaired pulmonary function and NAFLD [16]. Additionally, another study has demonstrated that the predicted FEV₁% and FVC% exhibited a significant and inverse association with NAFLD [17]. Potential mediators of the link between lung and liver function include systemic inflammation [18], physical activity [19], and oxidative stress [20]. Despite these findings, the direct associations between pulmonary function and cirrhosis are still not well-established. Furthermore, while both environmental and genetic factors are known to influence the onset of cirrhosis [21], the potential modifying role of genetic predisposition in the associations between pulmonary function and cirrhosis has yet to be elucidated.

To fill these knowledge gaps, the current cohort study was designed with two primary objectives: 1) to explore the prospective associations between pulmonary function and the risk of developing cirrhosis; 2) to examine whether genetic predisposition to cirrhosis modulated the above associations.

Study Populations

This cohort study utilized data from the UK Biobank, which aims to study the environmental, social, and genetic causes of chronic diseases [22]. The UK Biobank is a comprehensive, prospective cohort study that enrolled over 500,000 participants aged 37 to 73 from 22 assessment centers across England, Scotland, and Wales between 2006 and 2010. Participants provided health-related data through touchscreen questionnaires, physical measurements, face-to-face interviews, medical diagnoses, and various biological samples such as blood, urine, and saliva.

In the present study, we excluded participants with incomplete lung function assessment data (n = 48,800), under 40 years old (n = 7), absence of genetic information or mismatch between genetic and self-reported sex (n = 9,152), with incomplete covariates data (n = 129,782), with self-reported or hospital diagnosed liver cirrhosis, severe NAFLD, other liver diseases (e.g., liver failure, HCC, liver transplant status, alcoholic liver disease, viral hepatitis, etc.), or a history of alcohol/drug abuse (n = 5,152) at baseline, or lost to follow-up (n = 825). Finally, a total of 308,678 participants were included in the final analyses (Fig. 1).

The UK Biobank Research has been approved by the Northwest Multi-Centre Research Ethics Committee and all participants have provided written informed consent to participate.

Assessment of pulmonary function

During recruitment, all participants were required to undergo spirometry before receiving bronchodilator treatment. They were instructed to perform two to three blows using a spirometer (Pneumotrac 6800; Vitalograph), under the supervision of a trained technician. A computer was used to assess the consistency of the first two blows, and if the difference in FVC and FEV₁ was within 5%, the third blow was omitted [23]. The spirometry results were then evaluated by the study staff, with the highest values of FEV₁ and FVC (the most accurate measurements) from the acceptable blows were used. According to a previous study, FEV₁ percent predicted was calculated as per GLI-2012 values using the Spiro package in R [23].

Preserved ratio impaired spirometry (PRISm) is a newly recognized precursor to chronic obstructive pulmonary disease (COPD) and is considered as a risk indicator for progressive lung dysfunction and mortality [23]. In this study, PRISm was defined by an FEV₁ of less than 80% predicted and an FEV₁ to FVC ratio of ≥ 0.70 [23]. Airflow obstruction was determined using an FEV₁ to FVC ratio of < 0.70, following the Global Initiative for Chronic Obstructive Lung Disease criteria for stage I-IV obstruction [24]. Control participants were those with an FEV₁ of ≥ 80% predicted and an FEV₁ to FVC ratio of ≥ 0.70.

Assessment of genetic risk score

To assess the genetic predisposition to cirrhosis, we utilized a genetic risk score (GRS) based on the UK Biobank's genetic data. The UK Biobank genetic data was genotyped, imputed, and subjected to quality control, as explained in a previous study [25]. We selected 6 specific single nucleotide polymorphisms (SNPs) (rs2642438, rs72613567, rs58542926, rs738409, rs1800562, and rs28929474) based on previous studies [26, 27]. The GRS for cirrhosis was calculated using the following formula: GRS = β1 × SNP1 + β2 × SNP2 + ... + βn × SNPn, where βn represents the effect size and SNPn denotes the number of risk alleles for each SNP. A higher cirrhosis-GRS score indicates a greater genetic predisposition to liver cirrhosis. For further analyses, the cirrhosis-GRS was categorized into three groups based on its distribution: high (tertile 3), intermediate (tertile 2), and low (tertile 1).

Ascertainment of cirrhosis

In the UK Biobank, follow-up data on cirrhosis and mortality were collected by electronically connecting to hospital admissions and cancer registries in England, Wales, and Scotland. Participants were followed from their initial visit to the assessment center and were examined for the first occurrence of cirrhosis. For those without an incident case or death, follow-up continued until the end of the study period, which was September 30, 2021 in England, February 28, 2018 in Wales, and July 31, 2021 in Scotland. Cirrhosis events were classified using the 10th International Classification of Diseases (ICD-10) codes, in line with a combination of diseases defined by these codes according to the latest expert consensus statements [28, 29]. The specific codes used for defining event cirrhosis were in Table S1.

Assessment of covariates

At baseline, demographic, socioeconomic, and lifestyle information were assessed through a touch-screen questionnaire. Body mass index (BMI) was calculated as weight in kilograms divided by height in meters squared (kg/m²). To evaluate the overall diet quality, we calculated a healthy diet score based on five key elements of a healthy diet model: vegetables, fruits, fish, unprocessed meat, and processed meat [30]. Physical activity was classified according to global health recommendations [31]. We equated one minute of vigorous physical activity to two minutes of moderate activity. Participants were grouped based on their total weekly physical activity into either < 150 minutes/week or ≥ 150 minutes/week of moderate activity. Hypertension was defined as having a systolic blood pressure ≥ 140 mmHg, a diastolic blood pressure ≥ 90 mmHg, self-reported hypertension, or the use of antihypertensive drugs [32]. Diabetes was defined as having a fasting blood glucose level ≥ 7.0 mmol/L, a glycosylated hemoglobin (HbA1c) level ≥ 48.0 mmol/L, self-reported diabetes, or a history of diabetes drug use [33]. Hyperlipidemia was defined as having a total cholesterol level ≥ 5.17 mmol/L, a triglyceride level ≥ 1.70 mmol/L, a low-density lipoprotein cholesterol level ≥ 3.37 mmol/L, self-reported hyperlipidemia, or a history of medication use for hyperlipidemia [34]. Cancer and CVD were identified through self-reporting. Additionally, cirrhosis-GRS, genotyping array, and the first 10 principal components of ancestry were included as covariates in the analyses.

Statistical analysis

Complete case analysis was applied in this study. Baseline characteristics of participants were presented as mean (SD) for continuous variables and number (percentage) for categorical variables, categorized by pulmonary function status (normal spirometry findings, PRISm, and airflow obstruction). Cox proportional hazards models were used to examine the associations between pulmonary function and the risk of cirrhosis, with normal spirometry findings as the reference group. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated. The proportional hazards assumption was verified using the Schoenfeld test, which yielded non-significant P value across all models. Four models were developed for analysis. Multicollinearity tests were conducted, revealing no issues.

To explore the potential modifying effect of cirrhosis-GRS on the associations between pulmonary function and incident cirrhosis, analyses were stratified by cirrhosis-GRS categories. A product term of pulmonary function status with cirrhosis-GRS was included in the multivariate-adjusted models. The joint association of pulmonary function status and cirrhosis-GRS with the risk of incident cirrhosis was assessed by creating a combined variable with 3\(\times\)3 groups, with the lowest risk combination (low cirrhosis-GRS and normal spirometry findings) as the reference group.

Several secondary analyses were performed to validate the robustness of our findings. Firstly, we stratified the participants by various factors such as sex, diabetes, hyperlipidemia, hypertension, and alcohol intake to examine whether the associations between pulmonary function status and the risk of cirrhosis varied across different subgroups. Secondly, a sensitivity analysis was conducted to validate the main results. This analysis involved using different assessment criteria, including the Global Lung Initiative definitions for FEV₁ and FVC with lower limit of normal (LLN) thresholds [35], as well as the evaluation of PRISm using a method from a previous UK Biobank cohort study [23]. Thirdly, we conducted a Fine and Gray competing risk analysis to evaluate the influence of non-cirrhosis death on the association between pulmonary function and cirrhosis. Fourthly, to mitigate the impact of reverse causality, we excluded participants who developed cirrhosis within the first 3 years of follow-up. Lastly, we excluded participants who had a diagnosis of cancer or CVD at the baseline.

All statistical analyses were performed using SAS version 9.4 (SAS Institute Inc., Cary, NC, USA) and R (version 4.0.5). A P value of less than 0.05 (two-sided) was considered statistically significant.

Baseline characteristics of the study population

A total of 308,678 participants (mean [SD] age: 55.8 [8.11] years; 149,650 males [48.5%]) were enrolled. Among these participants, 45,039 (14.59%) met the criteria for airflow obstruction, 32,085 (10.39%) for PRISm findings, and 231,554 (75.01%) for normal spirometry findings. During a median follow-up of 12.0 years, we observed 2,725 incident cirrhosis cases (cases per 10,000 person-years: 7.36). Table 1 presented the baseline characteristics of participants based on pulmonary function phenotypes. Participants identified as PRISm were predominantly female and less likely to be White. They tended to be older with lower levels of education and household income, alongside higher Townsend Deprivation Index scores. These individuals were more inclined to smoke, yet they consumed less alcohol. Their dietary habits were less healthy, and they exhibited lower levels of physical activity, contributing to higher BMI. Additionally, they exhibited elevated levels of SBP, DBP, FBG, HbA1c, and TG. This group also had a higher prevalence of diabetes, hypertension, hyperlipidemia, and CVD.

Table 1

Baseline characteristics of participants according to pulmonary function status (308,678) ^a
Characteristics	Pulmonary function status
Characteristics	Normal Spirometry Findings (n = 231,554)	PRISm Findings (n = 32,085)	Airflow Obstruction (n = 45,039)
Socio-demographics
Sex
female	123,110 (53.17) ^b	16,935 (52.78)	18,983 (42.15)
male	108,444 (46.83)	15,150 (47.22)	26,056 (57.85)
Age (years)	55.37 (8.08)	55.60 (8.13)	58.48 (7.73)
Ethnicity
White	223,095 (96.35)	28,463 (88.71)	43,277 (96.09)
Others	8,459 (3.65)	3,622 (11.29)	1,762 (3.91)
Education level, n (%)
Low	87,069 (37.60)	13,177 (41.07)	19,187 (42.60)
Intermediate	113,891 (49.19)	14,951 (46.60)	20,336 (45.15)
High	30,594 (13.21)	3,957 (12.33)	5,516 (12.25)
Townsend deprivation index	-1.60 (2.90)	-0.96 (3.24)	-1.19 (3.12)
Household income, ₤
< 31,000	97,461 (42.09)	16,259 (50.67)	24,459 (54.31)
≥ 31000	134,093 (57.91)	15,826 (49.33)	20,580 (45.69)
Lifestyles
Smoking status, n (%)
Current smoker	18,337 (7.92)	3,811 (11.88)	7,727 (17.16)
Ex-smoker	79,139 (34.18)	108,35 (33.77)	17,428 (38.70)
Non-smoker	134,078 (57.90)	17,439 (54.35)	19,884 (44.15)
Alcohol consumption, n (%)
≥ 3 times/week	108,850 (47.01)	12,600 (39.27)	22,249 (49.40)
≤ 2 times/week	86,602 (37.40)	11,903 (37.10)	15,174 (33.69)
Special occasions only	22,394 (9.67)	4,324 (13.48)	4,522 (10.04)
Never	13,708 (5.92)	3,258 (10.15)	3,094 (6.87)
Healthy diet score	3.19 (1.19)	3.08 (1.21)	3.09 (1.21)
Physical activity
< 150 min/week	42,819 (18.49)	7,789 (24.28)	8,760 (19.25)
≥ 150 min/week	188,735 (81.51)	24,296 (75.72)	36,369 (80.75)
Anthropometric indexes
BMI (kg/m²)	27.10 (4.47)	28.94 (5.57)	26.62 (4.42)
Blood pressure and biochemistry
SBP (mmHg)	138.39 (19.23)	140.68 (19.73)	140.96 (19.83)
DBP (mmHg)	82.97 (10.71)	83.55 (11.26)	82.18 (10.95)
FBG (mmol/L)	5.06 (1.10)	5.27 (1.59)	5.09 (1.18)
HbA1c (mmol/L)	35.38 (5.93)	37.67 (8.46)	36.27 (6.42)
TC (mmol/L)	5.72 (1.11)	5.59 (1.17)	5.63 (1.14)
TG (mmol/L)	1.71 (1.01)	1.91 (1.13)	1.73 (1.01)
LDL-C (mmol/L)	3.58 (0.85)	3.50 (0.88)	3.51 (0.86)
Individual history of disease, n (%)
Cardiovascular disease	9,249 (3.99)	2,497 (7.78)	3,060 (6.79)
Diabetes	11,738 (5.07)	3,720 (11.59)	2,943 (6.53)
Hypertension	119,501 (51.61)	19,151 (59.69)	26,132 (58.02)
Hyperlipidemia	185,965 (80.31)	26,430 (82.37)	36,846 (81.81)
^a Abbreviations: PRISm, preserved ratio impaired spirometry; BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; FBG, fasting blood glucose; HbA1c, glycated hemoglobin; TC, total cholesterol; TG, triglycerides; LDL-C, low-density lipoprotein cholesterol.
^b Continuous variables are expressed as mean (SD) and categorical variables are expressed as number (percentage).

Independent associations of pulmonary function and cirrhosis-GRS with the risk of cirrhosis

Table 2 presented the associations between pulmonary function and the risk of cirrhosis. In the crude model, compared to participants with normal spirometry findings, those with airflow obstruction (HR and 95% CI: 1.53 [1.39, 1.69]) and PRISm findings (HR [95% CI]: 1.71 [1.53, 1.90]) were associated with a higher risk of cirrhosis. These associations, although attenuated, remained significant after further adjustments. The fully adjusted HRs (95% CIs) of incident cirrhosis were 1.30 (1.16, 1.45) for PRISm findings and 1.19 (1.08, 1.32) for airflow obstruction.

Table 2

Associations of pulmonary function status with the risk of cirrhosis (308,678) ^a
	Pulmonary function status
	Normal Spirometry Findings (n = 231,554)	PRISm Findings (n = 32,085)	Airflow Obstruction (n = 45,039)
Cases, n	1,784	416	525
Person-years	2,734,082	374,603	526,121
Crude	1.00 (reference)	1.71 (1.53, 1.90) ^b	1.53 (1.39, 1.69)
Model 1 ^c	1.00 (reference)	1.48 (1.33, 1.65)	1.34 (1.21, 1.48)
Model 2 ^d	1.00 (reference)	1.38 (1.23, 1.54)	1.21 (1.09, 1.34)
Model 3 ^e	1.00 (reference)	1.30 (1.16, 1.45)	1.19 (1.08, 1.32)
^a Abbreviations: PRISm, preserved ratio impaired spirometry; BMI, body mass index; CVD, cardiovascular disease; GRS, genetic risk score.
^b Hazard ratio (95% confidence interval) (all such values).
^c Model 1 was adjusted for age, sex, and BMI.
^d Model 2: Model 1 + smoking status, drinking status, ethnicity, education level, Townsend deprivation index, household income, a healthy diet score, and physical activity.
^e Model 3: Model 2 + hypertension, diabetes, hyperlipidemia, CVD, cancer, cirrhosis-GRS, first 10 principal components of ancestry, and genotype measurement batch.

The association of cirrhosis-GRS with the risk of cirrhosis was presented in Table S2. A higher cirrhosis-GRS level was associated with an increased risk of developing cirrhosis. The multivariate-adjusted HRs (95% CIs) of incident cirrhosis were 1.00 (reference), 1.14 (1.03, 1.25), and 1.32 (1.20, 1.44) for the low, intermediate, and high cirrhosis-GRS groups, respectively.

Association between pulmonary function status, cirrhosis-GRS, and the risk of cirrhosis

Table 3 presented the associations between pulmonary function status and the risk of cirrhosis, stratified by categories of cirrhosis-GRS. No significant interaction between cirrhosis-GRS and pulmonary function was found (P for interaction = 0.49). After adjustments, individuals with PRISm findings had a 32% (HR [95% CI]: 1.32 [1.08, 1.62]), 41% (HR [95% CI]: 1.41 [1.15, 1.73]), and 21% (HR [95% CI]: 1.21 [1.02, 1.44]) increased risk of developing cirrhosis in individuals with low, intermediate, and high cirrhosis-GRS, respectively. However, a positive association between airflow obstruction and cirrhosis risk was only observed in the high cirrhosis-GRS subgroup (HR [95% CI]: 1.23 [1.06, 1.43]).

Table 3

Associations between pulmonary function status and the risk of cirrhosis stratified by genetic risk categories (308,678) ^a
GRS categories	Normal Spirometry Findings (n = 231,554)	PRISm Findings (n = 32,085)	Airflow Obstruction (n = 45,039)	P for interaction ^f
				0.49
Low GRS
Crude	1.00 (reference)	1.68 (1.38, 2.05) ^e	1.48 (1.23, 1.77)
Model 1 ^b	1.00 (reference)	1.48 (1.21, 1.80)	1.28 (1.07, 1.54)
Model 2 ^c	1.00 (reference)	1.38 (1.13, 1.69)	1.17 (0.97, 1.41)
Model 3 ^d	1.00 (reference)	1.32 (1.08, 1.62)	1.16 (0.97, 1.40)
Intermediate GRS
Crude	1.00 (reference)	1.74 (1.43, 2.11)	1.49 (1.24, 1.79)
Model 1 ^b	1.00 (reference)	1.59 (1.30, 1.93)	1.34 (1.11, 1.61)
Model 2 ^c	1.00 (reference)	1.47 (1.20, 1.79)	1.19 (0.99, 1.44)
Model 3 ^d	1.00 (reference)	1.41 (1.15, 1.73)	1.18 (0.98, 1.43)
High GRS
Crude	1.00 (reference)	1.70 (1.44, 2.00)	1.59 (1.37, 1.85)
Model 1 ^b	1.00 (reference)	1.41 (1.19, 1.67)	1.38 (1.19, 1.60)
Model 2 ^c	1.00 (reference)	1.31 (1.11, 1.56)	1.24 (1.07, 1.45)
Model 3 ^d	1.00 (reference)	1.21 (1.02, 1.44)	1.23 (1.06, 1.43)
^a Abbreviations: PRISm, preserved ratio impaired spirometry; BMI, body mass index; CVD, cardiovascular disease; GRS, genetic risk score.
^b Model 1 was adjusted for age, sex, and BMI.
^c Model 2: Model 1 + smoking status, drinking status, ethnicity, education level, Townsend deprivation index, household income, a healthy diet score, and physical activity.
^d Model 3: Model 2 + hypertension, diabetes, hyperlipidemia, CVD, cancer, first 10 principal components of ancestry, and genotype measurement batch.
^e Hazard ratio (confidence interval) (all such values).
^f P for interaction was calculated by involving the cross-product term of pulmonary function status and GRS in the fully adjusted Cox proportional hazards regression model.

The joint associations of pulmonary function and cirrhosis-GRS with cirrhosis risk were shown in Fig. 2. In the fully adjusted model, compared with participants with normal spirometry findings and low cirrhosis-GRS, those with PRISm or airflow obstruction combined with high cirrhosis-GRS had a 68% (HR [95% CI]: 1.68 [1.41, 2.00]) and 62% (HR [95% CI]: 1.62 [1.39, 1.90]) higher risk of developing cirrhosis, respectively.

Secondary analyses

In stratified analyses, the associations between pulmonary function and the risk of cirrhosis remained consistent across all examined subgroups (Table 4). There was no significant interaction observed between pulmonary function and potential effect modifiers (all P values for interactions > 0.05). In sensitivity analyses, HRs for cirrhosis with pulmonary function status, as defined by the Global Lung Initiative (Table S3) or a method from a previous UK Biobank cohort study (Table S4), yielded results similar to the primary analysis. Similar associations were also observed in competing risk analyses (Table S5). Additionally, the consistency of these associations persisted even when excluding participants who developed cirrhosis within the first 3 years of follow-up (Table S6) or those with a baseline diagnosis of cancer or CVD (Table S7).

Table 4

Associations between pulmonary function status and the risk of cirrhosis stratified by main risk factors (n = 308,678) ^a
Subgroups	Pulmonary function status			P for interaction ^b
Subgroups	Normal Spirometry Findings (n = 231,554)	PRISm Findings (n = 32,085)	Airflow Obstruction (n = 45,039)	P for interaction ^b
Sex				0.74
Male	1.00 (reference)	1.47 (1.27, 1.70) ^c	1.17 (1.03, 1.33)
Female	1.00 (reference)	1.10 (0.93, 1.31)	1.24 (1.06, 1.46)
diabetes				0.65
No	1.00 (reference)	1.29 (1.14, 1.47)	1.18 (1.06, 1.32)
Yes	1.00 (reference)	1.30 (1.04, 1.63)	1.23 (0.97, 1.58)
Hyperlipidemia				0.59
No	1.00 (reference)	1.14 (0.85, 1.53)	1.10 (0.87, 1.41)
Yes	1.00 (reference)	1.33 (1.18, 1.50)	1.21 (1.09, 1.35)
Hypertension				0.31
No	1.00 (reference)	1.20 (0.96, 1.49)	1.31 (1.10, 1.56)
Yes	1.00 (reference)	1.32 (1.16, 1.51)	1.14 (1.01, 1.29)
Alcohol consumption				0.35
Never/special occasions	1.00 (reference)	1.01 (0.79, 1.28)	1.17 (0.93, 1.47)
Regular drinking	1.00 (reference)	1.40 (1.24, 1.59)	1.20 (1.07, 1.34)
^a Abbreviations: BMI, body mass index; CVD, cardiovascular disease; GRS, genetic risk score; PRISm, preserved ratio impaired spirometry.
^b Calculated by using likelihood-ratio test. The interaction term of pulmonary function with each potential modifier was included in the model separately.
^c Hazard ratios (95% confidence intervals) (all such values). Multivariable Cox proportional regression was adjusted for age, sex, BMI, smoking status, drinking status, ethnicity, education level, Townsend deprivation index, household income, a healthy diet score, physical activity, hypertension, diabetes, hyperlipidemia, CVD, cancer, cirrhosis-GRS, first 10 principal components of ancestry, and genotype measurement batch.

In the present cohort study, utilizing a general population-based sample from the UK Biobank, we investigated the associations of pulmonary function, genetic predisposition, with the risk of cirrhosis in 308,678 middle-aged and older adults. Our findings showed that individuals with PRISm findings or airflow obstruction were at a higher risk of developing cirrhosis compared to those with normal spirometry findings. These associations were consistent across major subgroups and in sensitivity analyses, and were not significantly altered by the genetic risk of cirrhosis.

Previous studies on the associations between pulmonary function and liver function has predominantly focused on NAFLD [15–17]. For example, a large Korean cohort study found that reduced lung function was a risk factor for developing NAFLD, regardless of smoking history, with an increased risk corresponding to lower quartiles of FEV₁% and FVC% in a dose-response manner [15]. Another cross-sectionally study demonstrated that individuals with NAFLD had lower levels of predicted FVC% and FEV₁% compared to those without NAFLD. After adjusting for potential confounding factors, the lowest quartile of these parameters were associated with an increased prevalence of NAFLD, with fully adjusted odds ratios of 1.37 and 1.24, respectively [16]. Additionally, a previous cross-sectionally study showed significant inverse associations between predicted FEV₁%, FVC% and NAFLD, after adjusting for multiple covariates. A restrictive lung pattern was notably associated with moderate and severe NAFLD, whereas an obstructive lung pattern did not show a significant association [17]. However, the association between pulmonary function and cirrhosis, a critical prognostic outcome of NAFLD, has not been extensively studied. It's important to note that cirrhosis, often resulting from conditions beyond NAFLD, represents a more severe and irreversible stage of liver disease. Meanwhile, previous studies have largely concentrated on simple lung function parameters, such as FVC and FEV₁, without a comprehensive analysis of their broader implications. These parameters alone do not fully elucidate the association between lung and liver functions. Our findings filled these gaps and contributes uniquely to the existing literature by demonstrating significant positive associations of PRISm findings and airflow obstruction with an increased risk of developing cirrhosis. Notably, the association between pulmonary function and cirrhosis was found to be stronger in participants with PRISm results compared to those with airflow obstruction. This difference may be due to PRISm being a newly recognized precursor to COPD, whereas airflow obstruction is essentially equivalent to established COPD. Individuals with airflow obstruction are likely to receive more lifestyle modification recommendations for overall health improvement, unlike those with PRISm, which is potentially reversible but may not be accompanied by similar health advice. Therefore, understanding the association between PRISm and cirrhosis can aid in early identification and treatment of patients with reduced lung function. Such interventions could mitigate harm and have significant public health implications, such as for reducing the disease burden of cirrhosis. Moreover, our results indicated that there was no significant interaction between genetic risk and pulmonary function in relation to the risk of cirrhosis. This finding underscores the importance of regular screening and management of pulmonary function across the entire population, regardless of their genetic predisposition to cirrhosis. It highlights the potential value of pulmonary health as a universal consideration in cirrhosis prevention strategies. Further research is essential to validate and expand upon our findings, potentially leading to more comprehensive and effective approaches in managing and mitigating the risk of cirrhosis.

While the exact mechanisms linking lung function to cirrhosis are not fully understood, several plausible explanations could account for this association. First, systemic inflammation might play a key role. Inhalation of harmful environmental pollutants can lead to inflammation in the airspaces, triggering the release of pro-inflammatory cytokines, such as interleukin (IL)-6, from alveolar macrophages. This inflammatory response could cause airway damage and reduce lung function [18]. These cytokines might then enter the systemic circulation, contributing to widespread inflammation, a known factor in the development of hepatocyte fat accumulation [36], which can progress to cirrhosis. Second, reduced lung function can lead to decreased physical activity [19], potentially exacerbating obesity [37] and metabolic syndrome [38], which are closely associated with the development of cirrhosis [39]. Third, oxidative stress within the body might also link decreased lung function with cirrhosis [20, 40]. Elevated oxidative stress can damage the liver and accelerate the progression of liver fibrosis [20]. Therefore, compromised lung function could adversely affect liver health and facilitate the development of cirrhosis through these interconnected pathways.

Our study possesses several notable strengths. First, it contributes as the first evidence of the longitudinal associations between pulmonary function, genetic predisposition, and the risk of cirrhosis. Second, the pulmonary function indicators utilized in this study, including PRISm and airflow obstruction, offered a more precise reflection of actual pulmonary function. The results providing a comprehensive view of pulmonary health in relation to cirrhosis risk. Third, the robustness of our study is further reinforced by its cohort design, substantial sample size, and extended duration of follow-up. The comprehensive and detailed information on a wide range of confounding factors, coupled with rigorous sensitivity analyses, significantly enhances the reliability and validity of our findings. These methodological strengths collectively contribute to the robustness and credibility of our study, making it a valuable addition to existing research in this area.

This study has several limitations that need to be considered. First, due to the nature of the observational study design, we cannot determine a causal association between pulmonary function and the risk of cirrhosis. Second, the UK Biobank had a low response rate (5.47%) and potential selection bias. However, the generalizability of risk factor associations in the UK Biobank remains robust despite the low response rate [41]. Third, for using the complete case analysis, we excluded some participants due to missing data on pulmonary function assessments and covariates, might introduce potential bias. It is crucial to acknowledge that this method can yield biased estimates if the missing data are not completely at random. Fourth, although we adjusted for a considerable number of confounding factors, the possibility of residual confounding due to unmeasured or unknown variables cannot be entirely ruled out. Fifth, as our study focused on middle-aged to older adults, the findings may not be applicable to other age groups. Finally, the diagnosis of incident cirrhosis cases relied on hospital inpatient records and death registration, which may result in potential underestimation of the true incidence. However, it is unlikely that undiagnosed or under-reported cases would be specific to the baseline lung function status, suggesting that the impact on the HR estimation would be minimal [42].

In conclusion, our findings suggest that both PRISm and airflow obstruction were associated with an increased risk of cirrhosis in middle-aged and older adults, regardless of their genetic susceptibility to this disease. This finding underscores the importance of early screening for PRISm. Interventions following such screenings could potentially lead to a significant reduction in the incidence of cirrhosis.

BMI

Body mass index

CVD

cardiovascular disease

COPD

chronic obstructive pulmonary disease

confidence interval

DBP

diastolic blood pressure

FBG

fasting blood glucose

FEV₁

forced expiratory volume in one second

FVC

forced vital capacity

GRS

genetic risk score

HRs

Hazard ratios

HbA1c

glycated hemoglobin

HCC

hepatocellular carcinoma

LDL-C

low-density lipoprotein cholesterol

LLN

lower limit of normal

NAFLD

non-alcoholic fatty liver disease

PRISm

preserved ratio impaired spirometry

SBP

systolic blood pressure

SNPs

single nucleotide polymorphisms

total cholesterol

triglycerides.

Ethics approval and consent to participate：

All participants voluntarily provided written consent for their involvement in the study, and the UK Biobank received approval from the Northwest Research Ethics Committee (06/MRE08/65).

Consent for publication:

Not applicable.

Availability of data and materials:

Data are available in a public, open access repository. This research has been conducted using the UK Biobank Resource under Application Number 63454. The UK Biobank data are available on application to the UK Biobank (www.ukbiobank.ac.uk/).

Conflict of Interest:

The authors declare no conflict of interest.

Role of the Funder/Sponsor:

This study was supported by the LiaoNing Revitalization Talents Program (grant number XLYC2203168 to Yang Xia), the Young Elite Scientists Sponsorship Program by the China Association for Science and Technology (grant number YESS20200151 to Yang Xia), the 345 Talent Project of Shengjing Hospital of China Medical University (grant number M0294 to Yang Xia), and the Scientific Research Project of the Liaoning Province Education Department (grant number LJKMZ20221149 to Yang Xia).

Author Contributions:

Rongchang Guo: conceptualization; writing–original draft. Lanbo Wang: formal analysis; writing–original draft. Tiancong Liu: formal analysis; writing–original draft. Shiwen Li: formal analysis. Yashu Liu: visualization. Honghao Yang: writing–review & editing. Liangkai Chen: writing–review & editing. Chao Ji: conceptualization; writing–review & editing; funding acquisition; supervision. Yang Xia: conceptualization; formal analysis; data curation; writing–review & editing; supervision; project administration.

Acknowledgements：

The authors wish to acknowledge all participants.

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No competing interests reported.

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Pulmonary function, genetic predisposition, and the risk of cirrhosis: A prospective cohort study

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Abstract

Background

Methods

Results

Conclusion

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Introduction

Materials and Methods

Study Populations

Assessment of pulmonary function

Assessment of genetic risk score

Ascertainment of cirrhosis

Assessment of covariates

Statistical analysis

Results

Baseline characteristics of the study population

Independent associations of pulmonary function and cirrhosis-GRS with the risk of cirrhosis

Association between pulmonary function status, cirrhosis-GRS, and the risk of cirrhosis

Secondary analyses

Discussion

Conclusion

Abbreviations

Declarations

References

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